Melanoma is a type of skin cancer that begins in pigment-producing cells called melanocytes. This cancer typically occurs in areas that are only occasionally sun-exposed; tumors are most commonly found on the back in men and on the legs in women. Melanoma usually occurs on the skin (cutaneous melanoma), but in about 5 percent of cases it develops in melanocytes in other tissues, including the eyes (uveal melanoma) or mucous membranes that line the body's cavities, such as the moist lining of the mouth (mucosal melanoma). Melanoma can develop at any age, but it most frequently occurs in people in their fifties to seventies and is becoming more common in teenagers and young adults.

Melanoma may develop from an existing mole or other normal skin growth that becomes cancerous (malignant); however, many melanomas are new growths. Melanomas often have ragged edges and an irregular shape. They can range from a few millimeters to several centimeters across. They can also be a variety of colors: brown, black, red, pink, blue, or white.

Most melanomas affect only the outermost layer of skin (the epidermis). If a melanoma becomes thicker and involves multiple layers of skin, it can spread to other parts of the body (metastasize).

A large number of moles or other pigmented skin growths on the body, generally more than 25, is associated with an increased risk of developing melanoma. Melanoma is also a common feature of genetic syndromes affecting the skin such as xeroderma pigmentosum. Additionally, individuals who have previously had melanoma are nearly nine times more likely than the general population to develop melanoma again. It is estimated that about 90 percent of individuals with melanoma survive at least 5 years after being diagnosed.

In the United States, melanoma is the fifth most common cancer in men, affecting 30 in 100,000 men per year, and the sixth most common cancer in women, affecting 18 in 100,000 women per year. About 1 in 43 individuals in the United States will develop melanoma in their lifetime. Light-skinned people have a 20 times greater risk of developing melanoma than dark-skinned people.

Melanoma is caused by a combination of environmental and genetic factors. The greatest environmental risk factor for developing melanoma is exposure to ultraviolet (UV) radiation from the sun. The risk for melanoma is greatest in individuals who have brief but intense sun exposure rather than moderate, long-term exposure. UV radiation can also come from tanning beds (indoor tanning).

UV radiation damages DNA. Most of the time, this kind of DNA damage causes cells to self-destruct (undergo apoptosis) or permanently stop cell division (undergo senescence). However, melanocytes are more resistant than other kinds of cells to the effects of UV radiation. Even if their DNA is damaged, melanocytes are unlikely to undergo apoptosis. As abnormal melanocytes continue to grow, they accumulate genetic mutations, particularly in genes that control cell growth and division (proliferation), senescence, and apoptosis. Ultimately, the cells become able to proliferate without control or limit and can resist cell death, leading to the formation and growth of a melanoma.

Most cases of melanoma are sporadic, which means that the genetic changes are acquired during a person's lifetime and are present only in the melanocytes that give rise to the melanoma. These changes, which are called somatic mutations, are not inherited. Studies suggest that in some cases somatic variations in multiple genes, each with a small effect, combine to increase the risk of developing the condition. Many of these gene variations are associated with a light complexion and increased freckling and moles. However, it is unclear what contribution each of these genetic changes makes to disease risk. Other somatic gene mutations have large effects on melanoma risk and a mutation in one gene is enough to significantly increase the risk of developing cancer. Somatic mutations in the BRAF and CDKN2A genes are some of the most common in sporadic melanoma.

In about 10 percent of cases, melanoma occurs in multiple members of the same family. Unlike sporadic melanoma, these familial cases are typically caused by inherited genetic changes that increase the risk of developing this type of cancer. These genetic changes, which are classified as germline mutations, are present in essentially all of the body's cells. The primary genes involved in familial melanoma are CDKN2A and MC1R. The CDKN2A gene plays a role in regulating cell senescence and the MC1R gene influences skin pigmentation. Shared nongenetic factors can also influence the development of melanoma in family members; for example, family members may live in the same sun-exposed environment. In people with germline mutations, changes in other genes, together with environmental and lifestyle factors, also contribute to the possible development of melanoma.

Most cases of melanoma are sporadic, which means that they occur in people with no apparent history of the disorder in their family. When the disorder is familial, it can be due to shared environmental factors or shared genetic factors or both. The genetic factors are usually inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to increase the risk of developing melanoma.

When melanoma occurs as part of a genetic syndrome, the risk of melanoma follows the inheritance pattern of the syndrome.

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.

Bladder cancer

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Breast cancer

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Melanoma

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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 BAP1 gene provides instructions for making a protein called ubiquitin carboxyl-terminal hydrolase BAP1 (shortened to BAP1). This protein functions as a deubiquitinase, which means it removes a molecule called ubiquitin from certain proteins. The presence of ubiquitin molecules on a protein can affect the activity of the protein and its interactions with other proteins. The ubiquitin "tag" also promotes breakdown (degradation) of a protein. By removing ubiquitin, BAP1 helps regulate the function of many proteins involved in diverse cellular processes. The BAP1 protein is thought to help control cell growth and division (proliferation) and cell death. Studies suggest that it is involved in the progression of cells through the step-by-step process they take to replicate themselves (called the cell cycle) and that it plays roles in repairing damaged DNA and controlling the activity of genes.

Although the exact mechanism is unclear, the BAP1 protein acts as a tumor suppressor. Tumor suppressor proteins help prevent cells from growing and dividing too rapidly or in an uncontrolled way.

Health Conditions Related to Genetic Changes

BAP1 tumor predisposition syndrome

Mutations in the BAP1 gene cause BAP1 tumor predisposition syndrome. People with this condition have an increased risk of developing many types of noncancerous (benign) and cancerous (malignant) tumors, particularly certain tumors of the skin (atypical Spitz tumors, cutaneous melanoma, and basal cell carcinoma); eyes (uveal melanoma); kidneys (clear cell renal cell carcinoma); and a tissue called the mesothelium that lines the chest, abdomen, and internal organs (malignant mesothelioma). Researchers are still determining whether other forms of cancer are linked to BAP1 tumor predisposition syndrome.

Affected individuals inherit a mutation in one copy of the BAP1 gene. These mutations, which are present in essentially every cell of the body, are classified as germline mutations. Most germline BAP1 gene mutations lead to an abnormally short BAP1 protein that is likely broken down prematurely. Other germline mutations change single protein building blocks (amino acids) in the BAP1 protein and likely impair its function. In most cases, a second, non-inherited (somatic) mutation occurs in the normal copy of the gene in cells that give rise to tumors. Together, the germline and somatic mutations lead to a loss of BAP1 protein function in tumor cells.

Reduction or loss of this protein's function likely prevents the removal of ubiquitin molecules from certain proteins. Although it is unclear exactly how changes in BAP1 function lead to BAP1 tumor predisposition syndrome, researchers speculate that altered activity of proteins normally regulated by BAP1 deubiquitination may promote cell proliferation or survival, resulting in tumor formation.

Cholangiocarcinoma

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Melanoma

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Other cancers

Somatic BAP1 gene mutations have been found in uveal melanoma, malignant mesothelioma, and clear cell renal cell carcinoma tumors in the absence of a germline BAP1 gene mutation. In these cases, the cancers occur in people with no family history of the cancer and are considered sporadic. Affected individuals do not develop additional tumor types associated with BAP1 tumor predisposition syndrome (described above).

Other Names for This Gene

• BRCA1 associated protein-1 (ubiquitin carboxy-terminal hydrolase)
• cerebral protein 6
• cerebral protein-13
• HUCEP-13
• hucep-6
• KIAA0272
• ubiquitin carboxyl-terminal hydrolase BAP1
• UCHL2

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

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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

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Gastrointestinal stromal tumor

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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

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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.

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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

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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 MC1R gene provides instructions for making a protein called the melanocortin 1 receptor. This receptor plays an important role in normal pigmentation. The receptor is primarily located on the surface of melanocytes, which are specialized cells that produce a pigment called melanin. Melanin is the substance that gives skin, hair, and eyes their color. Melanin is also found in the light-sensitive tissue at the back of the eye (the retina), where it plays a role in normal vision.

Melanocytes make two forms of melanin, eumelanin and pheomelanin. The relative amounts of these two pigments help determine the color of a person's hair and skin. People who produce mostly eumelanin tend to have brown or black hair and dark skin that tans easily. Eumelanin also protects skin from damage caused by ultraviolet (UV) radiation in sunlight. People who produce mostly pheomelanin tend to have red or blond hair, freckles, and light-colored skin that tans poorly. Because pheomelanin does not protect skin from UV radiation, people with more pheomelanin have an increased risk of skin damage caused by sun exposure.

The melanocortin 1 receptor controls which type of melanin is produced by melanocytes. When the receptor is activated, it triggers a series of chemical reactions inside melanocytes that stimulate these cells to make eumelanin. If the receptor is not activated or is blocked, melanocytes make pheomelanin instead of eumelanin.

Common variations (polymorphisms) in the MC1R gene are associated with normal differences in skin and hair color. Certain genetic variations are most common in people with red hair, fair skin, freckles, and an increased sensitivity to sun exposure. These MC1R polymorphisms reduce the ability of the melanocortin 1 receptor to stimulate eumelanin production, causing melanocytes to make mostly pheomelanin. Although MC1R is a key gene in normal human pigmentation, researchers believe that the effects of other genes also contribute to a person's hair and skin coloring.

The melanocortin 1 receptor is also active in cells other than melanocytes, including cells involved in the body's immune and inflammatory responses. The receptor's function in these cells is unknown.

Health Conditions Related to Genetic Changes

Melanoma

Certain variations in the MC1R gene increase the risk of developing melanoma, a type of skin cancer that begins in melanocytes. These variations reduce the ability of the melanocortin 1 receptor to stimulate eumelanin production in melanocytes, resulting in fair skin. Because eumelanin normally protects skin from the harmful effects of UV radiation, a lack of this pigment leaves skin more vulnerable to damage from sun exposure. Skin damage caused by UV radiation from the sun is a major risk factor for developing melanoma.

Studies suggest that other variations in the MC1R gene may also increase the risk of developing melanoma in the absence of UV radiation-related skin damage. In these cases, melanomas can occur in people of dark or light skin coloring. These cancers are often associated with mutations in additional genes related to melanoma risk, such as the BRAF and CDKN2A genes. Researchers are working to explain the complex relationship among MC1R variations, other genetic and environmental factors, and melanoma risk.

Oculocutaneous albinism

Certain genetic changes in the MC1R gene modify the appearance of people with oculocutaneous albinism type 2. This form of albinism, which is caused by mutations in the OCA2 gene, is characterized by fair hair, light-colored eyes, creamy white skin, and vision problems. People with genetic changes in both the OCA2 and MC1R genes have many of the usual features of oculocutaneous albinism type 2; however, they typically have red hair instead of the usual yellow, blond, or light brown hair seen with this condition.

Other Names for This Gene

• MC1-R
• melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor)
• Melanocortin-1 receptor
• melanocyte stimulating hormone receptor
• melanotropin receptor
• MSH-R
• MSHR_HUMAN

Genomic Location

Normal Function

The MITF gene provides instructions for making a protein called melanocyte inducing transcription factor. This protein plays a role in the development, survival, and function of certain types of cells. To carry out this role, the protein attaches to specific areas of DNA and helps control the activity of particular genes. On the basis of this action, the protein is called a transcription factor.

Melanocyte inducing transcription factor helps control the development and function of pigment-producing cells called melanocytes. Within these cells, this protein controls production of the pigment melanin, which contributes to hair, eye, and skin color. Melanocytes are also found in the inner ear and play an important role in hearing. Additionally, melanocyte inducing transcription factor regulates the development of specialized cells in the eye called retinal pigment epithelial cells. These cells nourish the retina, the part of the eye that detects light and color. Some research indicates that melanocyte inducing transcription factor also regulates the development of cells that break down and remove bone (osteoclasts) and cells that play a role in allergic reactions (mast cells).

The structure of melanocyte inducing transcription factor includes three critically important regions. Two of the regions, called the helix-loop-helix motif and the leucine-zipper motif, are critical for protein interactions. These motifs allow molecules of melanocyte inducing transcription factor to interact with each other or with other proteins that have a similar structure, creating a two-protein unit (dimer) that functions as a transcription factor. The other region, known as the basic motif, binds to specific areas of DNA, allowing the dimer to control gene activity.

Health Conditions Related to Genetic Changes

Melanoma

MITF gene variants (also called mutations) have also been found in people with an aggressive form of skin cancer called melanoma. Most of these variants are somatic, meaning that they occur during a person's lifetime and are present only in cells that give rise to the melanoma. Occasionally the variant is inherited and is found in every cell of the body (known as a germline variant).

Some of the MITF gene variants associated with melanoma increase cell growth and division (proliferation) directly. Other variants have an indirect effect, increasing the activity (expression) of other genes involved in proliferation and resulting in the abnormal cell growth that occurs in melanoma.

Tietz syndrome

MITF gene variants have been identified in people with Tietz syndrome, which is characterized by profound hearing loss from birth, fair skin, and light-colored hair. Researchers suggest that Tietz syndrome may be a severe form of Waardenburg syndrome (described below).

The MITF gene variants that cause Tietz syndrome either delete or change a single protein building block (amino acid) in the basic motif region of the melanocyte inducing transcription factor structure. Dimers incorporating the abnormal melanocyte inducing transcription factor cannot be transported into the cell nucleus to bind with DNA. As a result, most of the dimers are unavailable to bind to DNA, which affects the development of melanocytes and the production of melanin. The resulting reduction or absence of melanocytes in the inner ear leads to hearing loss. Decreased melanin production (hypopigmentation) accounts for the light skin and hair color that are characteristic of Tietz syndrome.

Waardenburg syndrome

Variants in the MITF gene have been identified in people with Waardenburg syndrome type II, a disorder that can cause hearing loss and changes in coloring (pigmentation) of the hair, skin, and eyes. Some MITF gene variants change the amino acids used to make melanocyte inducing transcription factor, which alters the helix-loop-helix or leucine-zipper motif. Other variants result in an abnormally small version of the protein. Researchers believe that both types of variant disrupt the formation of dimers. Although some dimers are produced, the amount is insufficient for full development of melanocytes. As a result, there is a shortage of melanocytes in certain areas of the skin, hair, eyes, and inner ear. This shortage leads to hearing loss and the patchy loss of pigmentation associated with Waardenburg syndrome.

Other Names for This Gene

• homolog of mouse microphthalmia
• melanogenesis associated transcription factor
• microphthalmia-associated transcription factor
• MITF_HUMAN
• WS2A

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

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Autoimmune lymphoproliferative syndrome

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Cholangiocarcinoma

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Core binding factor acute myeloid leukemia

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Cytogenetically normal acute myeloid leukemia

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Epidermal nevus

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Lung cancer

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Melanoma

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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 OCA2 gene (formerly called the P gene) provides instructions for making a protein called the P protein. This protein is located in melanocytes, which are specialized cells that produce a pigment called melanin. Melanin is the substance that gives skin, hair, and eyes their color. Melanin is also found in the light-sensitive tissue at the back of the eye (the retina), where it plays a role in normal vision.

Although the exact function of the P protein is unknown, it is essential for normal pigmentation and is likely involved in the production of melanin. Within melanocytes, the P protein may transport molecules into and out of structures called melanosomes (where melanin is produced). Researchers believe that this protein may also help regulate the relative acidity (pH) of melanosomes. Tight control of pH is necessary for most biological processes.

Health Conditions Related to Genetic Changes

Angelman syndrome

The OCA2 gene is located in a region of chromosome 15 that is often deleted in individuals with Angelman syndrome. A loss of this gene does not cause the characteristic neurologic features of Angelman syndrome; however, people with this condition who are missing one copy of the OCA2 gene tend to have unusually light-colored hair and fair skin. Cells with only one copy of the OCA2 gene make a reduced amount of P protein compared with cells with two functional copies of this gene, which affects the coloring of the hair and skin.

A small percentage of people with Angelman syndrome also have oculocutaneous albinism type 2. This condition occurs when people have two nonfunctional copies of the OCA2 gene in each cell. In addition to a deletion in chromosome 15 that removes one copy of the OCA2 gene, these individuals have a variant (also known as a mutation) in the OCA2 gene on the other copy of chromosome 15. As a result, cells make little or no functional P protein. A lack of P protein disrupts the production of melanin, leading to the characteristic features of albinism.

Oculocutaneous albinism

More than 80 variants in the OCA2 gene have been identified in people with oculocutaneous albinism type 2. People with this form of albinism often have light yellow, blond, or light brown hair; creamy white skin; light-colored eyes; and problems with vision. The most common OCA2 variant is a large deletion in the gene, which is found in many affected individuals of sub-Saharan African heritage. Other OCA2 gene variants, including changes in single DNA building blocks (base pairs) and small deletions, are more common in other populations. Variants in the OCA2 gene disrupt the normal production of melanin, which reduces coloring of the hair, skin, and eyes and affects vision.

Prader-Willi syndrome

The region of chromosome 15 containing the OCA2 gene is often deleted in individuals with Prader-Willi syndrome. A loss of this gene does not cause intellectual disability and the other characteristic features of Prader-Willi syndrome; however, people with this condition who are missing one copy of the OCA2 gene tend to have unusually light-colored hair and fair skin. Cells missing a copy of the OCA2 gene make less P protein than cells with two functional copies of the gene, which affects the coloring of the hair and skin.

Oculocutaneous albinism type 2 also occurs in a small number of people with Prader-Willi syndrome. This condition occurs when people have two nonfunctional copies of the OCA2 gene in each cell. In addition to a deletion in chromosome 15 that removes one copy of the OCA2 gene, these individuals have a variant in the OCA2 gene on the other copy of chromosome 15. As a result, cells make little or no functional P protein. A lack of P protein disrupts the production of melanin, leading to the characteristic features of albinism.

Melanoma

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Other Names for This Gene

• BOCA
• Melanocyte-specific transporter protein
• oculocutaneous albinism II
• oculocutaneous albinism II (pink-eye dilution homolog, mouse)
• P gene
• P_HUMAN
• PED
• Pink-eyed dilution protein homolog

Genomic Location

Normal Function

The PLA2G6 gene provides instructions for making a type of enzyme called an A2 phospholipase. This type of enzyme is involved in breaking down (metabolizing) fats called phospholipids. Phospholipid metabolism is important for many body processes, including helping to maintain the integrity of the cell membrane. Specifically, the A2 phospholipase produced from the PLA2G6 gene, sometimes called PLA2 group VI, helps to regulate the levels of a compound called phosphatidylcholine, which is abundant in the cell membrane.

Health Conditions Related to Genetic Changes

Infantile neuroaxonal dystrophy

At least 50 mutations in the PLA2G6 gene have been identified in people with infantile neuroaxonal dystrophy, a progressive neurological disorder that causes intellectual disability and movement problems. Mutations in the PLA2G6 gene eliminate or severely impair the function of the PLA2 group VI enzyme. Impairment of PLA2 group VI enzyme function may disrupt cell membrane maintenance and contribute to the development of swellings called spheroid bodies in the axons, which are fibers that extend from nerve cells (neurons) and transmit impulses to muscles and other neurons. Although it is unknown how changes in this enzyme's function lead to the signs and symptoms of infantile neuroaxonal dystrophy, phospholipid metabolism problems have been seen in both this disorder and a similar disorder called pantothenate kinase-associated neurodegeneration. These disorders, as well as the more common Alzheimer's disease and Parkinson's disease, also are associated with changes in brain iron metabolism. Researchers are studying the links between phospholipid defects, brain iron, and damage to nerve cells, but have not determined how the iron accumulation that occurs in some individuals with infantile neuroaxonal dystrophy may contribute to the features of this disorder.

Melanoma

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Other disorders

PLA2G6 gene mutations can also cause atypical neuroaxonal dystrophy and PLA2G6-related dystonia-parkinsonism, which are conditions in which deterioration of neurological function (neurodegeneration) occurs later in life. The term PLA2G6-associated neurodegeneration (PLAN) is often used to include the entire spectrum of neurodegenerative disorders caused by mutations in PLA2G6.

Atypical neuroaxonal dystrophy (atypical NAD) is a disorder with signs and symptoms that are similar to those of infantile neuroaxonal dystrophy (described above) but that occur later and progress more slowly. Atypical NAD usually appears in early childhood but in some cases is not evident until the teenage years.

PLA2G6-related dystonia-parkinsonism is also caused by PLA2G6 gene mutations and involves movement abnormalities that occur in adulthood. Dystonia is involuntary tensing of the muscles, and parkinsonism comprises a group of movement problems including unusually slow movement (bradykinesia), muscle rigidity, tremors, and an inability to hold the body upright and balanced (postural instability).

Both of these later-onset conditions are caused by PLA2G6 gene mutations that are believed to have a less severe effect on PLA2 group VI enzyme function than the mutations that cause infantile neuroaxonal dystrophy.

Other Names for This Gene

• CaI-PLA2
• calcium-independent phospholipase A2
• cytosolic, calcium-independent phospholipase A2
• GVI
• INAD1
• iPLA2
• iPLA2beta
• NBIA2
• OTTHUMP00000028877
• PA2G6_HUMAN
• PARK14
• patatin-like phospholipase domain containing 9
• phospholipase A2, group VI
• phospholipase A2, group VI (cytosolic, calcium-independent)
• PLA2
• PNPLA9

Genomic Location

Normal Function

The SLC45A2 gene (also called MATP) provides instructions for making a protein that is located in specialized cells called melanocytes. These cells produce a pigment called melanin, which is the substance that gives skin, hair, and eyes their color. Melanin is also found in the light-sensitive tissue at the back of the eye (the retina), where it plays a role in normal vision.

Although the exact function of the SLC45A2 protein is unknown, it is likely involved in the production of melanin. This protein probably transports molecules necessary for the normal function of melanosomes, which are the structures in melanocytes where melanin is produced. Studies suggest that certain common variations (polymorphisms) in the SLC45A2 gene may be associated with normal differences in skin, hair, and eye coloring.

Health Conditions Related to Genetic Changes

Oculocutaneous albinism

More than 20 mutations in the SLC45A2 gene are responsible for oculocutaneous albinism type 4. The most common SLC45A2 mutation in the Japanese population switches a single protein building block (amino acid) in the SLC45A2 protein. Specifically, this mutation replaces the amino acid aspartic acid with the amino acid asparagine at protein position 157 (written as Asp157Asn or D157N). Other mutations, including changes in single amino acids and deletions or insertions of genetic material in the SLC45A2 gene, have also been reported in several populations worldwide. Mutations in this gene reduce or eliminate the function of the SLC45A2 protein in melanin production. Because this protein is important for normal pigmentation, its loss leads to changes in skin, hair, and eye coloration and problems with vision that are characteristic of oculocutaneous albinism type 4.

Melanoma

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Other Names for This Gene

• AIM-1
• AIM1
• MATP
• melanoma antigen AIM1
• membrane associated transporter
• membrane-associated transporter protein
• S45A2_HUMAN
• solute carrier family 45, member 2

Genomic Location

Normal Function

The TERT gene provides instructions for making one component of an enzyme called telomerase. Telomerase maintains structures called telomeres, which are composed of repeated segments of DNA found at the ends of chromosomes. Telomeres protect chromosomes from abnormally sticking together or breaking down (degrading). In most cells, telomeres become progressively shorter as the cell divides. After a certain number of cell divisions, the telomeres become so short that they trigger the cell to stop dividing or to self-destruct (undergo apoptosis). Telomerase counteracts the shortening of telomeres by adding small repeated segments of DNA to the ends of chromosomes each time the cell divides.

In most types of cells, telomerase is either undetectable or active at very low levels. However, telomerase is highly active in cells that divide rapidly, such as cells that line the lungs and gastrointestinal tract, cells in bone marrow, and cells of the developing fetus. Telomerase allows these cells to divide many times without becoming damaged or undergoing apoptosis. Telomerase is also abnormally active in most cancer cells, which grow and divide without control or order.

The telomerase enzyme consists of two major components that work together. The component produced from the TERT gene is known as hTERT. The other component is produced from a gene called TERC and is known as hTR. The hTR component provides a template for creating the repeated sequence of DNA that telomerase adds to the ends of chromosomes. The hTERT component then adds the new DNA segment to chromosome ends.

Health Conditions Related to Genetic Changes

Dyskeratosis congenita

At least 40 mutations in the TERT gene have been identified in people with dyskeratosis congenita. This disorder is characterized by changes in skin coloring (pigmentation), white patches inside the mouth (oral leukoplakia), and abnormally formed fingernails and toenails (nail dystrophy). People with dyskeratosis congenita have an increased risk of developing several life-threatening conditions, including cancer and a progressive lung disease called pulmonary fibrosis. Many affected individuals also develop a serious condition called aplastic anemia, also known as bone marrow failure, which occurs when the bone marrow does not produce enough new blood cells.

Most of the TERT gene mutations that cause dyskeratosis congenita change single protein building blocks (amino acids) in the hTERT protein, causing it to be unstable or dysfunctional. The mutations interfere with telomerase function, leading to impaired maintenance of telomeres and reduced telomere length. Cells that divide rapidly are especially vulnerable to the effects of shortened telomeres. As a result, people with dyskeratosis congenita may experience a variety of problems affecting quickly dividing cells in the body such as cells of the nail beds, hair follicles, skin, lining of the mouth (oral mucosa), and bone marrow.

Breakage and instability of chromosomes resulting from inadequate telomere maintenance may lead to genetic changes that allow cells to divide in an uncontrolled way, resulting in the development of cancer in some people with dyskeratosis congenita.

Idiopathic pulmonary fibrosis

At least 70 mutations in the TERT gene have been identified in people with the progressive lung disease idiopathic pulmonary fibrosis. This condition causes scar tissue (fibrosis) to build up in the lungs, which makes the lungs unable to transport oxygen into the bloodstream effectively. Mutations in the TERT gene have been found in cases that run in families (familial pulmonary fibrosis) and, less commonly, in isolated (sporadic) cases. Some individuals with idiopathic pulmonary fibrosis due to TERT gene mutations have family members with other features of dyskeratosis congenita (described above), such as aplastic anemia or cancer.

Mutations in the TERT gene reduce or eliminate the function of telomerase, which allows telomeres to become abnormally short as cells divide. The shortened telomeres likely trigger cells that divide rapidly, such as cells that line the inside of the lungs, to stop dividing or to die prematurely. In people with idiopathic pulmonary fibrosis, shorter telomeres are associated with a more severe disease and a quicker decline in lung function. Additional research is needed to confirm how shortened telomeres contribute to the progressive scarring and lung damage characteristic of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis is a complex disease that is probably caused by a combination of genetic and environmental factors. Studies suggest that many affected people with TERT gene mutations may have also been exposed to environmental risk factors, such as cigarette smoke or certain kinds of dust or fumes. It is possible that mutations in the TERT gene increase a person's risk of developing idiopathic pulmonary fibrosis, and then exposure to certain environmental factors can trigger the disease.

Breast cancer

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Cholangiocarcinoma

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Melanoma

Mutations in the TERT gene have been associated with an increased risk of a type of skin cancer called melanoma. Researchers suggest that these mutations may impair telomere maintenance and result in DNA damage. Damage to genes that help control the growth and development of cells can cause uncontrolled cell growth and lead to development of cancer.

Cancers

Mutations in the TERT gene have also been associated with an increased risk of a form of blood cancer called acute myeloid leukemia. As in melanoma (described above), researchers think changes in the TERT gene may impair telomere maintenance, which leads to DNA damage. Damage to genes that help control the growth and development of blood cells can cause uncontrolled cell growth and promote the development of leukemia.

Other disorders

TERT gene mutations have also been found in people with isolated aplastic anemia, a form of bone marrow failure that occurs without the other physical features of dyskeratosis congenita (described above). Researchers suggest that mutations affecting different parts of the telomerase enzyme may account for the absence of these features. Some believe that isolated aplastic anemia caused by TERT gene mutations may actually represent a late-onset form of dyskeratosis congenita in which physical features such as nail dystrophy are mild and may not be noticeable.

Other Names for This Gene

• EST2
• hEST2
• TCS1
• telomerase catalytic subunit
• telomerase-associated protein 2
• TERT_HUMAN
• TP2
• TRT

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

Normal Function

The TYR gene provides instructions for making an enzyme called tyrosinase. This enzyme is located in melanocytes, which are specialized cells that produce a pigment called melanin. Melanin is the substance that gives skin, hair, and eyes their color. Melanin is also found in the light-sensitive tissue at the back of the eye (the retina), where it plays a role in normal vision.

Tyrosinase is responsible for the first step in melanin production. It converts a protein building block (amino acid) called tyrosine to another compound called dopaquinone. A series of additional chemical reactions convert dopaquinone to melanin in the skin, hair follicles, the colored part of the eye (the iris), and the retina.

Health Conditions Related to Genetic Changes

Oculocutaneous albinism

More than 100 mutations in the TYR gene have been identified in people with oculocutaneous albinism type 1. These mutations disrupt the normal production of melanin, which reduces coloring of the hair, skin, and eyes and causes problems with vision. Most TYR mutations eliminate the activity of tyrosinase, preventing melanocytes from producing any melanin throughout life. These mutations cause a form of oculocutaneous albinism called type 1A (OCA1A). People with this form of albinism have white hair, light-colored eyes, and very pale skin that does not tan. Other mutations in the TYR gene reduce but do not eliminate tyrosinase activity. These mutations, which allow some melanin to be produced, cause oculocutaneous albinism type 1B (OCA1B). People with type 1B are also born with white hair, light-colored eyes, and pale skin, but hair and eye color often darken over time and skin may tan.

Melanoma

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Other Names for This Gene

• LB24-AB
• Monophenol monooxygenase
• OCA1A
• OCAIA
• SK29-AB
• Tumor Rejection Antigen AB
• TYRO_HUMAN

Genomic Location

Normal Function

The TYRP1 gene provides instructions for making an enzyme called tyrosinase-related protein 1. This enzyme is located in melanocytes, which are specialized cells that produce a pigment called melanin. Melanin is the substance that gives skin, hair, and eyes their color. Melanin is also found in the light-sensitive tissue at the back of the eye (the retina), where it plays a role in normal vision.

Tyrosinase-related protein 1 is involved in the production of melanin, although its exact functions are unclear. Studies suggest that this enzyme may help stabilize tyrosinase, which is the enzyme responsible for the first step in melanin production. Tyrosinase-related protein 1 may also help determine the shape of melanosomes, which are the structures in melanocytes where melanin is produced.

Health Conditions Related to Genetic Changes

Oculocutaneous albinism

A small number of mutations in the TYRP1 gene have been found to cause oculocutaneous albinism type 3. This condition includes a form of albinism called rufous oculocutaneous albinism, which has been described primarily in dark-skinned people from southern Africa. Affected individuals have reddish-brown skin, ginger or red hair, and hazel or brown irises. Two TYRP1 mutations are known to cause this form of albinism in individuals from Africa. One mutation replaces a protein building block (amino acid) in tyrosine-related protein 1 with a signal that prematurely stops protein production. This mutation, written as Ser166Ter or S166X, affects the amino acid serine at protein position 166. The other mutation, written as 368delA, deletes a single DNA building block from the TYRP1 gene. Other alterations in this gene have been reported in a few affected people of non-African heritage. Most TYRP1 mutations lead to the production of an abnormally short, nonfunctional version of tyrosinase-related protein 1. Because this enzyme plays a role in normal pigmentation, its loss leads to the changes in skin, hair, and eye coloration that are characteristic of oculocutaneous albinism.

Melanoma

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Other Names for This Gene

• b-PROTEIN
• CAS2
• Catalase B
• CATB
• DHICA oxidase
• Glycoprotein 75
• GP75
• TRP
• TRP-1
• tyrosinase-related protein 1
• TYRP
• TYRP1_HUMAN

Genomic Location