Lung cancer is a disease in which certain cells in the lungs become abnormal and multiply uncontrollably to form a tumor. Lung cancer may not cause signs or symptoms in its early stages. Some people with lung cancer have chest pain, frequent coughing, blood in the mucus, breathing problems, trouble swallowing or speaking, loss of appetite and weight loss, fatigue, or swelling in the face or neck. Additional symptoms can develop if the cancer spreads (metastasizes) into other tissues. Lung cancer occurs most often in adults in their sixties or seventies. Most people who develop lung cancer have a history of long-term tobacco smoking; however, the condition can occur in people who have never smoked.

Lung cancer is generally divided into two types, small cell lung cancer and non-small cell lung cancer, based on the size of the affected cells when viewed under a microscope. Non-small cell lung cancer accounts for 85 percent of lung cancer, while small cell lung cancer accounts for the remaining 15 percent.

Small cell lung cancer grows quickly and in more than half of cases the cancer has spread beyond the lung by the time the condition is diagnosed. Small cell lung cancer often metastasizes, most commonly to the liver, brain, bones, and adrenal glands (small hormone-producing glands located on top of each kidney). After diagnosis, most people with small cell lung cancer survive for about 1 year; less than seven percent survive 5 years.

Non-small cell lung cancer is divided into three main subtypes: adenocarcinoma, squamous cell carcinoma, and large cell lung carcinoma. Adenocarcinoma arises from the cells that line the small air sacs (alveoli) located throughout the lungs. Squamous cell carcinoma arises from squamous cells that line the passages leading from the windpipe (trachea) to the lungs (bronchi). Large cell carcinoma arises from epithelial cells that line the lungs. Large cell carcinoma encompasses non-small cell lung cancers that do not appear to be adenocarcinomas or squamous cell carcinomas. The 5-year survival rate for people with non-small cell lung cancer is usually between 11 and 17 percent; it can be lower or higher depending on the subtype and stage of the cancer.

In the United States, lung cancer is the second most commonly diagnosed cancer, after breast cancer, accounting for about one-quarter of all cancer diagnoses. It is estimated that more than 222,500 people develop lung cancer each year. Approximately 6.6 percent of individuals will develop lung cancer during their lifetime. An estimated 72 to 80 percent of lung cancer cases occur in tobacco smokers. Lung cancer is the leading cause of cancer deaths, accounting for an estimated 27 percent of all cancer deaths in the United States.

Cancers occur when genetic mutations build up in critical genes, specifically those that control cell growth and division (proliferation) or the repair of damaged DNA. These changes allow cells to grow and divide uncontrollably to form a tumor. In nearly all cases of lung cancer, these genetic changes are acquired during a person's lifetime and are present only in certain cells in the lung. These changes, which are called somatic mutations, are not inherited. Somatic mutations in many different genes have been found in lung cancer cells. In rare cases, the genetic change is inherited and is present in all the body's cells (germline mutations).

Somatic mutations in the TP53, EGFR, and KRAS genes are common in lung cancers. The TP53 gene provides instructions for making a protein, called p53, that is located in the nucleus of cells throughout the body, where it attaches (binds) directly to DNA. The protein regulates cell growth and division by monitoring DNA damage. When DNA becomes damaged, p53 helps determine whether the DNA will be repaired or the cell will self-destruct (undergo apoptosis). The EGFR and KRAS genes each provide instructions for making a protein that is embedded within the cell membrane. When these proteins are turned on (activated) by binding to other molecules, signaling pathways are triggered within cells that promote cell proliferation.

TP53 gene mutations result in the production of an altered p53 protein that cannot bind to DNA. The altered protein cannot regulate cell proliferation effectively and allows DNA damage to accumulate in cells. Such cells may continue to divide in an uncontrolled way, leading to tumor growth. Mutations in the EGFR or KRAS gene lead to the production of a protein that is constantly turned on (constitutively activated). As a result, cells constantly receive signals to proliferate, leading to tumor formation. When these genetic changes occur in cells in the lungs, lung cancer develops.

Mutations in many other genes have been found to recur in lung cancer cases. Most of these genes are involved in the regulation of gene activity (expression), cell proliferation, the process by which cells mature to carry out specific functions (differentiation), and apoptosis.

Researchers have identified many lifestyle and environmental factors that expose individuals to cancer-causing compounds (carcinogens) and increase the rate at which somatic mutations occur, contributing to a person's risk of developing lung cancer. The greatest risk factor is long-term tobacco smoking, which increases a person's risk of developing lung cancer 25-fold. Other risk factors include exposure to air pollution, radon, asbestos, certain metals and chemicals, or secondhand smoke; long-term use of hormone replacement therapy for menopause; and a history of lung disease such as tuberculosis, emphysema, or chronic bronchitis. A history of lung cancer in closely related family members is also an important risk factor; however, because relatives with lung cancer are frequently smokers, it is unclear whether the increased risk is the result of genetic factors or exposure to secondhand smoke.

Most cases of lung cancer are not related to inherited genetic changes. These cancers are associated with somatic mutations that occur only in certain cells in the lung.

When lung cancer is related to inherited genetic changes, the cancer risk follows an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to increase a person's chance of developing the disease. It is important to note that people inherit an increased risk of cancer, not the disease itself. Not all people who inherit mutations in these genes will develop lung cancer.

Normal Function

The ALK gene provides instructions for making a protein called ALK receptor tyrosine kinase, which is part of a family of proteins called receptor tyrosine kinases (RTKs). Receptor tyrosine kinases transmit signals from the cell surface into the cell through a process called signal transduction. The process begins when the kinase is stimulated at the cell surface and then attaches to a similar kinase (dimerizes). After dimerization, the kinase is tagged with a marker called a phosphate group (a cluster of oxygen and phosphorus atoms) in a process called phosphorylation. Phosphorylation turns on (activates) the kinase. The activated kinase is able to transfer a phosphate group to another protein inside the cell, which is activated as a result. The activation continues through a series of proteins in a signaling pathway. These signaling pathways are important in many cellular processes such as cell growth and division (proliferation) or maturation (differentiation).

Although the specific function of ALK receptor tyrosine kinase is unknown, it is thought to act early in development to help regulate the proliferation of nerve cells.

Health Conditions Related to Genetic Changes

Neuroblastoma

At least 16 mutations in the ALK gene have been identified in some people with neuroblastoma, a type of cancerous tumor composed of immature nerve cells (neuroblasts). Neuroblastoma and other cancers occur when a buildup of genetic mutations in critical genes—those that control cell proliferation or differentiation—allows cells to grow and divide uncontrollably to form a tumor. In most cases, these genetic changes are acquired during a person's lifetime and are called somatic mutations. Somatic mutations are present only in certain cells and are not inherited. Less commonly, gene mutations that increase the risk of developing cancer can be inherited from a parent. Both types of mutation occur in neuroblastoma. Somatic mutations in the ALK gene occur during the development of some cases of sporadic neuroblastoma, and inherited mutations in the ALK gene increase the risk of developing familial neuroblastoma.

Mutations in the ALK gene change single protein building blocks (amino acids) in ALK receptor tyrosine kinase. The most common mutation in neuroblastoma replaces the amino acid arginine with the amino acid glutamine at position 1275 (written as Arg1275Gln or R1275Q). Arg1275Gln has been found in both familial and sporadic neuroblastoma and is the only common ALK gene mutation that has been found in both types of the condition.

Occasionally, extra copies of the ALK gene are found in people with neuroblastoma. This phenomenon, known as gene amplification, results in overexpression of ALK receptor tyrosine kinase.

Mutated or overexpressed ALK receptor tyrosine kinase no longer requires stimulation from outside the cell to be phosphorylated. As a result, the kinase and the downstream signaling pathway are constantly turned on (constitutively activated). Constitutive activation of ALK receptor tyrosine kinase may increase the proliferation of immature nerve cells, leading to neuroblastoma.

Lung cancer

MedlinePlus Genetics provides information about Lung cancer

Other cancers

Rearrangements of genetic material involving the ALK gene on chromosome 2 increase the risk of developing several other types of cancer. These rearrangements are somatic mutations, which means they occur during a person's lifetime and are present only in the cells that become cancerous.

One type of rearrangement, called a translocation, exchanges genetic material between chromosome 2 and another chromosome. At least 15 translocations involving the ALK gene have been identified in people with anaplastic large cell lymphoma (ALCL), a rare form of cancer involving immune cells called T cells. The most common translocation in ALCL occurs between chromosome 2 and chromosome 5, called t(2;5). This translocation fuses the ALK gene to the NPM gene and results in a fusion protein called NPM-ALK. In addition, at least seven translocations involving the ALK gene have been identified in inflammatory myofibroblastic tumor (IMT). IMT is a rare cancer characterized by a solid tumor composed of inflammatory cells and cells called myofibroblasts that are important in wound healing. About half of people with IMT have a translocation involving the ALK gene.

Another type of rearrangement, called an inversion, occurs when chromosome 2 is broken in two places and the resulting piece of DNA is reversed and re-inserted into the chromosome. A small group of people with non-small cell lung cancer, the most common type of lung cancer, have an inversion of chromosome 2. This inversion fuses the ALK gene with another gene called EML4 and results in the EML4-ALK fusion protein.

The fusion proteins created by these rearranged genes have functions of both ALK receptor tyrosine kinase and the partner protein. The presence of the partner protein allows phosphorylation of ALK receptor tyrosine kinase without dimerization. The fusion protein and signaling pathways activated by ALK receptor tyrosine kinase are constitutively activated, which may abnormally increase the proliferation of immature nerve cells, leading to cancer formation.

Other Names for This Gene

• ALK tyrosine kinase receptor
• anaplastic lymphoma kinase
• anaplastic lymphoma receptor tyrosine kinase
• CD246
• CD246 antigen
• NBLST3

Genomic Location

Normal Function

The BRAF gene provides instructions for making a protein that helps transmit chemical signals from outside the cell to the cell's nucleus. This protein is part of a signaling pathway known as the RAS/MAPK pathway, which controls several important cell functions. Specifically, the RAS/MAPK pathway regulates the growth and division (proliferation) of cells, the process by which cells mature to carry out specific functions (differentiation), cell movement (migration), and the self-destruction of cells (apoptosis). Chemical signaling through this pathway is essential for normal development before birth.

The BRAF gene belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous.

Health Conditions Related to Genetic Changes

Cardiofaciocutaneous syndrome

Mutations in the BRAF gene are the most common cause of cardiofaciocutaneous syndrome. This condition affects many parts of the body, particularly the heart (cardio-), facial features (facio-), and the skin and hair (cutaneous). At least 49 BRAF mutations have been identified in people with this disorder. These mutations change single protein building blocks (amino acids) in the BRAF protein. Almost all of these genetic changes abnormally activate the protein, which disrupts the tightly regulated RAS/MAPK signaling pathway in cells throughout the body. The altered signaling interferes with the normal development of many organs and tissues, resulting in the characteristic features of cardiofaciocutaneous syndrome.

Erdheim-Chester disease

At least one mutation in the BRAF gene has been identified in some people with Erdheim-Chester disease. This rare condition is characterized by the abnormal production and accumulation of immune system cells called histiocytes in many of the body's tissues. The disease most commonly affects the bones, causing bone thickening and pain, but the accumulation of histiocytes can also cause signs and symptoms affecting the brain, eyes, lungs, liver, kidneys, and other organs.

The BRAF gene mutation that causes this condition is somatic, meaning that it occurs during a person's lifetime and is present only in certain cells. The mutation affects a single amino acid in the BRAF protein. Specifically, the mutation replaces the amino acid valine with the amino acid glutamic acid at position 600 (written as Val600Glu or V600E). This mutation leads to production of a BRAF protein that is abnormally active, which disrupts regulation of cell proliferation and may allow histiocytes to grow and divide uncontrollably, leading to the abnormal accumulation of histiocytes that occurs in Erdheim-Chester disease.

Giant congenital melanocytic nevus

The V600E mutation (described above) in the BRAF gene has also been found to cause giant congenital melanocytic nevus. This condition is characterized by a large, noncancerous patch of abnormally dark skin that is present from birth and an increased risk of a type of skin cell cancer called melanoma (described below). In giant congenital melanocytic nevus, a somatic V600E mutation occurs during embryonic development in cells that will develop into pigment-producing skin cells (melanocytes). This mutation leads to production of a BRAF protein that is abnormally active, which disrupts regulation of cell proliferation. The unregulated cell proliferation of early melanocytes leads to a large patch of darkly pigmented skin characteristic of giant congenital melanocytic nevus. Additional gene mutations in cells within the nevus after birth can lead to melanoma in people with giant congenital melanocytic nevus.

Noonan syndrome

MedlinePlus Genetics provides information about Noonan syndrome

Noonan syndrome with multiple lentigines

At least two mutations in the BRAF gene have been found to cause Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome). This condition is characterized by multiple brown skin spots (lentigines), heart defects, short stature, a sunken or protruding chest, and distinctive facial features. The BRAF gene mutations change single amino acids in the BRAF protein: One mutation replaces the amino acid threonine with the amino acid proline at position 241 (written as Thr241Pro or T241P) and the other mutation replaces the amino acid leucine with the amino acid phenylalanine at position 245 (written as Leu245Phe or L245F).

The BRAF gene changes that cause Noonan syndrome with multiple lentigines are believed to abnormally activate the BRAF protein, which disrupts the regulation of the RAS/MAPK signaling pathway that controls cell functions such as proliferation. This misregulation can result in the various features of Noonan syndrome with multiple lentigines.

Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Gastrointestinal stromal tumor

MedlinePlus Genetics provides information about Gastrointestinal stromal tumor

Langerhans cell histiocytosis

Somatic mutations in the BRAF gene, most frequently the V600E mutation (described above), have been identified in some individuals with Langerhans cell histiocytosis. This disorder causes an abnormal accumulation of certain immune cells called Langerhans cells in multiple tissues and organs, which often leads to the formation of tumors called granulomas. Many researchers consider Langerhans cell histiocytosis to be a form of cancer, but this classification is controversial.

The BRAF gene mutations, which are found only in the abnormal Langerhans cells, cause the BRAF protein to be continuously active. The overactive protein may contribute to the development of Langerhans cell histiocytosis by allowing the Langerhans cells to grow and divide uncontrollably.

In some other forms of histiocytosis such as Erdheim-Chester disease (described above), the histiocytes do not include Langerhans cells; a disorder of that type is classified as a non-Langerhans cell histiocytosis. It is not clear why the V600E mutation can cause different forms of histiocytosis.

Lung cancer

MedlinePlus Genetics provides information about Lung cancer

Melanoma

The V600E mutation (described above) in the BRAF gene has also been found in about half of noninherited (sporadic) cases of melanoma. Melanoma is a type of skin cancer that begins in pigment-producing cells called melanocytes. In this cancer, a somatic V600E mutation occurs during a person's lifetime, likely caused by ultraviolet (UV) radiation from the sun or other environmental risk factors. This mutation often leads only to the formation of a noncancerous mole. At least one additional mutation is necessary for the development of melanoma.

Multiple myeloma

MedlinePlus Genetics provides information about Multiple myeloma

Cancers

Somatic mutations in the BRAF gene are common in several types of cancer. Normally, the BRAF protein is switched on and off in response to signals that control cell growth and development. Somatic mutations cause the BRAF protein to be continuously active and to transmit messages to the nucleus even in the absence of these chemical signals. The overactive protein may contribute to the growth of cancers by allowing abnormal cells to grow and divide without external signals.

The V600E mutation (described above) is the most common BRAF gene mutation found in human cancers. This mutation has frequently been found in cancers of the colon and rectum, ovary, and thyroid gland. Several other somatic mutations in the BRAF gene have also been associated with cancer.

Other Names for This Gene

• 94 kDa B-raf protein
• B-raf 1
• B-Raf proto-oncogene serine/threonine-protein kinase
• BRAF1
• BRAF1_HUMAN
• Murine sarcoma viral (v-raf) oncogene homolog B1
• p94
• RAFB1
• v-raf murine sarcoma viral oncogene homolog B

Genomic Location

Normal Function

The CDKN2A gene provides instructions for making several proteins. The most well-studied are the p16(INK4A) and the p14(ARF) proteins. Both function as tumor suppressors, which means they keep cells from growing and dividing too rapidly or in an uncontrolled way. Both proteins are also involved in stopping cell division in older cells (senescence).

The p16(INK4A) protein attaches (binds) to two other proteins called CDK4 and CDK6. These proteins help regulate the cell cycle, which is the cell's way of replicating itself in an organized, step-by-step fashion. CDK4 and CDK6 normally stimulate the cell to continue through the cycle and divide. However, binding of p16(INK4A) blocks CDK4's or CDK6's ability to stimulate cell cycle progression. In this way, p16(INK4A) controls cell division. Cells begin to produce p16(INK4A) when they are no longer able to undergo cell division.

The p14(ARF) protein protects a different protein called p53 from being broken down. The p53 protein is an important tumor suppressor that is essential for regulating cell division, senescence, and self-destruction (apoptosis). By protecting p53, p14(ARF) also helps prevent tumor formation. The p14(ARF) and p53 proteins are often made in cells that are unable to undergo cell division.

Health Conditions Related to Genetic Changes

Bladder cancer

MedlinePlus Genetics provides information about Bladder cancer

Head and neck squamous cell carcinoma

Mutations in the CDKN2A gene are found in up to one-quarter of head and neck squamous cell carcinomas (HNSCC). This type of cancerous tumor occurs in the moist lining of the mouth, nose, and throat. CDKN2A gene mutations associated with this condition are acquired during a person's lifetime and are found only in tumor cells; these changes are known as somatic mutations. Most of these mutations lead to production of little or no functional p16(INK4A) protein. Without p16(INK4A) to regulate cell growth and division (proliferation), cells can continue to grow and divide without control, which can lead to tumor formation.

A different type of alteration involving the CDKN2A gene can result in reduced amounts or an absence of the p16(INK4A) or p14(ARF) protein. This alteration, known as promoter hypermethylation, turns off the production of p16(INK4A) or p14(ARF). Without one of these tumor suppressors, cells can grow and divide unchecked, leading to the development of cancer.

Lung cancer

MedlinePlus Genetics provides information about Lung cancer

Melanoma

Mutations in the CDKN2A gene are also associated with melanoma, a type of skin cancer that begins in pigment-producing cells called melanocytes. CDKN2A gene mutations are found in up to 40 percent of familial cases of melanoma, in which multiple family members develop the cancer. These mutations, classified as germline mutations, are typically inherited and are present in essentially all of the body's cells. The CDKN2A gene mutations found in melanoma result in a nonfunctional p16(INK4A) protein. In many cases, a second, somatic mutation occurs in the normal copy of the gene in melanocytes. In about half of melanomas, part or all of the CDKN2A gene is missing (deleted). In many other cases, the CDKN2A gene has a mutation or is turned off (inactive). Somatic mutations in other genes involved in cell growth are also needed for a melanoma to develop. Together, the germline and somatic mutations impair the function of proteins that regulate division and senescence, leading to uncontrolled cell growth and the formation of a melanoma.

Individuals with a CDKN2A gene mutation tend to develop melanoma at an earlier age than those without a mutation in the gene. They also tend to develop other cancers during their lifetime, particularly cancers of the pancreas or lung.

Other cancers

Germline mutations affecting the CDKN2A gene are associated with other cancers, including breast cancer and pancreatic cancer. In some families, CDKN2A gene mutations are associated with development of only one type of cancer. In other families, mutations can lead to a cancer predisposition syndrome, which increases the risk of developing multiple types of cancer. CDKN2A gene mutations involved in cancer impair production of functional p16(INK4A) or, less commonly, p14(ARF), which can result in uncontrolled cell growth and tumor formation.

Somatic CDKN2A gene mutations have been found in some people with brain tumors and in children with a blood cancer called acute lymphoblastic leukemia.

Other Names for This Gene

• ARF
• CDK4 inhibitor p16-INK4
• CDK4I
• CDKN2
• cell cycle negative regulator beta
• CMM2
• cyclin-dependent kinase 4 inhibitor A
• cyclin-dependent kinase inhibitor 2A
• cyclin-dependent kinase inhibitor 2A (melanoma, p16, inhibits CDK4)
• cyclin-dependent kinase inhibitor 2A isoform p12
• cyclin-dependent kinase inhibitor 2A isoform p14ARF
• cyclin-dependent kinase inhibitor 2A isoform p16gamma
• cyclin-dependent kinase inhibitor 2A isoform p16INK4a
• INK4
• INK4A
• MLM
• MTS-1
• MTS1
• multiple tumor suppressor 1
• P14
• P14ARF
• P16
• P16-INK4A
• P16INK4
• P16INK4A
• P19
• P19ARF
• TP16

Genomic Location

Normal Function

The EGFR gene provides instructions for making a receptor protein called the epidermal growth factor receptor, which spans the cell membrane so that one end of the protein remains inside the cell and the other end projects from the outer surface of the cell. This positioning allows the receptor to attach (bind) to other proteins, called ligands, outside the cell and to receive signals that help the cell respond to its environment. Ligands and receptors fit together like keys into locks. Epidermal growth factor receptor binds to at least seven different ligands. The binding of a ligand to epidermal growth factor receptor allows the receptor to attach to another nearby epidermal growth factor receptor protein (dimerize), turning on (activating) the receptor complex. As a result, signaling pathways within the cell are triggered that promote cell growth and division (proliferation) and cell survival.

Health Conditions Related to Genetic Changes

Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Lung cancer

At least eight mutations in the EGFR gene have been associated with lung cancer. Lung cancer is a disease in which certain cells in the lungs become abnormal and multiply uncontrollably to form a tumor. Lung cancer may not cause signs or symptoms in its early stages. Nearly all these EGFR gene mutations occur during a person's lifetime (somatic) and are present only in cancer cells.

Somatic mutations in the EGFR gene most often occur in a type of lung cancer called non-small cell lung cancer, specifically a form called adenocarcinoma. These mutations are most common in people with the disease who have never smoked. Somatic EGFR gene mutations occur more frequently in Asian populations than in white populations, occurring in 30 to 40 percent of affected Asians compared to 10 to 15 percent of whites with lung cancer.

Most of the somatic EGFR gene mutations that are associated with lung cancer delete genetic material in a part of the gene known as exon 19 or change DNA building blocks (nucleotides) in another region called exon 21. These gene changes result in a receptor protein that is constantly turned on (constitutively activated), even when it is not bound to a ligand. As a result, cells constantly receive signals to proliferate and survive, leading to tumor formation. When these genetic changes occur in cells in the lungs, lung cancer can develop. Additional genetic, environmental, and lifestyle factors contribute to a person's cancer risk.

Lung cancers with EGFR gene mutations tend to respond to treatments that specifically target the overactive epidermal growth factor receptor protein that allows cancer cells to constantly grow and divide.

Other Names for This Gene

• cell growth inhibiting protein 40
• cell proliferation-inducing protein 61
• erb-b2 receptor tyrosine kinase 1
• ERBB
• ERBB1
• HER1
• mENA
• NISBD2
• PIG61
• proto-oncogene c-ErbB-1
• receptor tyrosine-protein kinase erbB-1

Genomic Location

Normal Function

The KRAS gene provides instructions for making a protein called K-Ras that is part of a signaling pathway known as the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell to grow and divide (proliferate) or to mature and take on specialized functions (differentiate). The K-Ras protein is a GTPase, which means it converts a molecule called GTP into another molecule called GDP. In this way the K-Ras protein acts like a switch that is turned on and off by the GTP and GDP molecules. To transmit signals, it must be turned on by attaching (binding) to a molecule of GTP. The K-Ras protein is turned off (inactivated) when it converts the GTP to GDP. When the protein is bound to GDP, it does not relay signals to the cell's nucleus.

The KRAS gene belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous. The KRAS gene is in the Ras family of oncogenes, which also includes two other genes: HRAS and NRAS. These proteins play important roles in cell division, cell differentiation, and the self-destruction of cells (apoptosis).

Health Conditions Related to Genetic Changes

Cardiofaciocutaneous syndrome

Mutations in the KRAS gene are an uncommon cause of cardiofaciocutaneous syndrome, accounting for less than 5 percent of cases. Several mutations in the KRAS gene have been identified in people with characteristic features of the disorder, which include heart defects, distinctive facial features, and skin abnormalities. These mutations are present in all of the body's cells and are known as germline mutations. The mutations change single protein building blocks (amino acids) in the K-Ras protein. The altered protein shows increased GTP binding and a decreased ability to convert GTP to GDP. These effects lead to prolonged activation of the K-Ras protein, which alters tightly regulated RAS/MAPK signaling during development. The altered signaling interferes with the development of organs and tissues throughout the body, leading to the varied signs and symptoms of cardiofaciocutaneous syndrome.

Noonan syndrome

MedlinePlus Genetics provides information about Noonan syndrome

Autoimmune lymphoproliferative syndrome

MedlinePlus Genetics provides information about Autoimmune lymphoproliferative syndrome

Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Core binding factor acute myeloid leukemia

MedlinePlus Genetics provides information about Core binding factor acute myeloid leukemia

Epidermal nevus

MedlinePlus Genetics provides information about Epidermal nevus

Lung cancer

At least three mutations in the KRAS gene have been associated with lung cancer. Lung cancer is a disease in which certain cells in the lungs become abnormal and multiply uncontrollably to form a tumor. Lung cancer may not cause signs or symptoms in its early stages. These KRAS gene mutations are somatic, which means they are acquired during a person's lifetime and are present only in tumor cells. Somatic mutations are not inherited. Nearly all of the KRAS gene mutations associated with lung cancer change the amino acid glycine at position 12 or 13 (Gly12 or Gly13) or change the amino acid glutamine at position 61 (Gln61) in the K-Ras protein. These mutations result in a K-Ras protein that is constantly turned on (constitutively activated) and directing cells to proliferate in an uncontrolled way, which leads to tumor formation. When these genetic changes occur in cells in the lungs, lung cancer can develop.

KRAS gene mutations are found in 15 to 25 percent of all lung cancer cases but are more frequent in white populations than in Asian populations; 25 to 50 percent of whites with lung cancer have KRAS gene mutations, whereas 5 to 15 percent of Asians with lung cancer have KRAS gene mutations.

KRAS gene mutations are much more common in long-term tobacco smokers with lung cancer than in nonsmokers. Lung cancers with KRAS gene mutations typically indicate a poor prognosis and are associated with resistance to several cancer treatments.

Other cancers

Somatic mutations in the KRAS gene are involved in the development of several types of cancer, particularly pancreatic and colorectal cancers. These mutations lead to a K-Ras protein that is more strongly overactivated than the mutations that cause cardiofaciocutaneous syndrome (described above). The abnormal K-Ras protein is always active and can direct cells to proliferate in an uncontrolled way.

Other disorders

Germline mutations in the KRAS gene also cause a disorder whose major features overlap with those of cardiofaciocutaneous syndrome (described above) and two related disorders called Noonan syndrome and Costello syndrome. This condition has been described as the KRAS mutation-associated phenotype. People with this condition have variable signs and symptoms that include mild to moderate intellectual disability, distinctive facial features, short stature, an unusually large head (macrocephaly), and hair that is sparse and thin.

At least nine mutations in the KRAS gene have been reported in people with this disorder. Each of these mutations changes single amino acids in the K-Ras protein. These genetic changes abnormally activate the protein, which alters chemical signaling in cells throughout the body. The altered signaling interferes with the normal development of many organs and tissues, resulting in the characteristic features of the KRAS mutation-associated phenotype.

Other Names for This Gene

• C-K-RAS
• c-K-ras protein
• c-K-ras2 protein
• c-Kirsten-ras protein
• cellular c-Ki-ras2 proto-oncogene
• K-ras p21 protein
• KI-RAS
• Kirsten rat sarcoma viral oncogene homolog
• KRAS1
• PR310 c-K-ras oncogene
• RASK2
• RASK_HUMAN
• transforming protein p21
• v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog

Genomic Location

Normal Function

The MAP2K1 gene provides instructions for making a protein known as MEK1 protein kinase. This protein is part of a signaling pathway called the RAS/MAPK pathway, which transmits chemical signals from outside the cell to the cell's nucleus. RAS/MAPK signaling helps control the growth and division (proliferation) of cells, the process by which cells mature to carry out specific functions (differentiation), cell movement (migration), and the self-destruction of cells (apoptosis). MEK1 protein kinase appears to be essential for normal development before birth and for survival after birth.

Health Conditions Related to Genetic Changes

Cardiofaciocutaneous syndrome

At least 13 mutations in the MAP2K1 gene have been identified in people with cardiofaciocutaneous syndrome. This condition affects many parts of the body, particularly the heart (cardio-), facial features (facio-), and the skin and hair (-cutaneous).

The MAP2K1 gene mutations that cause cardiofaciocutaneous syndrome are germline mutations, which means that they are present in cells throughout the body. Each mutation changes a single protein building block (amino acid) in MEK1 protein kinase. The genetic changes abnormally activate the protein, which disrupts the tightly regulated RAS/MAPK signaling pathway in many types of cells. The altered signaling interferes with the normal development of many organs and tissues, resulting in the characteristic features of cardiofaciocutaneous syndrome.

Melorheostosis

At least three mutations in the MAP2K1 gene have been identified in people with melorheostosis. This rare disease causes the abnormal growth of new bone tissue on the surface of existing bones. The new bone has a characteristic "dripping candle wax" or flowing appearance on x-rays.

The mutations associated with melorheostosis are described as somatic. Somatic mutations occur during a person's lifetime and are present only in certain cells, in this case, bone cells in a particular area of the body. The known mutations change single amino acids in MEK1 protein kinase. The mutations lead to the production of a version of the protein that is overactive, which increases RAS/MAPK signaling in bone tissue. The increased signaling disrupts the regulation of bone cell proliferation and allows new bone to grow abnormally. Studies suggest that increased RAS/MAPK signaling also stimulates excess bone remodeling, a normal process in which old bone is broken down and new bone is created to replace it. These changes in bone growth and turnover underlie the bone abnormalities characteristic of melorheostosis.

Noonan syndrome with multiple lentigines

At least one mutation in the MAP2K1 gene has been found to cause Noonan syndrome with multiple lentigines (formerly called LEOPARD syndrome). This condition is characterized by multiple brown skin spots (lentigines), heart defects, short stature, a sunken or protruding chest, and distinctive facial features.

The identified MAP2K1 gene mutation is a germline mutation that replaces the amino acid glutamic acid with the amino acid glycine at position 102 (written as Glu102Gly or E102G) in MEK1 protein kinase. This change likely results in increased activation of the RAS/MAPK signaling pathway in cells throughout the body. The increased signaling interferes with the normal development of many organs and tissues, resulting in the characteristic features of Noonan syndrome with multiple lentigines.

It is unclear why the E102G mutation causes Noonan syndrome with multiple lentigines and other germline mutations in the MAP2K1 gene cause different disorders, such as cardiofaciocutaneous syndrome (described above).

Langerhans cell histiocytosis

MedlinePlus Genetics provides information about Langerhans cell histiocytosis

Lung cancer

MedlinePlus Genetics provides information about Lung cancer

Noonan syndrome

MedlinePlus Genetics provides information about Noonan syndrome

Other cancers

Mutations in the MAP2K1 gene have also been found in several forms of cancer. Like the mutations that cause melorheostosis (described above), cancer-associated mutations in this gene are somatic. They occur only in the cells that ultimately give rise to cancer. Somatic mutations in the MAP2K1 gene have been reported in several forms of blood cell cancer (leukemia and lymphoma), lung cancer, and a form of skin cancer called melanoma. The genetic changes lead to an overactive MEK1 protein kinase, which increases activation of the RAS/MAPK signaling pathway in particular tissues. The increased signaling allows cells to grow and divide too quickly, leading to cancer.

Other Names for This Gene

• Dual Specificity Mitogen-Activated Protein Kinase Kinase 1
• ERK Activator Kinase 1
• MAP Kinase Kinase 1
• MAPK/ERK kinase 1
• MAPKK1
• MEK-1
• MEK-1 Protein Kinase
• MEK1
• MKK-1 Protein Kinase
• MKK1
• MKK1 Protein Kinase
• MP2K1_HUMAN
• PRKMK1
• protein kinase, mitogen-activated, kinase 1 (MAP kinase kinase 1)

Genomic Location

Normal Function

The NF1 gene provides instructions for making a protein called neurofibromin. This protein is produced in many types of cells, including nerve cells and specialized cells called oligodendrocytes and Schwann cells that surround nerves. These specialized cells form myelin sheaths, which are the fatty coverings that insulate and protect certain nerve cells.

Neurofibromin acts as a tumor suppressor protein. Tumor suppressors normally prevent cells from growing and dividing too rapidly or in an uncontrolled way. This protein appears to prevent cell overgrowth by turning off another protein (called ras) that stimulates cell growth and division. Other potential functions for neurofibromin are under investigation.

Health Conditions Related to Genetic Changes

Neurofibromatosis type 1

More than 1,000 NF1 mutations that cause neurofibromatosis type 1 have been identified. Most of these mutations are unique to a particular family. Many NF1 mutations result in the production of an extremely short version of neurofibromin. This shortened protein cannot perform its normal job of inhibiting cell division. When mutations occur in both copies of the NF1 gene in Schwann cells, the resulting loss of neurofibromin allows noncancerous tumors called neurofibromas to form. Research indicates that the formation of neurofibromas requires the interaction of Schwann cells with other cells, including mast cells. Mast cells are normally involved in wound healing and tissue repair.

Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Lung cancer

MedlinePlus Genetics provides information about Lung cancer

Cancers

In rare cases, inactivation of one copy of the NF1 gene in each cell increases the risk of developing juvenile myelomonocytic leukemia (JMML). Juvenile myelomonocytic leukemia is cancer of blood-forming tissue that usually occurs in children younger than 2. This condition causes the bone marrow to make an excessive number of immature white blood cells that cannot carry out their normal infection-fighting functions. These abnormal cells can build up in the blood and bone marrow, leaving less room for healthy white blood cells, red blood cells, and platelets. Children affected by this disorder may experience fatigue, fever, and easy bleeding or bruising.

Other Names for This Gene

• Neurofibromatosis Type 1 Protein
• Neurofibromatosis-related protein NF-1
• neurofibromin 1 (neurofibromatosis, von Recklinghausen disease, Watson disease)
• NF1 GRP
• NF1 Protein
• NF1-GAP-Related Protein
• NF1_HUMAN

Genomic Location

Normal Function

The NRAS gene provides instructions for making a protein called N-Ras that is involved primarily in regulating cell division. Through a process known as signal transduction, the protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell to grow and divide (proliferate) or to mature and take on specialized functions (differentiate). The N-Ras protein is a GTPase, which means it converts a molecule called GTP into another molecule called GDP. The N-Ras protein acts like a switch, and it is turned on and off by the GTP and GDP molecules. To transmit signals, the N-Ras protein must be turned on by attaching (binding) to a molecule of GTP. The N-Ras protein is turned off (inactivated) when it converts the GTP to GDP. When the protein is bound to GDP, it does not relay signals to the cell's nucleus.

The NRAS gene belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous. The NRAS gene is in the Ras family of oncogenes, which also includes two other genes: HRAS and KRAS. The proteins produced from these three genes are GTPases. These proteins play important roles in cell division, cell differentiation, and the self-destruction of cells (apoptosis).

Health Conditions Related to Genetic Changes

Giant congenital melanocytic nevus

At least two mutations in the NRAS gene have been found to cause giant congenital melanocytic nevus. This condition is characterized by a large, noncancerous patch of abnormally dark skin that is present from birth and an increased risk of a type of skin cell cancer called melanoma. The NRAS gene mutations that cause this condition are somatic, meaning that they occur during a person's lifetime and are present only in certain cells. The mutations occur during embryonic development in cells that will develop into pigment-producing skin cells (melanocytes). The mutations that cause this condition affect a single protein building block (amino acid) in the N-Ras protein. Specifically, the mutations replace the amino acid glutamine at position 61 with either lysine or arginine (written as Gln61Lys or Q61K and Gln61Arg or Q61R). These mutations lead to production of an N-Ras protein that is constantly turned on (constitutively active). Instead of triggering cell growth in response to particular signals from outside the cell, the overactive protein directs cells to grow and divide constantly. The uncontrolled cell growth of early melanocytes leads to a large patch of darkly pigmented skin characteristic of giant congenital melanocytic nevus. Uncontrolled cell growth of melanocytes after birth contributes to the risk of developing melanoma in people with giant congenital melanocytic nevus.

Noonan syndrome

MedlinePlus Genetics provides information about Noonan syndrome

Autoimmune lymphoproliferative syndrome

MedlinePlus Genetics provides information about Autoimmune lymphoproliferative syndrome

Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Core binding factor acute myeloid leukemia

MedlinePlus Genetics provides information about Core binding factor acute myeloid leukemia

Cytogenetically normal acute myeloid leukemia

MedlinePlus Genetics provides information about Cytogenetically normal acute myeloid leukemia

Epidermal nevus

MedlinePlus Genetics provides information about Epidermal nevus

Lung cancer

MedlinePlus Genetics provides information about Lung cancer

Melanoma

MedlinePlus Genetics provides information about Melanoma

Cancers

Somatic mutations in the NRAS gene are involved in the development of several types of cancer. These mutations lead to an N-Ras protein that is constitutively active and can direct cells to grow and divide without control. Studies suggest that NRAS gene mutations are common in the aggressive skin cancer melanoma, including individuals without giant congenital melanocytic nevus (described above). Mutations in the NRAS gene have also been found in other types of cancer.

For reasons that are unclear, inherited mutations in the NRAS gene do not appear to increase the risk of cancer in people with Noonan syndrome.

Other Names for This Gene

• GTPase NRas
• GTPase NRas precursor
• N-ras
• N-ras protein part 4
• neuroblastoma RAS viral (v-ras) oncogene homolog
• neuroblastoma RAS viral oncogene homolog
• NRAS1
• NS6
• RASN_HUMAN
• transforming protein N-Ras
• v-ras neuroblastoma RAS viral oncogene homolog

Genomic Location

Normal Function

The PIK3CA gene provides instructions for making the p110 alpha (p110α) protein, which is one piece (subunit) of an enzyme called phosphatidylinositol 3-kinase (PI3K). The p110α protein is called the catalytic subunit because it performs the action of PI3K, while the other subunit (produced by a different gene) regulates the enzyme's activity.

Like other kinases, PI3K adds a cluster of oxygen and phosphorus atoms (a phosphate group) to other proteins through a process called phosphorylation. PI3K phosphorylates certain signaling molecules, which triggers a series of additional reactions that transmit chemical signals within cells. PI3K signaling is important for many cell activities, including cell growth and division (proliferation), movement (migration) of cells, production of new proteins, transport of materials within cells, and cell survival. Studies suggest that PI3K signaling may be involved in the regulation of several hormones and may play a role in the maturation of fat cells (adipocytes).

Health Conditions Related to Genetic Changes

Bladder cancer

Somatic mutations in the PIK3CA gene have been found in some cases of bladder cancer. Bladder cancer is a disease in which certain cells in the bladder become abnormal and multiply uncontrollably to form a tumor. Bladder cancer may cause blood in the urine, pain during urination, frequent urination, the feeling of needing to urinate without being able to, or lower back pain.

Bladder cancer is generally divided into two types, non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC), based on where in the bladder the tumor is located. A PIK3CA gene mutation has been found in about half of NMIBC tumors. These mutations change single amino acids in the p110α protein. The altered p110α subunit appears to allow PI3K to become overactive. The increased signaling by PI3K likely contributes to uncontrolled cell growth and division and the formation of bladder cancer.

Epidermal nevus

Mutations in the PIK3CA gene have been found in up to a quarter of people with a certain type of epidermal nevus (plural: nevi). Specifically, PIK3CA gene mutations are associated with some keratinocytic epidermal nevi, which are abnormal skin growths that are composed of skin cells called keratinocytes. PIK3CA gene mutations have not been found in other types of epidermal nevi.

The most common PIK3CA gene mutation found in epidermal nevi replaces the protein building block (amino acid) glutamic acid with the amino acid glycine at position 545 of the p110α protein (written as Glu545Gly or E545G). Studies suggest that this mutation causes cells to grow and divide more than normal. The resulting overgrowth of skin cells leads to formation of epidermal nevi. The genetic changes associated with this condition are somatic mutations and are present only in the cells of the nevus.

Despite the involvement of PIK3CA gene mutations in many cancers (described above) and the overgrowth of cells caused by changes in this gene, individuals with an epidermal nevus do not appear to have an elevated risk of developing cancer.

Klippel-Trenaunay syndrome

At least five mutations in the PIK3CA gene have been found to cause Klippel-Trenaunay syndrome. This condition is characterized by a red birthmark called a port-wine stain, abnormal overgrowth of soft tissues (such as skin and muscles) and bones, and vein malformations. The PIK3CA gene mutations associated with this condition arise randomly in one cell during the early stages of development before birth. These changes, which are called somatic mutations, are not inherited. As cells continue to divide during development, cells arising from the first abnormal cell will have the mutation, and other cells will not. This mixture of cells with and without a genetic mutation is known as mosaicism.

The PIK3CA gene mutations associated with Klippel-Trenaunay syndrome change single protein building blocks (amino acids) in the p110α protein. These changes lead to production of an altered p110α subunit that makes PI3K abnormally active. The altered enzyme triggers unregulated chemical signaling in cells, which allows cells to grow and divide continuously. Increased cell proliferation leads to abnormal growth of the bones, soft tissues, and blood vessels.

Despite the involvement of PIK3CA gene mutations in cancer (described below) and the overgrowth of cells caused by changes in this gene, individuals with Klippel-Trenaunay syndrome do not appear to have an elevated risk of developing cancer.

Megalencephaly-capillary malformation syndrome

At least 15 mutations in the PIK3CA gene have been found to cause a condition known as megalencephaly-capillary malformation syndrome (MCAP), which is characterized by overgrowth of the brain (megalencephaly) and abnormalities caused by enlargement of small blood vessels in the skin (capillary malformations). The mutations that cause MCAP overlap with those that cause Klippel-Trenaunay syndrome (described above). These mutations are not inherited from a parent; they arise randomly in one cell during the early stages of development before birth and lead to mosaicism. The presence of the mutation in different tissues helps explain why multiple conditions can be caused by the same gene mutations.

Most PIK3CA gene mutations involved in MCAP change single amino acids in the p110α protein. These mutations lead to the production of an altered p110α subunit that makes PI3K abnormally active. The resulting unregulated signaling allows cells to grow and divide continuously. Increased cell proliferation in the brain and other tissues and organs leads to the overgrowth characteristic of MCAP.

Despite the involvement of the PIK3CA gene mutations in many cancers (described below) and the overgrowth of cells caused by changes in this gene, individuals with MCAP do not appear to have an elevated risk of developing cancer.

Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Cowden syndrome

MedlinePlus Genetics provides information about Cowden syndrome

Head and neck squamous cell carcinoma

MedlinePlus Genetics provides information about Head and neck squamous cell carcinoma

Lung cancer

MedlinePlus Genetics provides information about Lung cancer

Ovarian cancer

MedlinePlus Genetics provides information about Ovarian cancer

Other disorders

Mutations in the PIK3CA gene, including those found in some cancers, have been found to cause several other conditions related to overgrowth of tissues. These conditions include hemimegalencephaly; fibroadipose hyperplasia; and a condition called congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal or spinal abnormalities (CLOVES) syndrome. Hemimegalencephaly is characterized by enlargement of one side of the brain and can cause seizures and intellectual disability. Fibroadipose hyperplasia causes overgrowth of fibrous and fatty (adipose) tissues in various regions of the body, which leads to enlargement of different portions of the body, such as the lower body, an individual arm or leg, or one or more fingers or toes. CLOVES syndrome has multiple features, including an overgrowth of adipose tissue in the abdomen that is often associated with a reddish birthmark on the skin over it, in addition to blood vessel, skin, and bone abnormalities. It is unknown whether individuals with these disorders have an elevated risk of developing cancer.

As in Klippel-Trenaunay syndrome, MCAP, and epidermal nevus (each described above), the genetic changes involved in these disorders occur early in development and are found in only some of the body's cells. This mosaicism helps explain why different conditions involving different parts of the body can be caused by the same gene mutations. Together, the overgrowth disorders caused by PIK3CA gene mutations are known as the PIK3CA-related overgrowth spectrum (PROS).

Cancers

Somatic mutations in the PIK3CA gene are found in many other types of cancer, including cancer of the ovary, breast, lung, brain, and stomach. These mutations are also involved in cancer of the colon (large intestine) and rectum, which are collectively referred to as colorectal cancer. These mutations change single amino acids in the p110α protein. Two common mutations occur in the same region and change the amino acid glutamate at position 542 or at position 545 of the p110α protein to the amino acid lysine (written as Glu542Lys and Glu545Lys, respectively). Two other common mutations occur in another region, changing the amino acid histidine at position 1047 of p110α to the amino acid arginine or leucine (written as His1047Arg and His1047Leu, respectively).

Cancer-associated PIK3CA gene mutations result in production of an altered p110α subunit that allows PI3K to signal without regulation. The increased signaling can contribute to an uncontrolled proliferation of cells, leading to the development of cancer. However, PIK3CA gene mutations may not cause cancer by themselves. Researchers suspect that some cases of cancer likely result from a combination of mutations in PIK3CA and mutations in other genes that influence cancer risk.

Other Names for This Gene

• p110-alpha
• phosphatidylinositol 3-kinase, catalytic, 110-KD, alpha
• phosphatidylinositol 3-kinase, catalytic, alpha polypeptide
• phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform
• phosphatidylinositol-4,5-bisphosphate 3-kinase 110 kDa catalytic subunit alpha
• phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha
• phosphoinositide-3-kinase, catalytic, alpha polypeptide
• PI3-kinase p110 subunit alpha
• PI3K
• PI3K-alpha
• PK3CA_HUMAN
• ptdIns-3-kinase subunit p110-alpha
• serine/threonine protein kinase PIK3CA

Genomic Location

Normal Function

The PRKN gene, one of the largest human genes, provides instructions for making a protein called parkin. Parkin plays a role in the cell machinery that breaks down (degrades) unneeded proteins by tagging damaged and excess proteins with molecules called ubiquitin. Ubiquitin serves as a signal to move unneeded proteins into specialized cell structures known as proteasomes, where the proteins are degraded. The ubiquitin-proteasome system acts as the cell's quality control system by disposing of damaged, misshapen, and excess proteins. This system also regulates the availability of proteins that are involved in several critical cell activities, such as the timing of cell division and growth. Because of its activity in the ubiquitin-proteasome system, parkin belongs to a group of proteins called E3 ubiquitin ligases.

Parkin appears to be involved in the maintenance of mitochondria, the energy-producing centers in cells. However, little is known about its role in mitochondrial function. Research suggests that parkin may help trigger the destruction of mitochondria that are not working properly.

Studies of the structure and activity of parkin have led researchers to propose several additional activities for this protein. Parkin may act as a tumor suppressor protein, which means it prevents cells from growing and dividing too rapidly or in an uncontrolled way. Parkin may also regulate the supply and release of sacs called synaptic vesicles from nerve cells. Synaptic vesicles contain chemical messengers that transmit signals from one nerve cell to another.

Health Conditions Related to Genetic Changes

Parkinson's disease

Researchers have identified more than 200 PRKN gene mutations that cause Parkinson's disease, a condition characterized by progressive problems with movement and balance. Mutations in this gene are associated with the juvenile form of Parkinson's disease, which appears before age 20, and some cases of the more common, late-onset form that begins after age 50.

Some PRKN gene mutations lead to an abnormally small parkin protein that is nonfunctional and is rapidly broken down (degraded) within cells. Other mutations insert, delete, or change DNA building blocks (nucleotides) in the PRKN gene, leading to a defective version of the parkin protein or preventing the production of this protein. The PRKN gene mutations associated with Parkinson's disease usually lead to a loss of parkin activity.

It is unclear how PRKN gene mutations cause Parkinson's disease. The loss of parkin activity probably disturbs the ubiquitin-proteasome system, which allows unneeded proteins to accumulate. A buildup of these proteins could disrupt normal cell activities such as the supply and release of synaptic vesicles, particularly those that contain a chemical messenger called dopamine. As parkin is normally abundant in the brain, its loss could lead to the impairment or death of nerve cells, including those that produce dopamine. Loss of dopamine-producing nerve cells is a characteristic feature of Parkinson's disease.

Mutations in the PRKN gene may also disrupt the regulation of mitochondria. Researchers speculate that mitochondrial dysfunction in dopamine-producing nerve cells may play an important role in causing the signs and symptoms of Parkinson's disease.

Leprosy

Studies suggest that common variations (polymorphisms) in the PRKN gene (and a neighboring gene called PACRG) can increase the risk of contracting Hansen disease, also known as leprosy. This disease affects the nerves and skin and is caused by the bacterium Mycobacterium leprae. It remains unclear how PRKN polymorphisms increase susceptibility to Hansen disease. Researchers believe that the ubiquitin-proteasome system may play a role in controlling infection. Polymorphisms in the PRKN gene may subtly alter parkin's function, making the ubiquitin-proteasome system less efficient.

Lung cancer

The PRKN gene spans part of a region on chromosome 6 known as FRA6E. This region is known as a fragile area because it is unstable and prone to breakage and rearrangement. Changes involving the FRA6E region have been reported in several forms of human cancer, including lung cancer. In some cancerous tumors, segments of the FRA6E region, including part or all of the PRKN gene, are abnormally deleted or duplicated. These genetic changes are described as somatic because they occur only in tumor cells and are not inherited. As a result of these alterations, parkin activity is reduced or absent in these cells. Because parkin is thought to act as a tumor suppressor, a shortage of this protein's function could allow cells to grow and divide in an uncontrolled manner, leading to tumor formation.

Ovarian cancer

Changes involving the FRA6E region (described above) have also been reported in ovarian cancer. These changes include abnormal deletion or duplication of segments of the FRA6E region, including part or all of the PRKN gene. As a result of these somatic alterations, parkin activity is reduced or absent in affected cells. Because parkin is thought to act as a tumor suppressor, a shortage of this protein's function could allow cells to grow and divide in an uncontrolled manner, leading to tumor formation.

Cancers

Deletion or duplication of segments of the FRA6E region that involve the PRKN gene have also been found in glioblastoma (a form of brain cancer) and colorectal cancer. As a result of these somatic alterations, parkin activity is reduced or absent in tumor cells. Because parkin is thought to act as a tumor suppressor, a shortage of this protein's function could allow cells to grow and divide in an uncontrolled manner, leading to tumor formation.

Other Names for This Gene

• AR-JP
• PARK2
• parkin
• Parkinson disease (autosomal recessive, juvenile) 2, parkin
• parkinson protein 2, E3 ubiquitin protein ligase (parkin)
• PDJ
• PRKN2_HUMAN
• ubiquitin E3 ligase

Genomic Location

Normal Function

The PTEN gene provides instructions for making an enzyme that is found in almost all tissues in the body. The enzyme acts as a tumor suppressor, which means that it helps regulate cell division by keeping cells from growing and dividing (proliferating) too rapidly or in an uncontrolled way. To function, the PTEN enzyme attaches (binds) to another PTEN enzyme (dimerizes) then binds to the cell membrane. The PTEN enzyme modifies other proteins and fats (lipids) by removing phosphate groups, each of which consists of a cluster of oxygen and phosphorus atoms. Enzymes with this function are called phosphatases.

The PTEN enzyme is part of a chemical pathway that signals cells to stop dividing and triggers cells to self-destruct through a process called apoptosis. Evidence suggests that this enzyme also helps control cell movement (migration), the sticking (adhesion) of cells to surrounding tissues, and the formation of new blood vessels (angiogenesis). Additionally, it likely plays a role in maintaining the stability of a cell's genetic information. All of these functions help prevent uncontrolled cell proliferation that can lead to the formation of tumors.

Health Conditions Related to Genetic Changes

Bannayan-Riley-Ruvalcaba syndrome

More than 30 mutations in the PTEN gene have been found to cause Bannayan-Riley-Ruvalcaba syndrome. Common features of this condition include a large head size (macrocephaly), multiple noncancerous tumors and tumor-like growths called hamartomas, and dark freckles on the penis in males. Bannayan-Riley-Ruvalcaba syndrome is one of several related conditions that are often considered together as PTEN hamartoma tumor syndrome (described below).

Some of the mutations that cause Bannayan-Riley-Ruvalcaba syndrome change single DNA building blocks (base pairs) in the PTEN gene or insert or delete a small number of base pairs. Other mutations result in an abnormally short enzyme or reduce the amount of enzyme that is produced. In about 10 percent of cases, Bannayan-Riley-Ruvalcaba syndrome results from the deletion of a large amount of genetic material that includes part or all of the PTEN gene. All of these genetic changes prevent the PTEN enzyme from regulating cell proliferation effectively, which can lead to uncontrolled cell growth and the formation of hamartomas and other types of tumors. Research is needed to determine what role PTEN gene mutations play in causing macrocephaly and the other features of Bannayan-Riley-Ruvalcaba syndrome.

Breast cancer

Inherited mutations in the PTEN gene increase the risk of developing breast cancer. In many cases, this increased risk occurs as part of Cowden syndrome (described below). Inherited mutations in the PTEN gene are thought to account for only a small fraction of all breast cancer cases.

Noninherited (somatic) PTEN gene mutations occur in some breast cancers in women without a family history of the disease. Somatic mutations are not inherited and do not occur as part of a familial cancer syndrome. They are acquired during a person's lifetime and occur only in certain cells in the breast. These mutations impair the tumor suppressor function of the PTEN enzyme, allowing cells to grow and divide without control or order. This uncontrolled cell growth contributes to the formation of a cancerous tumor. Studies suggest that a loss of functional PTEN enzyme is also related to poor responsiveness to a drug called trastuzumab (Herceptin), which is used to treat breast cancer.

Cowden syndrome

Researchers have identified more than 300 mutations in the PTEN gene that can cause Cowden syndrome or a similar disorder called Cowden-like syndrome. These conditions are characterized by the growth of multiple hamartomas and an increased risk of developing certain cancers, particularly breast cancer (described above), thyroid cancer, and cancer of the uterine lining (endometrial cancer). Cowden syndrome and Cowden-like syndrome are considered to be part of PTEN hamartoma tumor syndrome (described below).

Mutations that cause Cowden syndrome and Cowden-like syndrome include changes in a small number of base pairs and, in some cases, deletions of a larger amount of genetic material from the PTEN gene. These mutations lead to the production of a PTEN enzyme that does not function properly or does not work at all. The altered enzyme is unable to restrain cell division or signal abnormal cells to die, which contributes to the development of hamartomas and cancerous tumors.

Autism spectrum disorder

PTEN gene mutations have been identified in several people who have both an unusually large head size and the characteristic features of autism spectrum disorder, which affects communication and social interaction. Many of these mutations change single protein building blocks (amino acids) in the PTEN enzyme or lead to the production of an abnormally short version of the enzyme. Researchers are studying how changes in the PTEN gene are related to the risk of developing autism spectrum disorder. Some of these mutations have also been reported in families with PTEN hamartoma tumor syndrome (described below), and it is unclear how these mutations can cause different disorders.

Prostate cancer

Studies suggest that somatic mutations in the PTEN gene may be the most frequent genetic changes in prostate cancer. Mutations in the PTEN gene reduce or eliminate the tumor suppressor function of the PTEN enzyme. The loss of this enzyme's function likely permits certain cells to divide uncontrollably, contributing to the growth of cancerous tumors. In some cases, the presence of PTEN gene mutations is associated with more advanced stages of tumor growth.

Bladder cancer

MedlinePlus Genetics provides information about Bladder cancer

Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Head and neck squamous cell carcinoma

MedlinePlus Genetics provides information about Head and neck squamous cell carcinoma

Lung cancer

MedlinePlus Genetics provides information about Lung cancer

Other disorders

Several related conditions caused by mutations in the PTEN gene, including Bannayan-Riley-Ruvalcaba syndrome and Cowden syndrome (described above), are often considered together as PTEN hamartoma tumor syndrome. The mutations that cause these conditions are present in cells throughout the body and are often inherited from a parent. Some of the mutations that cause PTEN hamartoma tumor syndrome lead to a defective version of the PTEN enzyme that cannot perform its function as a tumor suppressor. Other mutations prevent the PTEN gene from producing any enzyme at all. Without functional PTEN enzyme, cell division is not controlled effectively and damaged cells continue to divide inappropriately, leading to the development of hamartomas and other tumors.

In some published case reports, mutations in the PTEN gene have been associated with Proteus syndrome, a rare condition characterized by asymmetric overgrowth of the bones, skin, and other tissues. However, many researchers now believe that individuals with PTEN gene mutations and asymmetric overgrowth do not meet the strict guidelines for a clinical diagnosis of Proteus syndrome. Instead, these individuals have a condition that is considered part of PTEN hamartoma tumor syndrome. One name that has been proposed for the condition is segmental overgrowth, lipomatosis, arteriovenous malformations, and epidermal nevus (SOLAMEN) syndrome; another is type 2 segmental Cowden syndrome. However, some scientific articles still refer to PTEN-related Proteus syndrome.

Other cancers

Somatic mutations in the PTEN gene are among the most common genetic changes found in human cancers. The cancers associated with somatic mutations are not inherited and do not occur as part of a cancer syndrome. Somatic mutations in the PTEN gene have been reported in many types of cancer, and studies suggest that PTEN may be the most frequently mutated gene in endometrial cancer. PTEN gene mutations are also commonly found in brain tumors called glioblastomas and astrocytomas, and in an aggressive form of skin cancer called melanoma. Mutations in the PTEN gene reduce or eliminate the tumor suppressor function of the PTEN enzyme. The loss of this enzyme's function likely permits certain cells to divide uncontrollably, contributing to the growth of cancerous tumors. In some cases, the presence of PTEN gene mutations is associated with more advanced stages of tumor growth.

Other Names for This Gene

• MMAC1
• mutated in multiple advanced cancers 1
• phosphatase and tensin homolog (mutated in multiple advanced cancers 1)
• phosphatase and tensin homolog deleted on chromosome 10
• protein-tyrosine phosphatase PTEN
• PTEN-MMAC1 protein
• PTEN1
• PTEN_HUMAN
• TEP1
• TEP1 phosphatase

Genomic Location

Normal Function

The RB1 gene provides instructions for making a protein called pRB. This protein acts as a tumor suppressor, which means that it regulates cell growth and keeps cells from dividing too fast or in an uncontrolled way. Under certain conditions, pRB stops other proteins from triggering DNA replication, the process by which DNA makes a copy of itself. Because DNA replication must occur before a cell can divide, tight regulation of this process controls cell division and helps prevent the growth of tumors. Additionally, pRB interacts with other proteins to influence cell survival, the self-destruction of cells (apoptosis), and the process by which cells mature to carry out special functions (differentiation).

Health Conditions Related to Genetic Changes

Retinoblastoma

Hundreds of mutations in the RB1 gene have been identified in people with retinoblastoma, a rare type of eye cancer that typically affects young children. This cancer develops in the retina, which is the specialized light-sensitive tissue at the back of the eye that detects light and color. Researchers estimate that 40 percent of all retinoblastomas are germinal, which means that RB1 mutations occur in all of the body's cells and can be passed to the next generation. The other 60 percent are non-germinal, which means that RB1 mutations occur only in the eye and cannot be passed to the next generation.

In germinal retinoblastoma, an RB1 mutation is present in all of the body's cells. For retinoblastoma to develop, the other copy of the RB1 gene also must be mutated or lost. This second mutation typically occurs early in life in retinal cells. Cells with two altered copies of the RB1 gene produce no functional pRB and are unable to regulate cell division effectively. As a result, retinal cells lacking functional pRB can divide uncontrollably to form cancerous tumors. Some studies suggest that additional genetic changes can influence the development of retinoblastoma; these changes may help explain variations in the development and growth of tumors in different people.

In people with germinal retinoblastoma, RB1 mutations increase the risk of several other cancers outside the eye. Specifically, these people are more likely to develop a cancer of the pineal gland in the brain (pinealoma), a type of bone cancer known as osteosarcoma, cancers of soft tissues such as muscle, and an aggressive form of skin cancer called melanoma.

Non-germinal retinoblastoma occurs in people with no history of the disorder in their family. Affected individuals are born with two normal copies of the RB1 gene. Then, usually in early childhood, both copies of the gene in retinal cells acquire mutations or are lost. These non-inherited genetic changes are known as somatic mutations. Somatic mutations in both copies of the RB1 gene prevent the cells from producing any functional pRB. The loss of this protein allows retinal cells to grow and divide without control or order, leading to the development of a cancerous tumor.

Bladder cancer

Somatic RB1 gene mutations have been identified in people with bladder cancer. These changes prevent pRB from regulating cell division effectively, leading to uncontrolled growth and division of affected cells and tumor formation.

Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Lung cancer

Somatic mutations in the RB1 gene have also been found in lung cancer. As in other forms of cancer, these genetic changes make the pRB protein ineffective, and cells can grow and divide without control, forming a tumor.

Other cancers

Somatic mutations in the RB1 gene are associated with many other types of cancer. In addition to the cancers listed above, changes in the RB1 gene have been reported in some cases of breast cancer, melanoma, and a bone cancer known as osteosarcoma. Somatic RB1 mutations have also been identified in some leukemias, which are cancers of blood-forming cells. Somatic RB1 mutations in cancer cells inactivate pRB so it can no longer regulate cell division effectively.

Other Names for This Gene

• p105-Rb
• PP110
• PPP1R130
• RB
• RB1 gene
• RB_HUMAN
• retinoblastoma 1
• Retinoblastoma 1 (including osteosarcoma)
• Retinoblastoma-1
• Retinoblastoma-associated protein

Genomic Location

Normal Function

The RET gene provides instructions for producing a protein that is involved in signaling within cells. This protein appears to be essential for the normal development of several kinds of nerve cells, including nerves in the intestine (enteric neurons) and the portion of the nervous system that controls involuntary body functions such as heart rate (the autonomic nervous system). The RET protein is also necessary for normal kidney development and the production of sperm (spermatogenesis).

The RET protein spans the cell membrane, so that one end of the protein remains inside the cell and the other end projects from the outer surface of the cell. This positioning of the protein allows it to interact with specific factors outside the cell and to receive signals that help the cell respond to its environment. When molecules that stimulate growth and development (growth factors) attach to the RET protein, a complex cascade of chemical reactions inside the cell is triggered. These reactions instruct the cell to undergo certain changes, such as dividing or maturing to take on specialized functions.

Health Conditions Related to Genetic Changes

Nonsyndromic paraganglioma

Mutations in the RET gene increase the risk of developing a type of paraganglioma called pheochromocytoma. Paragangliomas are tumors of the nervous system that are usually noncancerous (benign). Pheochromocytomas specifically affect the adrenal glands, which are small hormone-producing glands located on top of each kidney. Pheochromocytomas are a feature of multiple endocrine neoplasia type 2 (described below), but they can also be nonsyndromic, which means they occur without the other signs and symptoms of the syndrome. RET gene mutations associated with nonsyndromic pheochromocytoma change single amino acids in the RET protein. As in multiple endocrine neoplasia type 2, the mutations likely result in an overactive RET protein that can trigger cells to grow and divide uncontrollably and can lead to the formation of tumors.

Hirschsprung disease

Mutations in the RET gene are the most common genetic cause of Hirschsprung disease, a disorder that causes severe constipation or blockage of the intestine. More than 200 RET gene mutations are known to cause this condition. These genetic changes result in a nonfunctional version of the RET protein that cannot interact with growth factors or transmit signals within cells. Without RET protein signaling, enteric nerves do not develop properly. These nerves control contractions that move stool through the intestine, and their absence leads to the intestinal problems characteristic of Hirschsprung disease.

Multiple endocrine neoplasia

More than 25 mutations in the RET gene are known to cause a form of multiple endocrine neoplasia called type 2. Multiple endocrine neoplasia typically involves the development of tumors in two or more of the body's hormone-producing glands, called endocrine glands. These tumors can be noncancerous or cancerous. Multiple endocrine neoplasia type 2 is divided into three subtypes: type 2A, type 2B, and familial medullary thyroid carcinoma. These subtypes are distinguished by their characteristic signs and symptoms and risk of specific tumors.

Most of the RET gene mutations that cause multiple endocrine neoplasia type 2 change single protein building blocks (amino acids) in the RET protein. Type 2A most often results from a mutation that substitutes the amino acid arginine for the amino acid cysteine at position 634 (written as Cys634Arg or C634R). More than 90 percent of cases of type 2B are caused by a mutation that replaces the amino acid methionine with the amino acid threonine at position 918 (written as Met918Thr or M918T). Several amino acid substitutions can cause familial medullary thyroid carcinoma.

The mutations responsible for multiple endocrine neoplasia type 2 result in an overactive RET protein that can transmit signals without first attaching to growth factors outside the cell. The overactive protein likely triggers cells to grow and divide abnormally, which can lead to the formation of tumors in the endocrine system and other tissues. The overactivating RET gene mutations that cause multiple endocrine neoplasia type 2 are very different from the inactivating mutations that cause Hirschsprung disease (described above); these two disorders rarely occur in the same individual.

Lung cancer

MedlinePlus Genetics provides information about Lung cancer

Other cancers

Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes, which are called somatic mutations, are not inherited. Somatic changes in the RET gene have been identified in several nonhereditary (sporadic) cancers. Chromosomal rearrangements involving the RET gene are one of the most common causes of a sporadic form of thyroid cancer called papillary thyroid carcinoma (also known as RET/PTC). Additionally, a nonfamilial form of medullary thyroid carcinoma (a type of thyroid cancer that can also occur as part of multiple endocrine neoplasia, described above) can be caused by somatic mutations in the RET gene.

Other Names for This Gene

• cadherin family member 12
• cadherin-related family member 16
• CDHF12
• CDHR16
• HSCR1
• hydroxyaryl-protein kinase
• MEN2A
• MEN2B
• MTC1
• PTC
• rearranged during transfection
• ret proto-oncogene (multiple endocrine neoplasia and medullary thyroid carcinoma 1, Hirschsprung disease)
• RET-ELE1
• RET/PTC
• RET51
• RET_HUMAN

Genomic Location

Normal Function

The RIT1 gene provides instructions for making a protein that helps cells survive during periods of cellular stress, such as unusually high energy demands. As part of a signaling pathway known as the RAS/MAPK pathway, the RIT1 protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell to grow and divide (proliferate) or to mature and take on specialized functions (differentiate). The RIT1 protein is a GTPase, which means it converts a molecule called GTP into another molecule called GDP. To transmit signals during periods of cellular stress, the RIT1 protein is turned on by attaching (binding) to a molecule of GTP. The RIT1 protein is turned off (inactivated) when it converts the GTP to GDP. When the protein is bound to GDP, it does not relay signals to the cell's nucleus.

The RIT1 gene belongs to a class of genes known as oncogenes. When mutated, oncogenes have the potential to cause normal cells to become cancerous. The RIT1 gene is in the Ras family of oncogenes, which also includes three other genes: KRAS, HRAS, and NRAS. These proteins play important roles in cell division, cell differentiation, and the self-destruction of cells (apoptosis).

Health Conditions Related to Genetic Changes

Noonan syndrome

At least 14 mutations in the RIT1 gene have been found to cause Noonan syndrome. This condition is characterized by mildly unusual facial characteristics, short stature, heart defects, bleeding problems, skeletal malformations, and many other signs and symptoms. People with Noonan syndrome caused by RIT1 gene mutations often have swelling caused by a buildup of fluid (lymphedema). Rarely, people with Noonan syndrome caused by a RIT1 gene mutation develop cancer, including a blood cancer called acute lymphoblastic leukemia.

The RIT1 gene mutations associated with Noonan syndrome change single protein building blocks (amino acids) in the RIT1 protein. The mutations lead to the production of an altered RIT1 protein that is either continuously turned on (active) or has prolonged activation, rather than promptly switching on and off in response to other cellular proteins. The abnormally active protein alters normal RAS/MAPK signaling and leads to abnormal cell proliferation, which disrupts the development of organs and tissues throughout the body, resulting in the signs and symptoms of Noonan syndrome.

Lung cancer

MedlinePlus Genetics provides information about Lung cancer

Cancers

Mutations in the RIT1 gene have been found in several different types of blood cell cancer (leukemia), including acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML), and a bone marrow disease called myelodysplastic syndrome (MDS). Similar to the RIT1 gene mutations that cause Noonan syndrome (described above), the mutations involved in these cancers likely result in a constitutively active protein. As a result, cell growth is continuously promoted and cells grow and divide uncontrollably leading to cancer formation. Unlike the Noonan syndrome mutations, the RIT1 gene mutations associated with leukemia are somatic mutations, which means they occur during a person's lifetime and are not inherited.

Other Names for This Gene

• GTP-binding protein Roc1
• MGC125864
• MGC125865
• Ras-like without CAAX 1
• ras-like without CAAX protein 1
• RIBB
• RIT
• ROC1

Genomic Location

Normal Function

The SMARCA4 gene provides instructions for making a protein called BRG1, which forms one piece (subunit) of several different protein groupings called SWI/SNF protein complexes. SWI/SNF complexes regulate gene activity (expression) by a process known as chromatin remodeling. Chromatin is the network of DNA and protein that packages DNA into chromosomes. The structure of chromatin can be changed (remodeled) to alter how tightly DNA is packaged. Chromatin remodeling is one way gene expression is regulated during development; when DNA is tightly packed, gene expression is lower than when DNA is loosely packed. The BRG1 protein uses a molecule called ATP to provide energy for chromatin remodeling, although the protein's specific role in remodeling is unclear.

Through their ability to regulate gene activity, SWI/SNF complexes are involved in many processes, including repairing damaged DNA; copying (replicating) DNA; and controlling the growth, division, and maturation (differentiation) of cells. Through these processes, the BRG1 protein and other SWI/SNF subunits are thought to act as tumor suppressors, which keep cells from growing and dividing too rapidly or in an uncontrolled way.

Health Conditions Related to Genetic Changes

Coffin-Siris syndrome

Approximately 40 variants (also known as mutations) in the SMARCA4 gene have been found to cause Coffin-Siris syndrome. This condition is characterized by delayed development, abnormalities of the fifth (pinky) fingers or toes, and characteristic facial features that are described as coarse. The SMARCA4 gene variants involved in Coffin-Siris syndrome are germline variants, which means that they are present in cells throughout the body. The variants change single protein building blocks (amino acids) in or remove an amino acid from the BRG1 protein. Although it is unclear how these changes affect SWI/SNF complexes, researchers suggest that SMARCA4 gene variants result in abnormal chromatin remodeling. Disturbance of this process alters the activity of many genes and disrupts several cellular processes, which could explain the diverse signs and symptoms of Coffin-Siris syndrome. People with Coffin-Siris syndrome do not appear to have an increased risk of cancer (see below).

Rhabdoid tumor predisposition syndrome

At least six germline variants in the SMARCA4 gene have been identified in people with rhabdoid tumor predisposition syndrome (RTPS). RTPS is characterized by a high risk of developing cancerous (malignant) growths called rhabdoid tumors. These tumors most often occur in the brain and spinal cord (central nervous system) or in the kidney, but they can occur in other organs and tissues of the body. Some affected children also develop noncancerous (benign) tumors called schwannomas, which grow on nerves. Women with RTPS are at increased risk of developing a rare type of ovarian cancer called small cell cancer of the ovary, hypercalcemic type (SCCOHT).

In addition to the germline variant affecting one copy of the SMARCA4 gene in each cell, an additional genetic change that deletes the normal copy of the gene is needed for a tumor to develop. This additional change is present only in the cancerous cells. Such changes are known as somatic variants. In combination, the germline and somatic variants lead to the absence of BRG1 protein. This absence likely impairs the tumor suppressor functions of the protein, but the specific mechanism that leads to rhabdoid tumors is unknown.

Lung cancer

MedlinePlus Genetics provides information about Lung cancer

Other cancers

Somatic variants in both copies of the SMARCA4 gene, which result in the absence of SMARCA4 protein, cause noninherited (sporadic) rhabdoid tumors in children. Somatic variants in the SMARCA4 gene have also been found in certain other types of cancer, particularly lung cancer and other cancers in the chest called SMARCA4-deficiency thoracic sarcomas. The mechanism by which variants in the SMARCA4 gene contribute to these tumors is unknown, although it is thought that changes in SWI/SNF complexes are involved. These changes may impair normal cell differentiation, which leads to the overgrowth of certain cell types, causing cancer. Alternatively, abnormal SWI/SNF complexes may disrupt the regulation of genes that help control the growth and division of cells, which leads to cancer. It is likely that other genetic changes in addition to SMARCA4 gene variants are necessary for cancer development.

Other Names for This Gene

• ATP-dependent helicase SMARCA4
• BAF190
• BAF190A
• brahma protein-like 1
• BRG1
• BRG1-associated factor 190A
• BRM/SWI2-related gene 1
• FLJ39786
• hSNF2b
• MRD16
• nuclear protein GRB1
• protein brahma homolog 1
• protein BRG-1
• RTPS2
• SMCA4_HUMAN
• SNF2
• SNF2-beta
• SNF2-like 4
• SNF2L4
• SNF2LB
• sucrose nonfermenting-like 4
• SWI2
• transcription activator BRG1

Genomic Location

Normal Function

The STK11 gene (also called LKB1) provides instructions for making an enzyme called serine/threonine kinase 11. This enzyme is a tumor suppressor, which means that it helps keep cells from growing and dividing too fast or in an uncontrolled way. This enzyme helps certain types of cells correctly orient themselves within tissues (polarization) and assists in determining the amount of energy a cell uses. This kinase also promotes a type of programmed cell death known as apoptosis. In addition to its role as a tumor suppressor, serine/threonine kinase 11 function appears to be required for normal development before birth.

Health Conditions Related to Genetic Changes

Breast cancer

Inherited changes in the STK11 gene greatly increase the risk of developing breast cancer, as well as other types of cancer, as part of Peutz-Jeghers syndrome (described above). These mutations are thought to account for only a small fraction of all breast cancer cases.

Peutz-Jeghers syndrome

Inherited mutations in the STK11 gene cause Peutz-Jeghers syndrome, a condition characterized by the development of noncancerous growths called hamartomatous polyps in the gastrointestinal tract and a greatly increased risk of developing several types of cancer. More than 340 STK11 gene mutations have been identified in people with this condition. Many of these mutations result in the production of an abnormally short, nonfunctional version of the serine/threonine kinase 11 enzyme. Other mutations change single protein building blocks (amino acids) used to build the enzyme. Mutations in the STK11 gene impair the enzyme's tumor suppressor function, allowing cells to grow and divide without control or order. This uncontrolled cell growth can lead to the formation of hamartomatous polyps and cancerous tumors.

Lung cancer

MedlinePlus Genetics provides information about Lung cancer

Ovarian cancer

MedlinePlus Genetics provides information about Ovarian cancer

Other cancers

Noninherited (somatic) mutations in the STK11 gene have been found in various forms of cancer. Somatic mutations are acquired during a person's lifetime and are present only in certain cells. They do not occur as part of a cancer syndrome. Somatic STK11 gene mutations have been identified in a form of lung cancer called non-small cell lung carcinoma, cervical cancer, colorectal cancer, an aggressive type of skin cancer called melanoma, and pancreatic cancer. These mutations impair the function of serine/threonine kinase 11, which can allow cells to grow and divide uncontrollably and contribute to the formation of a cancerous tumor.

Other Names for This Gene

• LKB1
• PJS
• serine/threonine kinase 11 (Peutz-Jeghers syndrome)
• Serine/threonine-protein kinase 11
• STK11_HUMAN

Genomic Location

Normal Function

The TP53 gene provides instructions for making a protein called tumor protein p53 (or p53). This protein acts as a tumor suppressor, which means that it regulates cell division by keeping cells from growing and dividing (proliferating) too fast or in an uncontrolled way.

The p53 protein is located in the nucleus of cells throughout the body, where it attaches (binds) directly to DNA. When the DNA in a cell becomes damaged by agents such as toxic chemicals, radiation, or ultraviolet (UV) rays from sunlight, this protein plays a critical role in determining whether the DNA will be repaired or the damaged cell will self-destruct (undergo apoptosis). If the DNA can be repaired, p53 activates other genes to fix the damage. If the DNA cannot be repaired, this protein prevents the cell from dividing and signals it to undergo apoptosis. By stopping cells with mutated or damaged DNA from dividing, p53 helps prevent the development of tumors.

Because p53 is essential for regulating DNA repair and cell division, it has been nicknamed the "guardian of the genome."

Health Conditions Related to Genetic Changes

Breast cancer

Inherited changes in the TP53 gene greatly increase the risk of developing breast cancer, as well as several other forms of cancer, as part of a rare cancer syndrome called Li-Fraumeni syndrome (described below). These mutations are thought to account for only a small fraction of all breast cancer cases.

Noninherited (somatic) mutations in the TP53 gene are much more common than inherited mutations, occurring in 20 to 40 percent of all breast cancers. These somatic mutations are acquired during a person's lifetime and are present only in cells that become cancerous. The cancers associated with somatic mutations do not occur as part of a cancer syndrome. Most of these mutations change single protein building blocks (amino acids) in the p53 protein, which reduces or eliminates the protein's tumor suppressor function. This altered p53 protein cannot regulate cell proliferation effectively. Specifically, it is unable to trigger apoptosis in cells with mutated or damaged DNA. As a result, DNA damage can accumulate in cells. Such cells may continue to divide in an uncontrolled way, leading to tumor growth.

Compared with breast cancers without TP53 gene mutations, tumors with these genetic changes tend to have a poorer prognosis: They are more likely to be aggressive, to be resistant to treatment with certain anti-cancer drugs and radiation, and to come back (recur) after treatment.

Bladder cancer

Somatic TP53 gene mutations have been found in some cases of bladder cancer. Bladder cancer is a disease in which certain cells in the bladder become abnormal and multiply uncontrollably to form a tumor. Bladder cancer may cause blood in the urine, pain during urination, frequent urination, the feeling of needing to urinate without being able to, or lower back pain.

Bladder cancer is generally divided into two types, non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC), based on where in the bladder the tumor is located. About half of NMIBC tumors have TP53 gene mutations. Most of these mutations change single amino acids in p53. This altered p53 protein cannot regulate cell growth and division and is unable to trigger apoptosis in cells with mutated or damaged DNA. As a result, DNA damage can accumulate in cells. If such cells continue to divide in an uncontrolled way, they can lead to the formation of bladder cancer.

Cholangiocarcinoma

MedlinePlus Genetics provides information about Cholangiocarcinoma

Head and neck squamous cell carcinoma

Somatic mutations in the TP53 gene have been found in nearly half of all head and neck squamous cell carcinomas (HNSCC). This type of cancerous tumor occurs in the moist lining of the mouth, nose, and throat. Most of the TP53 gene mutations involved in HNSCC change single amino acids in p53; these changes impair the protein's function. Without functioning p53, cell proliferation is not regulated. As a result, cells accumulate DNA damage and continue to divide in an uncontrolled way, leading to tumor growth.

Li-Fraumeni syndrome

Although somatic mutations in the TP53 gene are found in many types of cancer, Li-Fraumeni syndrome appears to be the only cancer syndrome associated with inherited mutations in this gene. This condition greatly increases the risk of developing several types of cancer, including breast cancer; bone cancer; and cancers of soft tissues (such as muscle) called soft tissue sarcomas, particularly in children and young adults. At least 140 different mutations in the TP53 gene have been identified in individuals with Li-Fraumeni syndrome.

Many of the mutations associated with Li-Fraumeni syndrome change single amino acids in the part of the p53 protein that binds to DNA. Other mutations delete small amounts of DNA from the gene. These mutations result in an altered p53 protein that cannot regulate cell proliferation effectively and is unable to trigger apoptosis in cells with mutated or damaged DNA. As a result, DNA damage can accumulate in cells. Such cells may continue to divide in an uncontrolled way, leading to the growth of tumors.

Lung cancer

Somatic mutations in the TP53 gene have been found in nearly half of all lung cancers. Lung cancer is a disease in which certain cells in the lungs become abnormal and multiply uncontrollably to form a tumor. Signs and symptoms may not occur in early stages of the disease.

Lung cancer is generally divided into two types, small cell lung cancer and non-small cell lung cancer, based on the size of the affected cells when viewed under a microscope. Small cell lung cancers nearly always have TP53 gene mutations; however, these mutations may also occur in non-small cell lung cancer. TP53 gene mutations change single amino acids in p53, which impair the protein's function. Without functioning p53, cell proliferation is not regulated effectively and DNA damage can accumulate in cells. Such cells may continue to divide in an uncontrolled way, leading to tumor growth. Additional genetic, environmental, and lifestyle factors contribute to a person's cancer risk; in lung cancer, the greatest risk factor is being a long-term tobacco smoker.

Melanoma

MedlinePlus Genetics provides information about Melanoma

Ovarian cancer

Somatic TP53 gene mutations are common in ovarian cancer, occurring in almost half of ovarian tumors. These mutations result in a p53 protein that is less able to control cell proliferation. Specifically, it is unable to trigger apoptosis in cells with mutated or damaged DNA. As a result, DNA damage can accumulate in cells. Such cells may continue to divide in an uncontrolled way, leading to tumor growth.

Wilms tumor

MedlinePlus Genetics provides information about Wilms tumor

Other cancers

Somatic mutations in the TP53 gene are the most common genetic changes found in human cancer, occurring in about half of all cancers. In addition to the cancers described above, somatic TP53 gene mutations have been identified in several types of brain tumor, colorectal cancer, liver cancer, a type of bone cancer called osteosarcoma, a cancer of muscle tissue called rhabdomyosarcoma, and a cancer called adrenocortical carcinoma that affects the outer layer of the adrenal glands (small hormone-producing glands on top of each kidney).

Most TP53 mutations change single amino acids in the p53 protein, which leads to the production of an altered version of the protein that cannot control cell proliferation and is unable to trigger apoptosis in cells with mutated or damaged DNA. As a result, DNA damage can accumulate in cells. Such cells may continue to divide in an uncontrolled way, leading to tumor growth.

Other Names for This Gene

• antigen NY-CO-13
• cellular tumor antigen p53
• P53
• P53 tumor suppressor
• P53_HUMAN
• phosphoprotein p53
• transformation-related protein 53
• TRP53
• tumor protein p53 (Li-Fraumeni syndrome)
• tumor suppressor p53

Genomic Location