Genetic profiling of basal cell carcinomas detects postzygotic mosaicism in basal cell naevus syndrome

Abstract

Summary Basal cell naevus syndrome (BCNS) is associated with germline mutations in the PTCH1 gene. Postzygotic mosaicism can also cause BCNS. Here we describe two patients, one with multiple basal cell carcinomas (BCCs) and one with clinical BCNS, who had no PTCH1 mutation in DNA extracted from blood. In both patients, we performed genetic analysis on different BCCs, revealing the presence of a shared PTCH1 mutation in all tumours. Our findings show that in patients with symptoms of BCNS and initial absence of a PTCH1 mutation in blood, genetic profiling of BCCs can detect postzygotic mosaicism. What's already known about this topic? Basal cell naevus syndrome (BCNS) is associated with germline mutations in the PTCH1 gene, but it can also be caused by low‐grade postzygotic mosaicism in PTCH1. What does this study add? In patients suspected of having BCNS or patients with multiple basal cell carcinomas (BCCs) with a special distribution on the body and no mutation detected in blood, it is worthwhile to search for a shared PTCH1 mutation in their BCCs as this can detect postzygotic mosaicism. This information is important to ensure proper surveillance programmes, choose the right therapy and provide adequate genetic counselling.

A guideline for the clinical management of basal cell naevus syndrome (Gorlin–Goltz syndrome)*

“…The SUFU gene is responsible in approximately 4% of BCNS cases 21 . Mutation loads < 5%, which could conceivably be present in cases with postzygotic mosaicism (in PTCH1 or SMO ), are impossible to detect using Sanger sequencing 11,12,26 . Mutations in the PTCH2 gene have also been reported, 10,27,28 but probably have an insignificant contribution to the cause of BCNS 29 .…”

“… 21 Mutation loads < 5%, which could conceivably be present in cases with postzygotic mosaicism (in PTCH1 or SMO ), are impossible to detect using Sanger sequencing. 11 , 12 , 26 Mutations in the PTCH2 gene have also been reported, 10 , 27 , 28 but probably have an insignificant contribution to the cause of BCNS. 29 If a variation is found, the relevance of the mutation and its consequences for the protein function should be verified according to the standards and guidelines set forward by (inter)national organizations.…”

Molecular mechanism of extracutaneous tumours in patients with basal cell nevus syndrome

“…This, in turn, causes GLI transcription factors to become active (GLIA),3 which leads to proliferation, suppression of apoptosis and angiogenesis. Other causative mutations for the BCNS phenotype are germline mutations in SUFU or postzygotic mutations in PTCH1 or SMO 2 4 5. According to the two-hit hypothesis,6 a mutation needs to be accompanied by a second hit in the wild-type allele of a TSG leading to its inactivation, for example, a second mutation, gene loss or a promoter hypermethylation event, in order to result in loss of functionality and subsequent induction of tumourigenesis.…”

Mosaicism: time matters

“…In this issue of the BJD , Reinders et al . report two patients with multiple basal cell carcinomas (BCCs), in whom postzygotic mosaic mutations were responsible for phenotypes resembling those resulting from germline mutations …”