CDKN2a mutation-negative melanoma families have increased risk exclusively for skin cancers but not for other malignancies

Germline CDKN2A mutations are found in 5-20% of melanoma families. Numerous studies have shown that carriers of CDKN2A mutations have increased risks of non-melanoma cancers, but so far there have been no studies investigating cancer risks in CDKN2A wild type (wt) melanoma families. In this prospective cohort study, index melanoma cases (n=224) and their first-degree relatives (n = 944) were identified from 154 confirmed CDKN2A wt melanoma families. Cancer diagnoses in family members and matched controls were obtained from the Swedish Cancer Registry. Relative risks (RR), odds ratios (OR) and two-sided 95% confidence intervals (95% CI) were calculated. In index cases and first-degree relatives, the prospective RR for melanoma was 56.9 (95% CI 31.4-102.1) and 7.0 (95% CI 4.2-11.4), respectively, and for squamous cell skin cancers 9.1 (95% CI 6.0-13.7) and 3.4 (95% CI 2.2-5.2), respectively. In neither group, elevated risks were seen for non-skin cancers. In a subgroup analysis, CDKN2A wt melanoma families with young (<40 years) melanoma cases were found to have increased risk of non-skin cancers (RR 1.5, 95% CI 1.0-1.5). Further, MC1R gene variants were increased in familial melanoma cases compared to controls (OR 2.4, 95% CI 1.6-3.4). Our findings suggest that in the majority of CDKN2A wt melanoma families, a segregation of variants in low-risk melanoma genes such as MC1R causes increased skin cancer susceptibility, rather than mutations in high-risk cancer predisposing genes, such mutations are more probable to be found in melanoma families with young melanoma cases. This study further supports an implication of CDKN2A mutation screening as a clinical test that determines counseling and follows up routines of melanoma families. What's new? In families with a history of melanoma, carriers of mutations in the CDKN2A gene are often at increased risk of both melanoma and non-melanoma cancers. Whether families lacking CDKN2A mutations, which make up the majority of melanoma families, have similar non-melanoma cancer risks is unclear. Here, members of CDKN2A wild-type melanoma families were found to have no increase in risk of non-skin cancer. The findings suggest that for most CDKN2A wild-type families, cancer predisposition may be attributed to low-risk rather than high-risk genes like CDKN2A. The novel insight has implications for counseling and surveillance of melanoma families.