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Germline Loss-of-Function Variants in ATM Gene May Contribute to Melanoma Predisposition

NEW YORK —The ATM gene may contribute to melanoma predisposition as loss-of-function variants in it confer a moderate risk of disease, according to a new study.

Germline variants in ATM have been implicated in the risk of numerous cancers and while SNPs in ATM have been tied to melanoma risk, the effect of ATM on melanoma predisposition has been unclear. ATM encodes a protein active in the DNA damage response and is activated by DNA double-strand breaks, including damage caused by UV radiation.

Using data from 22 sites in the US, Australia, and Europe, researchers from the GenoMEL and MelaNostrum consortia examined the prevalence of ATM variants among individuals with melanoma, as compared to controls. As they reported in Genetics in Medicine this week, they found that loss-of-function ATM variants and, to a lesser degree, variants of uncertain significance, were more common in the melanoma cohort than in controls.

The identification of ATM as a melanoma predisposition gene could have clinical benefits. "In the era of personalized medicine, DNA damage repair genes are promising targets for novel cancer therapies," co-senior author Paola Ghiorzo from the University of Genoa and her colleagues wrote in their paper, noting that PARP inhibitors are used to treat BRCA1/2-positive breast, ovarian, and pancreatic cancers, and, recently, castration-resistant ATM-deficient prostate cancer.

In their retrospective analysis, the researchers collected the germline ATM status of 2,104 unrelated individuals with cutaneous melanoma, including familial, multiple primary, and sporadic melanoma. These individuals underwent ATM genotyping by panel, exome, or genome sequencing. For controls, the researchers used data on 64,603 individuals from the Genome Aggregation Database who were of non-Finnish European ancestry.

After filtering, the cohort harbored more than 1,000 unique ATM variants, including 156 loss-of-function variants and 848 VUS. ATM loss-of-function variants were present in about 1 percent of melanoma cases in the cohort.

Still, individuals with melanoma were more likely to have variants categorized as loss-of-function variants or as a VUS. In particular, they found that an LOF variant was 2.6 times as likely to be found in their melanoma cohort than among the gnomAD controls and even more enriched among those with familial or multiple primary melanoma.

VUS were also associated, though to a lesser extent, with melanoma. Based on case-control data available from two of their centers, the researchers similarly noted an enrichment of loss-of-function variants and VUS among individuals with melanoma.

Additionally, familial data found that ATM variants co-segregated in 29 families and partially segregated in nine families with melanoma.

The findings suggested to the researchers that ATM may be a moderate risk gene for melanoma. "The implication of ATM in melanoma development is recent, but the activation of the ATM/ATR pathway in response to UV-induced replication stress has been documented," Ghiorzo and her colleagues wrote. "Thus, it is possible a defective activation of this pathway leads to malignant transformation and, if this is the case, ATM penetrance could be modulated by UV exposure and/or the co-occurrence of other inherited melanoma predisposing factors."

The researchers further noted that this study was part of a wider effort examining ATM and melanoma, which also aims to examine the contribution of rare missense variants to melanoma risk and tease out how ATM variants contribute functionally to melanoma development.

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