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

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 <= 40 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.