A high-penetrance intergenic variant at 9p21 confers melanoma susceptibility

Approximately 10% of cutaneous malignant melanoma cases are familial. Variants in CDKN2A account for up to 40% of melanoma-prone families, with an additional ~10% explained by other genes. Many CDKN2A mutation-negative families show linkage to chromosome-band 9p21, which harbors CDKN2A, suggesting non-coding variants may contribute to familial risk. Here, whole-genome sequencing revealed a novel 100 kb deletion mapping to 9p21 in a gene-desert region, 205 kb from CDKN2A, cosegregating in a four-case family from Genoa, Italy. The deletion overlaps melanocyte enhancers that interact with the promoters of CDKN2A p16 and p14 transcripts and is predicted to reduce p16 expression. Using a nearby rare exonic variant in MTAP (rs755147810) on the deletion haplotype, we searched for deletion carriers in WES data from high-risk melanoma patients and controls and identified 22 cases and a single control carrying rs755147810 and the deletion. The association with melanoma in case-control analysis was highly significant (3,319 cases and 5,680 controls; P=1.27x10^-6; OR=27.50). We observe loss-of-heterozygosity of the wild-type allele in a carrier's tumor sample. The founder haplotype with the most recent common ancestor dates approximately 26 generations, broadly overlapping the period when Italy was struck by devastating outbreaks of plague that decimated the population creating a genetic bottleneck. Our results provide evidence of a high-penetrance intergenic variant conferring melanoma susceptibility, with potential for genetic screening of high-risk individuals.