What Is an Inherited BAP1 Mutation? Cancer Surveillance and Treatment Guidance for Carriers

The BAP1 (BRCA1 Associated Protein 1) geneis a tumor suppressor gene that helps prevent cancer by regulating cell growth, DNA repair and cell death (apoptosis) . BAP1 mutations have been associated with cancers, including mesothelioma, uveal melanoma, cutaneous melanoma, and renal cell carcinoma . People with inherited BAP1 Tumor Predisposition Syndrome (BAP1-TPDS) have an increased lifetime risk of certain cancers.

General Information About Inherited BAP1 Mutations

• In the BAP1 gene, germline pathogenic variants (GPVs—including class 4 likely pathogenic and class 5 pathogenic variants) are associated with BAP1 tumor predisposition syndrome (BAP1-TPDS) (OMIM #614327), which follows an autosomal dominant inheritance pattern.
• Heterozygous BAP1 carriershave an increased lifetime risk of pleural and peritoneal mesothelioma, renal cell carcinoma, uveal and cutaneous melanoma and BAP1-inactivated melanocytic tumors (BIMTs) . These cancers are considered the core tumors of BAP1-TPDS.
• The risk of meningioma may be increased, but meningioma is not currently considered a core BAP1-associated tumor.
• For hepatocellular carcinoma, cholangiocarcinoma or other cancers, a definitive association with BAP1 has not yet been confirmed. However, an association with rhabdoid meningioma has been proposed.
• The overall lifetime cancer risk may reach 85%, although ascertainment bias may have led to an overestimate.
• Cancers generally develop at a younger age than in the general population and uveal melanoma, cutaneous melanoma, and renal cell carcinoma may be associated with poorer outcomes. However, some evidence suggests heterozygous BAP1 carriers may have a better prognosis in mesothelioma .

Associated Cancer Risks

The table above summarizes, for people carrying BAP1 mutations, the lifetime risks of particular cancers and the age ranges at diagnosis.

Management Recommendations

Surveillance:

• Kidney Cancer:

  • Annual kidney imaging is recommended from age 30.
  • The preferred method is MRI. If MRI is unavailable, kidney ultrasound may be an alternative.
  • MRI is recommended for ongoing monitoring of a known lesion.
  • Clinical genetics specialists should be consulted to arrange kidney cancer surveillance.

• Uveal Melanoma:

  • Annual dilated eye examinations are recommended from ages 16-18.
  • The examination should be performed by an ocular oncologist or an ophthalmologist with expertise in uveal melanoma .

• Cutaneous Melanoma:

  • From ages 18-20, annual dermatological assessmentis recommended, including a full-body examination and photography.

• Mesothelioma:

  • Routine mesothelioma surveillance is not currently recommended.
  • Neither chest X-rays nor MRI have sufficient evidence to support early detection of mesothelioma.
  • Prospective surveillance studies in heterozygous BAP1 carriers are needed.
  • For now, mesothelioma surveillance should therefore be performed only within research studies .
  • Patients should receive information about symptom awareness , with a low threshold for investigation.

Lifestyle Recommendations:

• Work that could involve asbestos exposure should be avoided, and care should be taken regarding exposure during home renovation.
• Information should be provided on sun protection and skin self-examination .
• Smoking cessation, reduced alcohol consumption and maintenance of a healthy weightshould be recommended to lower cancer risk.

Family Issues:

• At-risk relatives should be referred to discuss predictive genetic testing with clinical genetics specialists.
• Genetic testing generally begins at the age when surveillance starts (approximately 16-18 years) .
• Reproductive options should be discussed through referral to clinical genetics specialists.

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Related topic: Changing Genetic Inheritance Is Possible: A Way to Prevent Hereditary Cancer