483 PTCH1 inactivation is sufficient to cause basaloid follicular hamartoma in pediatric Nevoid basal cell carcinoma syndrome

Nevoid basal cell carcinoma syndrome (NBCS, Gorlin syndrome) is a rare autosomal-dominant entity and the most common hereditary form of basal cell cancer (BCC). Aberrant activation of Sonic hedgehog pathway underlies BCC onset, and germline mutations of its components, mostly tumor suppressor PTCH1, are causing NBCS. Basaloid lesions from pediatric patients with NBCS differ from adult BCCs, both clinically and histologically. Here, we report results of a whole exome sequencing of 15 basaloid lesions from three unrelated pediatric patients with NBCS, which correspond to basaloid follicular hamartomas (BFH). In the majority of the lesions examined (11/15), we found a complete inactivation of PTCH1. The somatic inactivation of the wild-type copy of PTCH1 occurred mostly by deletion of chromosome 9q (6/15 cases), somatic inactivating mutation (4/15 cases) or by copy-neutral LOH (1 case). In childhood BFHs, we observe 138.4 times less somatic mutations per Mb that in sporadic BCC and 39.3 times less mutations that in adult NBCS patients. Moreover, in lesions from children with NBCS, PTCH1 was the only gene affected by oncogenic events, compared to adult BCCs, which harbor in the absolute majority of cases additional mutations. Our findings indicate that complete inactivation of PTCH1 alone is not sufficient for BCC onset. Yet, in the absence of other oncogenic events, it leads to BFH development. We postulate BFH to be a benign, yet precursor lesion, which transforms into invasive BCC if additional second hit occurs. We suggest direct removal of such lesions or their close monitoring with immediate excision if any change occurs. BFHs should be recognized as initial stage of the cutaneous NBCS spectrum, allowing an early set up of multidisciplinary surveillance protocols.