BAP1 tumour predisposition syndrome
BAP1-TPDS; BAP1 cancer syndrome; familial BAP1 mutation
BAP1 tumour predisposition syndrome is an autosomal dominant cancer syndrome caused by germline mutations of the BAP1 tumour suppressor gene on chromosome 3p21.1. Affected individuals develop multiple distinctive cutaneous melanocytic lesions (BAP1-inactivated melanocytic tumours, "BAPomas"), as well as substantially elevated lifetime risks of uveal melanoma, cutaneous melanoma, mesothelioma and clear-cell renal cell carcinoma. Recognition matters because surveillance and family-screening protocols can detect tumours at curable stages, and BAPomas themselves are easily mistaken for benign Spitz naevi.
Genetics
- Germline loss-of-function mutations in BAP1 (BRCA1-associated protein 1) — a deubiquitinating enzyme and tumour suppressor on chromosome 3p21.1.
- Autosomal dominant inheritance with high but incomplete penetrance.
- The "second hit" — somatic loss of the wild-type allele — drives tumour formation in the affected tissue.
- BAP1 mutations are also acquired somatically in sporadic uveal melanoma, mesothelioma and renal cell carcinoma — distinguish from germline syndrome by family history and clinical features.
Clinical features
Cutaneous BAPoma (BAP1-inactivated melanocytic tumour)
- Multiple skin-coloured to pink/tan dome-shaped papules, 2–10 mm, on trunk, head, neck or limbs.
- Usually asymptomatic and may be overlooked or misdiagnosed as intradermal naevus, dermatofibroma, neurofibroma or Spitz naevus.
- Histology shows large epithelioid melanocytes with ground-glass cytoplasm; loss of BAP1 nuclear immunostaining is diagnostic.
- BAPomas are rarely the originator of melanoma but their presence is a critical clinical marker for the syndrome.
Associated cancers
- Uveal melanoma — lifetime risk ~10–30% across modern cohorts (Walpole 2018; O'Shea; Pilarski; surveillance series); often Class 2 (high-risk) tumours with worse prognosis.
- Cutaneous melanoma — lifetime risk ~10–15%.
- Mesothelioma — lifetime risk ~20–25%; both pleural and peritoneal occur, with pleural still slightly more common overall in most BAP1 cohorts but the peritoneal:pleural ratio markedly higher than in sporadic mesothelioma; commonly arises without asbestos exposure; younger age at onset.
- Clear-cell renal cell carcinoma — lifetime risk ~10%.
- Other reported cancers: meningioma, basal cell carcinoma, cholangiocarcinoma, lung adenocarcinoma.
Diagnosis
- Suspect in patients with multiple BAPomas, uveal melanoma at any age (particularly young), mesothelioma without asbestos exposure, or a personal/family history combining any two of the BAP1-spectrum cancers.
- Skin biopsy of a BAPoma — loss of BAP1 by immunohistochemistry, plus molecular confirmation of germline mutation.
- Refer to a clinical genetics service for germline BAP1 testing.
- Cascade testing of first-degree relatives.
Surveillance
No internationally agreed protocol exists; the following is a synthesis of expert consensus:
- Skin — annual full skin examination from age 20.
- Eye — annual ophthalmology review with dilated fundoscopy and ocular ultrasound from age 16.
- Renal / abdominal — abdominal MRI or ultrasound 1–3 yearly from age 30.
- Mesothelioma — no proven effective screening; counsel about symptoms (chest/abdominal pain, breathlessness, ascites) and avoid asbestos exposure.
- UV protection from infancy if family history of cutaneous melanoma.
Management of skin lesions
- BAPomas with stable benign appearance — observe.
- Atypical or changing BAPoma — excisional biopsy with full histology.
- Counselling about increased lifetime cancer risk and need for lifelong surveillance.
- Genetic counselling for the index case and family planning discussion.
References
- Carbone M et al. BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs. J Transl Med; 2012.
- Walpole S et al. Comprehensive study of the clinical phenotype of germline BAP1 variant-carrying families worldwide. J Natl Cancer Inst; 2018.
- Star P et al. Germline BAP1-positive patients: the dermatologist's role in their multidisciplinary care. Br J Dermatol; 2018.
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