Melanoma cases demonstrate increased carrier frequency of Phenylketonuria/hyperphenylalanemia mutations

Summary

Identifying novel melanoma genetic risk factors informs screening and prevention efforts. Mutations in the phenylalanine hydroxylase gene (the causative gene in phenylketonuria) lead to reduced pigmentation in untreated phenylketonuria patients, and reduced pigmentation is associated with greater melanoma risk. Therefore, we sought to characterize the relationship between phenylketonuria carrier status and melanoma risk. Using National Newborn Screening Reports, we determined the United States phenylketonuria/hyperphenylalanemia carrier frequency in Caucasians to be 1.76%. We examined three publically available melanoma datasets for germline mutations in the phenylalanine hydroxylase gene associated with classic phenylketonuria and/or hyperphenylalanemia. Mutations were identified in 29/814 melanoma patients, with a carrier frequency of 3.56%. There was a two-fold enrichment (p-value=3.4 x 10^-5) compared to the Caucasian frequency of hyperphenylalanemia/phenylketonuria carriers. These data demonstrate a novel association between phenylalanine hydroxylase carrier status and melanoma risk. Further functional investigation is warranted to determine the link between phenylalanine hydroxlase mutations and melanomagenesis.

This article is protected by copyright. All rights reserved.