Hereditary skin tumour syndromes

This panel covers a spectrum of germline predisposition syndromes whose shared feature is an increased risk of cutaneous and additional related tumours.

The largest group is a predisposition to melanoma due to . Affected individuals present with multiple atypical naevi and recurrent cutaneous melanomas.

predisposes to uveal and cutaneous melanoma, malignant mesothelioma, renal cell carcinoma, and characteristic BAP1-inactivated melanocytic tumours of the skin.

features multiple early-onset basal cell carcinomas, jaw keratocysts, and an elevated medulloblastoma risk.

The Muir-Torre variant of presents with sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas.

includes cutaneous and plexiform neurofibromas alongside its systemic features.

A single prevalence figure for the panel as a whole cannot be given. Familial melanomas account for about 10% of all malignant melanomas; the other syndromes contribute smaller fractions of non-melanoma skin and adnexal tumours.

The panel analyses fifteen autosomal dominant predisposition genes grouped by their principal tumour spectrum. Melanoma-predisposition genes are CDKN2A, CDK4, MITF, BAP1, and POT1. BAP1 additionally underlies the broader BAP1 tumour predisposition syndrome. Basal cell carcinoma and Gorlin syndrome arise from pathogenic variants in PTCH1, PTCH2, and SUFU. The Muir-Torre cutaneous tumours can be caused by variants in the Lynch mismatch-repair genes MLH1, MSH2, MSH6, and PMS2, as well as EPCAM deletions. NF1 causes neurofibromatosis type 1, and PTEN causes PTEN hamartoma tumour syndrome, which carries an associated cutaneous melanoma risk.

All panel genes confer a predominantly autosomal dominant predisposition to skin cancer: an affected individual typically carries one germline pathogenic variant, and each child of an affected individual has a 50% risk of inheriting it. Penetrance and tumour spectrum vary by gene and by individual.

A genetic cause for skin cancer can be suspected due to an individual’s tumour pattern, age at onset, and family history. Diagnosis rests on sequencing and copy-number analysis of the panel genes from a germline DNA sample. A confirmed pathogenic variant assigns the specific syndrome and directs entity-specific surveillance.

Beyond the panel syndromes, the differential diagnosis includes other genetic and acquired causes of early or multiple skin tumours:

• Xeroderma pigmentosum (XP): marked ultraviolet sensitivity with very early-onset, multiple melanomas and non-melanoma skin cancers from defective nucleotide-excision repair; XPC, ERCC2 and other XP genes (not on this panel).
• Sporadic cutaneous melanoma: single, later-onset melanoma without a familial multiple-naevus pattern; somatic BRAF or NRAS drivers without germline predisposition.
• Sporadic basal cell carcinoma: solitary, sun-exposed basal cell carcinoma without jaw keratocysts or a syndromic pattern; somatic hedgehog-pathway activation without a germline variant.
• Acquired immunosuppression-related skin cancer: multiple cutaneous squamous cell carcinomas in organ-transplant recipients or chronically immunosuppressed individuals; non-genetic.

• Genetic testing supports establishing the diagnosis by identifying the underlying pathogenic variant and providing a basis for genetic counselling.
• A confirmed result supports condition-specific surveillance and management options, which the treating physicians decide together with the affected individual.
• A known familial variant supports predictive testing of at-risk relatives, so they can clarify their personal risk and access surveillance and counselling where indicated.

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