PTCH mutations and deletions in patients with typical nevoid basal cell carcinoma syndrome and in patients with a suspected genetic predisposition to basal cell carcinoma: a French study

Abstract

The patched (PTCH) mutation rate in nevoid basal cell carcinoma syndrome (NBCCS) reported in various studies ranges from 40 to 80%. However, few studies have investigated the role of PTCH in clinical conditions suggesting an inherited predisposition to basal cell carcinoma (BCC), although it has been suggested that PTCH polymorphisms could predispose to multiple BCC (MBCC). In this study, we therefore performed an exhaustive analysis of PTCH (mutations detection and deletion analysis) in 17 patients with the full complement of criteria for NBCCS (14 sporadic and three familial cases), and in 48 patients suspected of having a genetic predisposition to BCC (MBCC and/or age at diagnosis p40 years and/or familial BCC). Eleven new germline alterations of the PTCH gene were characterised in 12 out of 17 patients harbouring the full complement of criteria for the syndrome (70%). These were frameshift mutations in five patients, nonsense mutations in five patients, a small inframe deletion in one patient, and a large germline deletion in another patient. Only one missense mutation (G774R) was found, and this was in a patient affected with MBCC, but without any other NBCCS criterion. We therefore suggest that patients harbouring the full complement of NBCCS criteria should as a priority be screened for PTCH mutations by sequencing, followed by a deletion analysis if no mutation is detected. In other clinical situations that suggest genetic predisposition to BCC, germline mutations of PTCH are not common.

Exon-level array CGH in a large clinical cohort demonstrates increased sensitivity of diagnostic testing for Mendelian disorders

“…This represents the largest number of patients tested concurrently for sequencing and copy number mutations in PTCH1. 11,12 For some disorders the positive rate in our data set was lower than that published elsewhere (see Supplementary Table S1 online). For example, only 3 out of 116 patients (2.6%) with von Hippel-Lindau syndrome had a deletion in the VHL gene, while the published deletion rate is up to 30%.…”

PTCH1 duplication in a family with microcephaly and mild developmental delay

“…In contrast to the loss-of-function mutations and genomic deletions of PTCH1 found in BCNS patients, 10 a few PTCH1 mutations have been identified in patients with HPE7. 11 -12 These mutations likely act in a gain-of-function fashion.…”

Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome)

“…Under pathogenic circumstances, constitutive activation of the hedgehog signaling pathway due to mutation of critical regulatory proteins leads to tumor cell proliferation. Loss of function mutations in PTCH1, which occur by a variety of mechanisms such as deletions, insertions, and nonsense and missense mutations [7], are thought to occur in *70 % of patients who fulfill diagnostic criteria for NBCCS [15,16]. In addition, loss of function SUFU germline mutations have also been recently associated with NBCCS in a subset of cases [16].…”