Joint contribution of MC1R and MITF alleles to melanoma risk in the age of polygenic risk scores.

Br J Dermatol i 2023; 188:770-776. https://doi.org/10.1093/bjd/ljad097 While few melanoma high-penetrance susceptibility genes have been identified beyond I CDKN2A i , the polygenic inheritance resulting from multiple low-medium risk alleles, interacting with the environment, has been recently clarified, owing to the advancement of sequencing techniques and the development of genome-wide association studies.[1] Common low-penetrance variants can be combined to provide polygenic risk scores (PRSs) and melanoma can arise from the joint action of multiple predisposing factors, including the combination of a number of alleles that have a small effect.[2] Recently, it has been proposed that the results of genetic testing of high-penetrance genes should be reported together with the data on low-intermediate penetrance genes,[3] while genetic testing of low-intermediate penetrance genes alone may be of very limited clinical utility. In this issue of the I BJD i , Wallingford I et al i .[6] show a joint effect between I MC1R i R-alleles and the I MITF i E318K variant in significantly increasing the risk of cutaneous melanoma. Most recent studies have focused particularly on I MC1R i , as it plays a key role in melanin synthesis, and I MITF i , whose E318K variant has been functionally validated and is associated with a moderate risk of cutaneous melanoma. [Extracted from the article]