Bladder cancer is a disease in which certain cells in the bladder become abnormal and multiply uncontrollably to form a tumor. The bladder is a muscular organ in the lower abdomen that stores urine until it can be removed (excreted) from the body.

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. Many of these signs and symptoms are nonspecific, which means they may occur in multiple disorders. People who have one or more of these nonspecific health problems often do not have bladder cancer, but have another condition such as an infection.

Bladder cancer develops when tumors form in the tissue that lines the bladder. There are several types of bladder cancer, categorized by the type of cell in the tissue that becomes cancerous. The most common type is transitional cell carcinoma (also known as urothelial carcinoma); others include squamous cell carcinoma and adenocarcinoma. If the tumor spreads (metastasizes) beyond the lining of the bladder into nearby tissues or organs, it is known as invasive bladder cancer.

In the United States, bladder cancer is the fourth most common type of cancer in men. Bladder cancer occurs four times more often in men than in women, with about 60,000 men and 18,000 women diagnosed with the condition each year.

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 bladder cancer, these genetic changes are acquired during a person's lifetime and are present only in certain cells in the bladder. These changes, which are called somatic mutations, are not inherited. Somatic mutations in many different genes have been found in bladder cancer cells. It is unclear whether genetic changes that are inherited and present in all of the body's cells (germline mutations) play a significant role in causing bladder cancer.

Somatic mutations in the FGFR3, PIK3CA, KDM6A, and TP53 genes are common in bladder cancers. Each of these genes plays a critical role in regulating gene activity and cell growth, ensuring cells do not grow and divide too rapidly or uncontrollably. It is likely that mutations in these genes disrupt normal gene regulation, contributing to the uncontrolled cell growth that can lead to tumor formation in bladder cancer. Mutations in many other genes have been found to be associated with bladder cancer; each of these additional genes is associated with a small percentage of cases. Most of these genes are also involved in regulating the normal activity of genes and the growth of cells.

Additionally, deletions of part or all of chromosome 9 are commonly found in bladder cancer. Research shows that several genes that control cell growth and division are located on chromosome 9. It is likely that a loss of one or more of these genes plays a role in the early development and progression of bladder cancer.

Researchers have identified many lifestyle and environmental factors that expose individuals to cancer-causing compounds (carcinogens), which increase the rate at which somatic mutations occur, contributing to a person's risk of developing bladder cancer. The greatest risk factor is long-term tobacco smoking. It is estimated that half of people with bladder cancer have a history of tobacco smoking. Other environmental risk factors include chronic bladder inflammation, exposure to certain industrial chemicals, certain herbal medicines common in Asia, a parasitic infection called schistosomiasis, and long-term use of urinary catheters.

Bladder cancer is typically not inherited. It is usually associated with somatic mutations that occur in certain cells in the bladder during a person's lifetime.

In rare families, the risk of bladder cancer is inherited. In these cases, 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 bladder cancer.

Normal Function

The ARID1A gene provides instructions for making a protein that forms one piece (subunit) of several different 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.

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. The ARID1A 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.

The ARID1A subunit is able to attach (bind) to DNA and is thought to help target SWI/SNF complexes to the chromatin location that needs to be remodeled.

Health Conditions Related to Genetic Changes

Coffin-Siris syndrome

More than 30 variants (also known as mutations) in the ARID1A gene can 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 ARID1A gene variants involved in Coffin-Siris syndrome lead to an abnormally short, nonfunctional protein. As a result, affected individuals have half the normal amount of functioning ARID1A protein. Although it is unclear how these changes affect SWI/SNF complexes, researchers suggest that ARID1A 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).

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Cancers

Variants in the ARID1A gene have been found in many types of cancer, including cancers of the ovaries and lining of the uterus (endometrium) in women and cancers of the kidney, stomach, bladder, lung, breast, and brain. These variants are somatic, which means they are acquired during a person's lifetime and are present only in tumor cells. The mechanism by which variants in the ARID1A gene contribute to cancer 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 ARID1A gene variants are necessary for cancer development.

Other Names for This Gene

• ARI1A_HUMAN
• ARID domain-containing protein 1A
• AT rich interactive domain 1A (SWI-like)
• AT-rich interactive domain-containing protein 1A
• B120
• BAF250
• BAF250a
• BM029
• brain protein 120
• BRG1-associated factor 250a
• C1orf4
• chromatin remodeling factor p250
• ELD
• hELD
• hOSA1
• MRD14
• osa homolog 1
• OSA1
• OSA1 nuclear protein
• P270
• SMARCF1
• SWI-like protein
• SWI/SNF complex protein p270
• SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily F member 1

Genomic Location

Normal Function

The ATM gene provides instructions for making a protein that is located primarily in the nucleus of cells, where it helps control the rate at which cells grow and divide. This protein also plays an important role in the normal development and activity of several body systems, including the nervous system and the immune system. Additionally, the ATM protein assists cells in recognizing damaged or broken DNA strands. DNA can be damaged by agents such as toxic chemicals or radiation. Breaks in DNA strands also occur naturally when chromosomes exchange genetic material during cell division. The ATM protein coordinates DNA repair by activating enzymes that fix the broken strands. Efficient repair of damaged DNA strands helps maintain the stability of the cell's genetic information.

Because of its central role in cell division and DNA repair, the ATM protein is of great interest in cancer research.

Health Conditions Related to Genetic Changes

Ataxia-telangiectasia

Researchers have identified several hundred variants (also called mutations) in the ATM gene that cause ataxia-telangiectasia. This disorder is characterized by progressive difficulty with coordinating movements (ataxia) beginning in early childhood. People with this disorder have variants in both copies of the ATM gene in each cell. Most of these variants disrupt protein production, resulting in an abnormally small, nonfunctional version of the ATM protein. Cells without any functional ATM protein are hypersensitive to radiation and do not respond normally to DNA damage. Instead of activating DNA repair, the altered ATM protein allows variants to accumulate in other genes, which may cause cells to grow and divide in an uncontrolled way. This kind of unregulated cell growth can lead to the formation of cancerous tumors. In addition, ATM gene variants can allow cells to die inappropriately, particularly affecting cells in a part of the brain involved in coordinating movements (the cerebellum). This loss of brain cells causes the movement problems characteristic of ataxia-telangiectasia.

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Other cancers

Research suggests that people who carry one alterd copy of the ATM gene in each cell may have an increased risk of developing several other types of cancer. In particular, some studies have shown that cancers of the breast, stomach, bladder, pancreas, lung, and ovaries occur more frequently in ATM gene variant carriers than in people who do not carry these variants. The results of similar studies, however, have been conflicting. Additional research is needed to clarify which other types of cancer, if any, are associated with ATM gene variants.

Other Names for This Gene

• AT mutated
• AT protein
• AT1
• ATA
• ataxia telangiectasia mutated
• ATM_HUMAN
• human phosphatidylinositol 3-kinase homolog
• serine-protein kinase ATM
• TEL1
• TELO1

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

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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.

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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 CREBBP gene provides instructions for making CREB binding protein, which regulates the activity of many genes in tissues throughout the body. This protein plays an essential role in controlling cell growth and division and prompting cells to mature and assume specialized functions (differentiate). CREB binding protein appears to be critical for normal development before and after birth. Studies show that this protein is involved in development of the brain and may also be involved in the formation of long-term memories.

CREB binding protein carries out its functions by turning on (activating) transcription, which is the first step in the production of proteins from the instructions stored in DNA. The CREB binding protein ensures the DNA is ready for transcription by attaching a small molecule called an acetyl group to proteins called histones (a process called acetylation). Histones are structural proteins that bind DNA and give chromosomes their shape. Acetylation of the histone changes the shape of the chromosome, making genes available for transcription. On the basis of this function, CREB binding protein is called a histone acetyltransferase.

In addition, CREB binding protein connects other proteins that start the transcription process (known as transcription factors) with the group of proteins that carries out transcription. On the basis of this function, CREB binding protein is called a transcriptional coactivator.

Health Conditions Related to Genetic Changes

Rubinstein-Taybi syndrome

Mutations in the CREBBP gene have been found to cause Rubinstein-Taybi syndrome, a condition characterized by short stature, moderate to severe intellectual disability, distinctive facial features, and broad thumbs and first toes. More than 300 mutations have been identified, including the loss (deletion) or addition (insertion) of genetic material in the gene and changes in single DNA building blocks (nucleotides).

Because one copy of the CREBBP gene is altered in people with Rubinstein-Taybi syndrome, their cells make only half of the normal amount of functional CREB binding protein. Although researchers are uncertain how a reduction in the amount of this protein leads to the features of Rubinstein-Taybi syndrome, it is clear that variations in the CREBBP gene disrupt normal development before and after birth. Problems with development of the brain are thought to underlie intellectual disability in people with Rubinstein-Taybi syndrome. Other features of the condition likely result from abnormal development of other systems.

Deletion of genetic material from the short (p) arm of chromosome 16 can cause severe Rubinstein-Taybi syndrome, which features an inability to grow or gain weight in infancy, serious infections, and abnormalities of certain organs, such as the heart or spleen, in addition to the classic symptoms of the condition. Multiple genes, including the CREBBP gene, are missing as a result of the deletion. Researchers believe that the loss of multiple genes in this region probably accounts for the serious complications associated with severe Rubinstein-Taybi syndrome. Some researchers suggest that these cases are a separate condition called chromosome 16p13.3 deletion syndrome. However, a few studies indicate that large deletions in the p arm of chromosome 16 do not always cause severe signs and symptoms, so it is unclear if the disorders are separate.

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Other disorders

Mutations in the CREBBP gene can cause a condition called Menke-Hennekam syndrome. While this condition shares some features with Rubinstein-Taybi syndrome (described above), such as intellectual disability and growth delays, individuals with Menke-Hennekam syndrome do not have the facial features and thumb and toe abnormalities characteristic of Rubinstein-Taybi syndrome. Other features of Menke-Hennekam syndrome are variable and can include vision or hearing impairment, recurrent seizures (epilepsy), frequent airway infections, and autistic behaviors that affect communication.

The CREBBP gene mutations that cause Menke-Hennekam syndrome occur in regions of the gene known as exon 30 or exon 31. They result in changes to single protein building blocks (amino acids) in CREB binding protein. Researchers suggest that these changes give the altered protein a new function, which alters development and causes the signs and symptoms of Menke-Hennekam syndrome.

In some people, a region of DNA on chromosome 16 that includes the CREBBP gene is copied (duplicated). This genetic change causes a condition called chromosome 16p13.3 duplication syndrome, which is characterized by intellectual disability, distinctive facial features (different from those of Rubinstein-Taybi syndrome, described above), abnormal thumbs, and rigid joints (arthrogryposis). Some affected individuals also have abnormalities of the heart, genitals, roof of the mouth, or the eyes.

While other genes can be included in the duplicated region, depending on its size, research shows that the CREBBP gene is most likely responsible for the characteristic signs and symptoms of chromosome 16p13.3 duplication syndrome. Researchers suspect that an extra copy of the CREBBP gene leads to the production of excess CREB binding protein and an increase in protein function. The resulting changes in gene transcription and protein production likely alter development of various systems, causing the signs and symptoms of chromosome 16p13.3 duplication syndrome.

Cancers

Genetic changes involving the CREBBP gene have been associated with certain types of cancer. These mutations are somatic, which means they are acquired during a person's lifetime and are present only in certain cells. In some cases, chromosomal rearrangements (translocations) disrupt the region of chromosome 16 that contains the CREBBP gene. For example, researchers have found a translocation between chromosome 8 and chromosome 16 in some people with a cancer of blood-forming cells called acute myeloid leukemia (AML). Another translocation, involving chromosomes 11 and 16, has been found in some people who have undergone cancer treatment. This chromosomal change is associated with the later development of AML and two other cancers of blood-forming tissues (chronic myelogenous leukemia and myelodysplastic syndrome). These are sometimes described as treatment-related cancers because the translocation between chromosomes 11 and 16 occurs following chemotherapy for other forms of cancer.

Somatic mutations in the CREBBP gene have also been found in people with another blood cell cancer called B-cell non-Hodgkin lymphoma. Many of these mutations reduce the amount of functional CREB binding protein. Other mutations impair the protein's histone acetyltransferase activity. Reduction of CREB binding protein activity in certain immune cells called B cells prevents the normal control of cell growth and division, contributing to the development of B-cell non-Hodgkin lymphoma.

Other Names for This Gene

• CBP
• CBP_HUMAN
• CREB binding protein (Rubinstein-Taybi syndrome)

Genomic Location

Normal Function

The EP300 gene provides instructions for making a protein called p300, which regulates the activity of many genes in tissues throughout the body. This protein plays an essential role in controlling cell growth and division and prompting cells to mature and take on specialized functions (differentiate). The p300 protein appears to be critical for normal development before and after birth.

The p300 protein carries out its functions by turning on (activating) transcription, which is the first step in the production of protein from the instructions stored in DNA. The p300 protein ensures the DNA is ready for transcription by attaching a small molecule called an acetyl group (a process called acetylation) to proteins called histones. Histones are structural proteins that bind DNA and give chromosomes their shape. Acetylation of the histone changes the shape of the chromosome, making genes available for transcription. On the basis of this function, the p300 protein is called a histone acetyltransferase.

In addition, the p300 protein connects other proteins that start the transcription process (known as transcription factors) with the group of proteins that carries out transcription. On the basis of this function, the p300 protein is called a transcriptional coactivator.

Health Conditions Related to Genetic Changes

Rubinstein-Taybi syndrome

More than 80 mutations in the EP300 gene have been identified in people with Rubinstein-Taybi syndrome, a condition characterized by short stature, moderate to severe intellectual disability, distinctive facial features, and broad thumbs and first toes. Genetic changes in the EP300 gene cause a small percentage of cases of this condition. Some mutations lead to the production of an abnormally small, nonfunctional version of the p300 protein, while other mutations prevent one copy of the gene from making any protein at all. These genetic changes all result in the loss of one functional copy of the EP300 gene in each cell, which reduces the amount of p300 protein by half. Although researchers are uncertain how a reduction in the amount of this protein leads to the specific features of Rubinstein-Taybi syndrome, it is clear that changes in the EP300 gene disrupt normal development before and after birth. Problems with development of multiple systems are thought to underlie the features of Rubinstein-Taybi syndrome.

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Other disorders

Mutations in the EP300 gene are a very rare cause of a condition called Menke-Hennekam syndrome. While this condition shares some features with Rubinstein-Taybi syndrome (described above), such as intellectual disability and growth delays, individuals with Menke-Hennekam syndrome do not have the facial features and thumb and toe abnormalities characteristic of Rubinstein-Taybi syndrome. Other features of Menke-Hennekam syndrome are variable and can include vision or hearing impairment, recurrent seizures (epilepsy), frequent airway infections, and autistic behaviors that affect communication.

The EP300 gene mutations that cause Menke-Hennekam syndrome occur in regions of the gene known as exon 30 or exon 31. They result in changes to single protein building blocks (amino acids) in the p300 protein. Researchers suggest that these changes give the altered protein a new function, which disrupts development and causes the signs and symptoms of Menke-Hennekam syndrome.

Cancers

Rarely, chromosomal rearrangements (translocations) involving chromosome 22 have been associated with certain types of cancer. These genetic changes are somatic, which means they are acquired during a person's lifetime and are present only in certain cells. In cancer cells, translocations can disrupt the region of chromosome 22 that contains the EP300 gene. For example, researchers have found a translocation between chromosome 8 and chromosome 22 in several people with a cancer of blood-forming cells called acute myeloid leukemia (AML). Another translocation, involving chromosomes 11 and 22, has been found in a small number of people who have undergone cancer treatment. This chromosomal change is associated with the development of AML following chemotherapy for other forms of cancer.

Somatic mutations in the EP300 gene have been identified in several other types of cancer. These mutations prevent the gene from producing any functional protein. Cells without the p300 protein cannot effectively restrain growth and division, allowing cancerous tumors to develop and grow. Somatic mutations in the EP300 gene have been found in a small number of solid tumors, including cancers of the colon and rectum, stomach, breast, and pancreas. Studies suggest that EP300 mutations may also play a role in the development of some prostate cancers. These genetic changes could help predict whether prostate tumors will increase in size or spread to other parts of the body.

Other Names for This Gene

• E1A-associated protein p300
• E1A-binding protein, 300kD
• EP300_HUMAN
• p300
• p300 E1A-Associated Coactivator

Genomic Location

Normal Function

The FGFR3 gene provides instructions for making a protein called fibroblast growth factor receptor 3. This protein is part of a family of four fibroblast growth factor receptors that share similar structures and functions. These proteins play a role in several important cellular processes, including regulation of cell growth and division (proliferation), determination of cell type, formation of blood vessels (angiogenesis), wound healing, and embryo development.

The FGFR3 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 allows the protein to interact with specific growth factors outside the cell and receive signals that control growth and development. When these growth factors attach to the FGFR3 protein, the protein is turned on (activated). This triggers a cascade of chemical reactions inside the cell that instruct the cell to undergo certain changes, such as maturing to take on specialized functions (differentiation).

Several versions (isoforms) of the FGFR3 protein are produced from the FGFR3 gene. The different isoforms are found in various tissues of the body, and they interact with a variety of growth factors. Many isoforms are found in the cells that form bones. Researchers believe that the FGFR3 protein regulates bone growth by limiting the formation of bone from cartilage. Cartilage is a tough but flexible tissue that makes up much of the skeleton during early development. The process of converting cartilage to bone is called ossification. One particular isoform of the FGFR3 protein is found specifically in cells that line the surfaces of the body (epithelial cells), including the cells that form the outermost layer of skin, called the epidermis.

Health Conditions Related to Genetic Changes

Achondroplasia

Two variants (also called mutations) in the FGFR3 gene cause more than 99 percent of cases of achondroplasia, which is the most common form of short-limbed dwarfism. Both variants lead to the same change in the FGFR3 protein. This change replaces the protein building block (amino acid) glycine with the amino acid arginine at a specific location within the FGFR3 protein. This genetic change causes the receptor to be overly active, which leads to the disturbances in bone growth that occur in people with this disorder.

Crouzon syndrome with acanthosis nigricans

A single FGFR3 gene variant has been identified in people with Crouzon syndrome with acanthosis nigricans. This rare condition causes premature joining of the bones of the skull (craniosynostosis), leading to a misshapen head and distinctive facial features. It also causes a skin abnormality called acanthosis nigricans that is characterized by thick, dark, velvety skin in body folds and creases.

The genetic change that causes Crouzon syndrome with acanthosis nigricans replaces the amino acid alanine with the amino acid glutamic acid at a specific position in the FGFR3 protein (known as A391E). The altered protein is activated more easily than normal, and this overactivity disrupts the normal growth of the skull bones and skin, leading to features of Crouzon syndrome with acanthosis nigricans.

Epidermal nevus

Variants in the FGFR3 gene have been found in approximately 30 percent of people with a certain type of epidermal nevus (plural: nevi). Specifically, FGFR3 gene variants are associated with some keratinocytic epidermal nevi, which are abnormal skin growths that are composed of skin cells called keratinocytes. FGFR3 gene variants have not been found in people with other types of epidermal nevi.

The most common FGFR3 gene variant in people with epidermal nevi changes a single amino acid in the FGFR3 protein. This variant creates a protein that turns on without the help of a growth factor, which means that the FGFR3 protein is constantly active. Studies suggest that cells with this FGFR3 gene variant grow larger and divide more often than normal cells. The resulting overgrowth of skin cells leads to epidermal nevi.

The FGFR3 gene variant found in people with epidermal nevi also occur in people with another skin abnormality called seborrheic keratosis and in people with skeletal disorders known as thanatophoric dysplasia, Crouzon syndrome with acanthosis nigricans, and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN). However, in contrast to the skeletal conditions, the variants associated with epidermal nevi (and seborrheic keratosis) are somatic variants. Somatic gene variants are not inherited; they are acquired during a person's lifetime and are present only in certain cells. In epidermal nevi, the variants occur during the early stages of development and are present only in the cells of the nevus, not in the normal skin cells surrounding it.

Hypochondroplasia

Multiple variants in the FGFR3 gene have been identified in people with hypochondroplasia, another form of short-limbed dwarfism that is milder than achondroplasia. Many cases are caused by one of two specific FGFR3 gene variants, both of which lead to the same change in the FGFR3 protein. This change replaces the amino acid asparagine with the amino acid lysine at a specific position in the FGFR3 protein (known as N540K). Other FGFR3 gene variants probably cause a small number of cases of hypochondroplasia. These hypochondroplasia-associated variants probably cause the receptor to be mildly overactive, which leads to the disturbances in bone growth that occur in people with this disorder.

Lacrimo-auriculo-dento-digital syndrome

At least one variant in the FGFR3 gene has been found to cause lacrimo-auriculo-dento-digital (LADD) syndrome. The main features of LADD syndrome are abnormal tear production, malformed ears with hearing loss, decreased saliva production, small teeth, and hand deformities. The FGFR3 gene variant that causes LADD syndrome replaces the amino acid aspartic acid with the amino acid asparagine at a specific position in the receptor protein (known as D513N). When a growth factor attaches to this modified version of FGFR3 receptor protein, the protein has difficulty triggering the normal chemical signals within the cell. These defects in cell signaling disrupt cell maturation and development, which results in abnormal formation of the ears, the skeleton, and the glands in the eyes and mouth in people with LADD syndrome.

Muenke syndrome

A single variant in the FGFR3 gene has been shown to cause Muenke syndrome, which is a condition that causes craniosynostosis and leads to a misshapen head and distinctive facial features. Additional signs and symptoms can include hearing loss, subtle hand and foot abnormalities, and developmental delays. The variant that causes Muenke syndrome substitutes the amino acid arginine for the amino acid proline at a specific position in the FGFR3 protein (known as P250R). This variant results in the production of a receptor that is overly active, which allows the bones of the skull to fuse sooner than normal.

The FGFR3 gene variant that causes Muenke syndrome has also been identified in some people with isolated coronal craniosynostosis. This condition is characterized by a premature fusion of the growth line that runs across the top of the head from ear to ear (the coronal suture). People with isolated coronal craniosynostosis do not have the other features that are sometimes associated with Muenke syndrome (such as hand and foot abnormalities).

SADDAN

One variant in the FGFR3 gene has been identified in people with SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans). SADDAN is characterized by short-limb dwarfism (achondroplasia); profound developmental delay; and thick, dark, velvety skin. The genetic change that causes this condition substitutes the amino acid methionine for the amino acid lysine at a specific position in the FGFR3 protein (known as K650M). Researchers believe that this variant strongly overactivates the FGFR3 protein, which leads to severe problems with bone growth. It remains uncertain how the variant causes developmental delays or acanthosis nigricans.

Thanatophoric dysplasia

Variants in the FGFR3 gene have been identified in people with thanatophoric dysplasia, which is a severe skeletal disorder characterized by extremely short limbs and a narrow chest. Most individuals with thanatophoric dysplasia are stillborn or die shortly after birth.

Most of these FGFR3 gene variants change a single amino acid in the FGFR3 protein or create a protein that is longer than normal. These variants cause type I thanatophoric dysplasia.

Only one FGFR3 gene variant has been shown to cause type II thanatophoric dysplasia. This variant affects a different part of the FGFR3 protein than the variants that cause type I thanatophoric dysplasia.

The genetic changes responsible for both types of thanatophoric dysplasia cause the FGFR3 receptor to be overactive, which leads to the severe problems with bone growth that occur in people with this condition.

Bladder cancer

Somatic variants in the FGFR3 gene have been found in some cases of bladder cancer. Bladder cancer is a disease in which certain cells in the bladder 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. Approximately 80 percent of NMIBC tumors have FGFR3 gene variants. FGFR3 gene variants change single amino acids in the FGFR3 protein, which appears to overactivate protein signaling. As a result, bladder cells are likely directed to grow and divide abnormally. This uncontrolled cell division leads to bladder cancer.

Multiple myeloma

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Other disorders

At least two FGFR3 gene variants have been found to cause a rare disorder called camptodactyly, tall stature, hearing loss (CATSHL) syndrome. Individuals with this condition are taller than average and typically have hearing loss. They can also have permanently bent fingers or toes (camptodactyly) and other skeletal abnormalities. Researchers suggest that the FGFR3 gene variants involved in CATSHL syndrome reduce the function of the FGFR3 protein, although it is unclear how the variants cause the signs and symptoms of the condition.

Variants in the FGFR3 gene have been found in 30 to 70 percent of people with seborrheic keratoses, which are small, dark, noncancerous (benign) tumors of the skin caused by overgrowth of skin cells. Seborrheic keratoses develop in adulthood and are seen in a majority of people older than age 50. The FGFR3 gene variants associated with seborrheic keratoses are somatic variants, which means that they are only found in the tumors and are not inherited. These variants change single amino acids in the FGFR3 protein. The altered FGFR3 proteins are abnormally active, which results in the overgrowth of skin cells. It has been suggested that the variants involved in seborrheic keratosis may be caused by exposure to ultraviolet light.

A somatic FGFR3 gene mutation that causes epidermal nevus can also cause Garcia-Hafner-Happle syndrome (also known as fibroblast growth factor receptor 3 epidermal nevus syndrome). This condition is characterized by a soft, velvety keratinocytic epidermal nevus and neurological problems, such as seizures, intellectual disability, underdevelopment of the tissue that connects the two halves of the brain (corpus callosum), and a loss of brain cells (cortical atrophy). It is thought that the neurological problems occur because the somatic variant affects brain cells in addition to cells in the skin.

Other cancers

In addition to bladder cancer, somatic variants in the FGFR3 gene have been associated with a cancer of white blood cells (multiple myeloma) and cervical cancer. Some cases of multiple myeloma are related to rearrangements (translocations) of genetic material between chromosome 14 and the region of chromosome 4 that contains the FGFR3 gene. Variants that have been associated with cervical cancer are changes in single DNA building blocks (nucleotides) in the FGFR3 gene.

FGFR3 gene variants that lead to multiple myeloma and cervical cancer are thought to overactivate the FGFR3 protein in certain cells. The mutated receptor directs the cells to grow and divide in the absence of signals from outside the cell. This uncontrolled division can lead to the overgrowth of cancer cells.

Other Names for This Gene

• ACH
• CD333
• CEK2
• FGFR-3
• FGR3_HUMAN
• fibroblast growth factor receptor 3 (achondroplasia, thanatophoric dwarfism)
• HBGFR
• hydroxyaryl-protein kinase
• JTK4
• tyrosine kinase JTK4

Genomic Location

Normal Function

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

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

Health Conditions Related to Genetic Changes

Costello syndrome

At least 15 mutations in the HRAS gene have been identified in people with Costello syndrome, a rare condition that affects many parts of the body and increases the risk of developing cancerous and noncancerous tumors. The mutations change single protein building blocks (amino acids) in a critical region of the H-Ras protein. The most common mutation accounts for more than 80 percent of all cases of Costello syndrome; it replaces the amino acid glycine with the amino acid serine at protein position 12 (written as Gly12Ser or G12S).

The HRAS gene mutations that cause Costello syndrome lead to the production of an H-Ras protein that is abnormally turned on (active) in cells throughout the body. Instead of triggering cell growth in response to signals from outside the cell, the overactive protein directs cells to grow and divide constantly. This uncontrolled cell division can result in the formation of noncancerous and cancerous tumors. Researchers are uncertain how mutations in the HRAS gene cause the other features of Costello syndrome (such as intellectual disability, distinctive facial features, and heart problems), but many of the signs and symptoms probably result from cell overgrowth and abnormal cell division.

Epidermal nevus

Mutations in the HRAS gene are involved in the development of abnormal, noncancerous patches of skin called epidermal nevi (singular: nevus). These patches are caused by an overgrowth of cells in the outer layer of skin (the epidermis).

HRAS gene mutations have been found in a majority of people with a certain type of epidermal nevus called a nevus sebaceous. This type is classified as an organoid epidermal nevus because it involves cells that make up structures (or organs) in the skin, usually the hair follicles, the sweat glands, or the sebaceous glands (glands in the skin that produce a substance that protects the skin and hair). Additional tumors often develop in the region of the nevus sebaceous. In rare cases, these tumors are cancerous.

HRAS gene mutations are less commonly found in keratinocytic epidermal nevi, a type of epidermal nevus that involves a particular type of epidermal cell called a keratinocyte. Keratinocytic epidermal nevi are not typically associated with additional tumors.

Epidermal nevi are caused by gene mutations that are acquired during the early stages of development before birth. The mutations are present only in the cells of the nevus and not the normal skin cells surrounding it. These changes, which are called somatic mutations, are not inherited. The somatic HRAS gene mutations involved in epidermal nevi, change single amino acids in the H-Ras protein. The most common mutation replaces the amino acid glycine with the amino acid valine at protein position 12 (written as Gly12Val or G12V). These mutations lead to production of an H-Ras protein that is always turned on. The affected skin cells grow and divide more than normal cells, resulting in epidermal nevi.

Bladder cancer

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Head and neck squamous cell carcinoma

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Other disorders

Somatic HRAS gene mutations are also involved in development of Schimmelpenning syndrome, which is a type of epidermal nevus syndrome. Affected individuals have a type of epidermal nevus called nevus sebaceous (described above) in addition to abnormalities of the brain, eyes, or bones. Problems with these other systems can include seizures, intellectual disability, extra or missing pieces of tissue in eye structures (choristomas or colobomas), underdeveloped bones, and a disorder called rickets that leads to softening and weakening of the bones. Schimmelpenning syndrome is caused by the same gene mutations involved in epidermal nevus. It is thought that the additional signs and symptoms occur because the somatic mutation affects other tissues in addition to the skin.

Other cancers

Somatic mutations in the HRAS gene are probably involved in the development of several additional types of cancer. These mutations lead to a version of the H-Ras protein that is always active and can direct cells to grow and divide without control. Studies suggest that HRAS gene mutations may be common in thyroid and kidney cancers. Increased activity (expression) of the HRAS gene has also been reported in other types of cancer.

Other Names for This Gene

• C-H-RAS
• Harvey murine sarcoma virus oncogene
• Harvey rat sarcoma viral oncogene homolog
• HRAS1
• Oncogene, G-RAS
• RASH1
• RASH_HUMAN
• Transformation gene: Oncogene HaMSV
• Transforming protein P21/H-RAS-1 (C-H-RAS)
• v-Ha-ras Harvey rat sarcoma viral oncogene homolog

Genomic Location

Normal Function

The KDM6A gene provides instructions for making an enzyme called lysine-specific demethylase 6A that is found in many organs and tissues of the body. Lysine-specific demethylase 6A functions as a histone demethylase. Histone demethylases are enzymes that modify proteins called histones. Histones are structural proteins that attach (bind) to DNA and give chromosomes their shape. By removing a molecule called a methyl group from histones (a process called demethylation), histone demethylases control (regulate) the activity of certain genes. Lysine-specific demethylase 6A appears to regulate certain genes that are important for development.

Lysine-specific demethylase 6A is also believed to act as a tumor suppressor, which means it normally helps prevent cells from growing and dividing in an uncontrolled way.

Health Conditions Related to Genetic Changes

Kabuki syndrome

Many variants (also known as mutations) in the KDM6A gene have been identified in people with Kabuki syndrome, a disorder characterized by distinctive facial features, intellectual disability, and abnormalities affecting other parts of the body.

Most of the KDM6A gene variants associated with Kabuki syndrome remove (delete) genetic material in the KDM6A gene sequence or result in a premature stop signal that leads to an abnormally short lysine-specific demethylase 6A enzyme. As a result of these changes, the enzyme is nonfunctional. A lack of functional lysine-specific demethylase 6A enzyme disrupts its role in histone demethylation and impairs proper regulation of certain genes in many of the body's organs and tissues, resulting in the abnormalities of development and function characteristic of Kabuki syndrome.

Although lysine-specific demethylase 6A is believed to act as a tumor suppressor, a loss of this enzyme's function does not seem to increase cancer risk in people with Kabuki syndrome.

Bladder cancer

Some gene variants are acquired during a person's lifetime and are present only in certain cells. These changes, which are called somatic variants, are not inherited. Somatic variants in the KDM6A 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 to 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 KDM6A gene variants. These KDM6A gene variants change single protein building blocks (amino acids) in the enzyme, which appears to impair the enzyme's role in histone demethylation. As a result, regulation of certain genes in bladder cells is disrupted, which likely leads to uncontrolled cell division and the formation of bladder cancer.

Cancers

Somatic variants in the KDM6A gene have been identified in cancers of the breast, esophagus, colon, kidney, and brain, and cancers of blood-forming cells called myeloid leukemia and multiple myeloma. Most of these variants result in an abnormally short, nonfunctional lysine-specific demethylase 6A enzyme that cannot perform its role as a tumor suppressor, resulting in the development of cancer.

Other Names for This Gene

• bA386N14.2
• bA386N14.2 (ubiquitously transcribed X chromosome tetratricopeptide repeat protein (UTX))
• histone demethylase UTX
• KABUK2
• KDM6A_HUMAN
• lysine (K)-specific demethylase 6A
• lysine-specific demethylase 6A
• ubiquitously transcribed tetratricopeptide repeat protein X-linked
• ubiquitously-transcribed TPR gene on the X chromosome
• ubiquitously-transcribed TPR protein on the X chromosome
• UTX

Genomic Location

Normal Function

The KMT2D gene, also known as MLL2, provides instructions for making an enzyme called lysine-specific methyltransferase 2D that is found in many organs and tissues of the body. Lysine-specific methyltransferase 2D functions as a histone methyltransferase. Histone methyltransferases are enzymes that modify proteins called histones. Histones are structural proteins that attach (bind) to DNA and give chromosomes their shape. By adding a molecule called a methyl group to histones (a process called methylation), histone methyltransferases control (regulate) the activity of certain genes. Lysine-specific methyltransferase 2D appears to activate certain genes that are important for development.

Lysine-specific methyltransferase 2D is also believed to act as a tumor suppressor, which means it normally helps prevent cells from growing and dividing in an uncontrolled way.

Health Conditions Related to Genetic Changes

Kabuki syndrome

Hundreds of variants (also known as mutations) in the KMT2D gene have been identified in people with Kabuki syndrome, a disorder characterized by distinctive facial features, intellectual disability, and abnormalities affecting other parts of the body.

The KMT2D gene variants associated with Kabuki syndrome change one building block (amino acid) in the lysine-specific methyltransferase 2D enzyme, delete genetic material in the KMT2D gene sequence, or result in a premature stop signal that leads to an abnormally short enzyme. As a result of these changes, the enzyme is nonfunctional. A lack of functional lysine-specific methyltransferase 2D enzyme disrupts its role in histone methylation and impairs proper activation of certain genes in many of the body's organs and tissues, resulting in the abnormalities of development and function characteristic of Kabuki syndrome.

Although lysine-specific methyltransferase 2D is believed to be a tumor suppressor, a loss of this enzyme's function does not seem to increase cancer risk in people with Kabuki syndrome.

Bladder cancer

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Coloboma

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Cancers

Some gene variants occur during a person's lifetime. Such changes, which are called somatic variants, are present only in certain cells. Somatic variants in the KMT2D gene have been identified in certain cancers. These include medulloblastomas, which are cancerous brain tumors that occur in childhood, and blood-related cancers called lymphomas. Most of these variants result in an abnormally short, nonfunctional lysine-specific methyltransferase 2D enzyme that cannot perform its role as a tumor suppressor, resulting in the development of cancer.

Increased amounts of lysine-specific methyltransferase 2D and altered distribution of the enzyme within cells have been identified in cancerous tumors of the breast and colon. It is unknown whether these changes result primarily from increased activity (overexpression) of the KMT2D gene, extra copies of the gene in tumor cells, altered stability or processing of the enzyme, or other mechanisms. Excess amounts of lysine-specific methyltransferase 2D may disrupt the regulation of other genes. As a result, cells may grow and divide too quickly or in an uncontrolled way, leading to cancer.

Other Names for This Gene

• AAD10
• ALL1-related protein
• ALR
• CAGL114
• histone-lysine N-methyltransferase MLL2
• KMT2B
• lysine (K)-specific methyltransferase 2D
• lysine N-methyltransferase 2B
• MLL2
• MLL2_HUMAN
• MLL4
• myeloid/lymphoid or mixed-lineage leukemia 2
• TNRC21
• trinucleotide repeat containing 21

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

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Cowden syndrome

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Head and neck squamous cell carcinoma

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Lung cancer

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Ovarian cancer

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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 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

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Cholangiocarcinoma

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Head and neck squamous cell carcinoma

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Lung cancer

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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 RAF1 gene provides instructions for making a protein that 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).

The RAF1 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

Noonan syndrome

More than 25 mutations causing Noonan syndrome have been identified in the RAF1 gene. Noonan syndrome is characterized by mildly unusual facial characteristics, short stature, heart defects, bleeding problems, skeletal malformations, and many other signs and symptoms. The RAF1 gene mutations change single protein building blocks (amino acids) in the RAF1 protein. These changes increase protein activity and disrupt the regulation of the RAS/MAPK signaling pathway causing problems with cell division, apoptosis, cell differentiation, and cell migration. Researchers believe that this disruption in normal cell processes plays a role in the signs and symptoms of Noonan syndrome, specifically cardiac abnormalities. It has been noted that people with Noonan syndrome caused by a RAF1 gene mutation have a greater incidence of heart defects than other people with Noonan syndrome, specifically a condition called hypertrophic cardiomyopathy, which is a thickening of the heart muscle that forces the heart to work harder to pump blood.

Noonan syndrome with multiple lentigines

At least two mutations in the RAF1 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 RAF1 gene mutations change single amino acids in the RAF1 protein: One mutation replaces the amino acid serine with the amino acid leucine at position 257 (written Ser257Leu or S257L) and the other mutation replaces the amino acid leucine with the amino acid valine at position 613 (written Leu613Val or L613V).

The RAF1 gene changes that cause Noonan syndrome with multiple lentigines are believed to abnormally activate the RAF1 protein, which disrupts the regulation of the RAS/MAPK signaling pathway that controls cell functions such as growth and division. This misregulation can result in the various features of Noonan syndrome with multiple lentigines.

Bladder cancer

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Cancers

Some gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes are called somatic mutations and are not inherited. Somatic mutations in the RAF1 gene are involved in the development of several types of cancer. These mutations lead to a RAF1 protein that is always active and can direct cells to grow and divide uncontrollably. Studies suggest that RAF1 gene mutations may be found in ovarian, lung, and colorectal cancers. Somatic mutations in the RAF1 gene are a rare cause of cancer.

For reasons that are unclear, inherited mutations in the RAF1 gene do not appear to increase the risk of cancer in people with Noonan syndrome with multiple lentigines or Noonan syndrome (described above).

Other Names for This Gene

• c-Raf
• CRAF
• Oncogene RAF1
• raf proto-oncogene serine/threonine protein kinase
• Raf-1
• RAF1_HUMAN

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

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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 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

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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

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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

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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