Assessing the genetic risk of nodular melanoma using a candidate gene approach

Nodular melanoma (NM) is a challenge to diagnose early due to its rapid growth and more atypical clinical presentation, making it the largest contributor to melanoma mortality.Our study aimed to perform a rare variant allele analysis of whole exome sequenced NM and non-NM patients (minor allele frequency ≤1% Non- Finnish European) for a set of 500 candidate genes potentially implicated in melanoma.This study recruited 131 NM and 194 non-NM participants from South-east Queensland and NM patients from Victoria to perform a comparative analysis of possible genetic differences or similarities between the two melanoma cohorts.Phenotypic analysis revealed that a majority of patients diagnosed with NM were older males with a higher frequency of fair skin and red hair than is seen in the general population. The distribution of common melanoma polygenic risk scores (PRS) was similar in NM and non-NM patients, with over 28% in the highest quantile of scores. There was also a similar frequency of carriage of familial/high penetrant melanoma gene and loss of function (LOF) variants. We identified 39 genes by filtering 500 candidate genes based on the greatest frequency in NM compared to non-NM cases. The genes with rare variant alleles of greatest frequency in NM included PTCH1, ARID2 and GHR. Rare variants in the SMO gene that interacts with PTCH1 as ligand and receptor were also identified, providing evidence that the Hedgehog pathway may contribute to NM risk. There was a cumulative effect in carrying multiple rare variants in the NM associated genes. A 14.8 fold increased ratio for NM compared to non-NM was seen when 2 rare variants alleles of the 39 genes were carried by a patient.This study highlights the importance of considering frequency of rare variant alleles to identify those at risk of NM in addition to known high penetrance genes.