Melanoma germline genetics: immune, cancer driver, and Wnt signaling genes

Polygenic susceptibility: immunity-related loci (deleterious coding variants in CPVL and IFIH1, HLA-A signal), pan-cancer driver genes (MYC, PIK3CA, CDKN1B) and the WNT/β-catenin pathway

This meta-analysis of 35 GWAS from 29 cohorts (69,871 cases, 1,616,233 controls) identifies 156 independent signals at 116 cutaneous melanoma risk loci, whereas only 54 common loci were previously known. It shows a strong link between susceptibility and immunity, with deleterious coding variants in CPVL and IFIH1 and a novel association at HLA-A; variant-to-gene mapping implicates pan-cancer driver genes for over a third of loci (MYC, PIK3CA, CDKN1B), and 22% of loci harbour candidate genes in the WNT/β-catenin pathway. A nevus count PRS was associated with acral lentiginous melanoma risk, the first evidence of a germline genetic effect on this rare subtype. A new melanoma PRS, validated in two cohorts, improves discrimination beyond age and sex (AUC above 0.70): above the 90th percentile, individuals reach the average risk of a 60-year-old as much as 30 years earlier.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

medRxiv preprint, not peer-reviewed. The sample size is considerable, but an AUC above 0.70 remains modest discrimination: the PRS cannot stratify a population on its own and could mainly help tailor skin surveillance, provided it is calibrated by ancestry, which the abstract does not detail. In cancer genetics clinics, these polygenic signals complement, without replacing, high-penetrance predisposition genes such as CDKN2A.

Analysis by Dr Thibaut Benquey