BAP1 Tumour Predisposition Syndrome

BAP1 tumour predisposition syndrome is an autosomal dominant disorder caused by germline BAP1 variants, with uveal melanoma, malignant mesothelioma, cutaneous melanoma, clear cell renal cell carcinoma and distinctive melanocytic tumours. Cancer can occur at young ages, often in more than one family member.

Pathophysiology. BAP1 is a nuclear deubiquitinase that controls chromatin, DNA repair and cell death. Loss of the second allele in tissue leads to tumours, with higher mesothelioma risk after asbestos exposure.

Penetrance is high but variable. Mesothelioma in BAP1 carriers is often peritoneal and may follow a more indolent course.

Surveillance rests on expert opinion because evidence is limited.

• BAP1-inactivated melanocytic tumours: dome shaped pink or skin coloured papules
• Uveal melanoma, often diagnosed in the 30s to 40s
• Mesothelioma (pleural or peritoneal)
• Cutaneous melanoma
• Clear cell renal cell carcinoma
• Basal cell carcinoma, meningioma, hepatocellular carcinoma, cholangiocarcinoma
• Family history of the same cancers in several relatives

• Genetic testing of BAP1 with deletion and duplication analysis, in people with uveal melanoma and a family history, mesothelioma at a young age, or two or more core BAP1 cancers.
• Immunohistochemistry: loss of nuclear BAP1 staining in a lesion supports the diagnosis.
• Skin examination: dermoscopy and biopsy of suspicious papules.
• Dilated eye examination by an ophthalmologist.
• Imaging of kidneys and, when symptomatic, of chest or abdomen.
• Cascade testing of adult relatives.

Differential diagnosis.

• Familial atypical multiple mole melanoma syndrome (CDKN2A)
• Spitz tumours and other atypical melanocytic lesions
• Hereditary renal cell cancer syndromes
• Sporadic mesothelioma with asbestos exposure
• Lynch syndrome
• Basal cell naevus syndrome

• Eye: dilated ophthalmological examination every year from about 11 years of age.
• Skin: full skin examination and dermoscopy every 6 to 12 months from 18 years. Remove suspicious melanocytic tumours.
• Kidney: yearly ultrasound or MRI from about 30 years.
• Mesothelioma and lung: avoid asbestos, radiation and smoking. No routine screening test is of proven value; consider imaging if there are symptoms.
• Uveal melanoma: plaque brachytherapy or proton beam therapy for the primary, with enucleation for large tumours.
• Metastatic uveal melanoma: for HLA-A*02:01 positive patients tebentafusp 20 microgram intravenously on day 1, 30 microgram on day 8, then 68 microgram weekly, with monitoring for cytokine release in the first 3 doses.
• Mesothelioma: pemetrexed 500 mg/m2 with cisplatin 75 mg/m2 intravenously every 3 weeks for up to 6 cycles, or nivolumab 360 mg every 3 weeks with ipilimumab 1 mg/kg every 6 weeks, in specialist care.
• Cutaneous melanoma: wide excision and sentinel node assessment by thickness, then adjuvant therapy by stage and BRAF status.
• Renal cancer: nephron sparing surgery when feasible.
• Genetic counselling: 50% chance of the variant for each child.

Special groups.

• Occupational exposure: carriers should avoid asbestos and other mesothelioma risks.

Monitoring. Yearly eye, skin and renal review, and a clinical review of symptoms. Update the family history at each visit.

Referral and escalation. Refer to clinical genetics and an ocular oncology service. Urgent for new visual symptoms, a changing skin lesion, pleuritic pain, abdominal swelling or haematuria.