BAP1 (BRCA1-associated protein 1) is a tumor suppressor gene that is commonly associated with the development of cancers such as mesothelioma, uveal melanoma, and other malignancies. BAP1 is located on chromosome 3p21.1 and encodes a deubiquitinating enzyme that plays a crucial role in DNA damage response and regulation of cell cycle progression. BAP1 loss-of-function mutations have been linked to a rare hereditary cancer syndrome called BAP1 tumor predisposition syndrome (BAP1-TPDS) or BAP1 cancer syndrome, which is characterized by the development of multiple malignancies in affected individuals.
BAP1-TPDS is caused by germline mutations in the BAP1 gene, which are inherited in an autosomal dominant manner. The syndrome is associated with an increased risk of developing various cancers, including mesothelioma, uveal melanoma, cutaneous melanoma, renal cell carcinoma, cholangiocarcinoma, and others. However, not all individuals with BAP1 mutations develop cancer, and the penetrance and expressivity of the syndrome can vary greatly among affected individuals.
The diagnosis of BAP1-TPDS is based on clinical and genetic criteria. The clinical diagnosis is usually established by the presence of multiple primary cancers or a family history of cancer consistent with an autosomal dominant pattern of inheritance. The genetic diagnosis is confirmed by the identification of a pathogenic germline BAP1 mutation in the affected individual or in a family member with a history of cancer.
The symptoms of BAP1-TPDS can vary depending on the type of cancer that develops in affected individuals. However, some general symptoms and signs that may be associated with the syndrome include:
Mesothelioma – This is a rare type of cancer that affects the lining of the lungs or abdomen. Symptoms may include chest pain, shortness of breath, cough, fatigue, weight loss, and others. Mesothelioma is strongly associated with exposure to asbestos, but individuals with BAP1 mutations may develop mesothelioma without a known exposure to asbestos.
Uveal melanoma – This is a rare type of cancer that develops in the eye. Symptoms may include blurred vision, floaters, or a dark spot on the iris. Uveal melanoma is often asymptomatic in its early stages, and routine eye exams are recommended for individuals with BAP1 mutations.
Cutaneous melanoma – This is a type of skin cancer that usually develops on sun-exposed areas of the skin. Symptoms may include a new or changing mole, a sore that does not heal, or a lump under the skin. Individuals with BAP1 mutations may have an increased risk of developing multiple primary melanomas.
Renal cell carcinoma – This is a type of kidney cancer that may cause symptoms such as blood in the urine, pain in the side or back, or a lump in the abdomen. Renal cell carcinoma is often asymptomatic in its early stages, and routine imaging studies may be recommended for individuals with BAP1 mutations.
Cholangiocarcinoma – This is a type of cancer that develops in the bile ducts. Symptoms may include jaundice, itching, abdominal pain, or weight loss. Cholangiocarcinoma is rare but may occur in individuals with BAP1 mutations.
The diagnosis of BAP1-TPDS is usually made by a genetic counselor or a medical geneticist who specializes in the diagnosis and management of hereditary cancer syndromes. The diagnostic process may include a detailed family history, a physical examination, imaging studies, and genetic testing. Genetic testing for BAP1 mutations typically involves sequencing the entire coding region of the gene to identify any pathogenic variants that may be present.
In conclusion, BAP1 tumor predisposition syndrome is a rare hereditary cancer syndrome that is associated with an increased risk of developing multiple malignancies, including mesothelioma, uveal melanoma, cutaneous melanoma, renal cell carcinoma, and cholangiocarcinoma. The diagnosis of BAP1-TPDS is based on clinical and genetic criteria, and genetic testing is recommended for individuals with a family history of cancer consistent with an autosomal dominant pattern of inheritance or for those with multiple primary cancers. Early detection and appropriate management of cancer in individuals with BAP1 mutations are crucial for improving outcomes and reducing cancer-related morbidity and mortality.