Increased Risk of Cancer Other Than Melanoma in CDKN2A Founder Mutation (p16-Leiden)-Positive Melanoma Families

Abstract

Purpose: We report the largest study to date analyzing the risk of cancers other than melanoma in melanoma families positive for the same CDKN2A mutation. Experimental Design: We studied family members of 22 families positive for the p16-Leiden founder mutation who had attended a surveillance clinic or were their close relatives. Within this cohort, observed and expected rates of cancer were computed by mutation status consisting of 221 (proven plus obligate) carriers, 639 (proven plus obligate) noncarriers, and 668 first-degree relatives whose carrier risk was estimated from the relationship to known carriers and the age and melanoma status of that person and their relatives. Results: Our analysis shows a relative risk (RR) of cancer other than melanoma and nonmelanoma skin cancer of 4.4 [95% confidence interval (95% CI), 3.3-5.6], predominantly attributable to the increased risk for pancreatic cancer (RR, 46.6; 95% CI, 24.7-76.4), but also for other cancers. We provide substantial proof for pancreatic cancer being a key component of the p16-Leiden phenotype. Inclusion of this cancer in a penetrance analysis leads to an estimated RR of pancreatic cancer for mutation carriers of 47.8 (95% CI,. Conclusions: This study shows clear evidence of increased risk of cancers other than melanoma in CDKN2A families carrying the p16-Leiden mutation. Further research is necessary to determine if similar risks apply to families with CDKN2A mutations other than p16-Leiden.

Prevalence of CDKN2A mutations in pancreatic cancer patients: implications for genetic counseling

“…8,14 There are several potential explanations for this difference. A reporting bias could exist (over reporting in pancreatic kindreds or underreporting in melanoma kindreds), and our study is limited by relying on proband report of cancer among relatives.…”

“…7 Brain, head/neck and nonmelanoma skin cancer have also been reported to be more common among mutation carriers. [8][9][10] The CDKN2A gene encodes two different proteins, read from alternate reading frames of a common second exon. The portion of the gene that encodes p16 is composed of three exons, and p16 is a recognized tumor suppressor because of its role in preventing progression through the G1 cell cycle checkpoint.…”

“…In addition, there has been a relative deficiency of data to estimate penetrance for known carriers of mutations predisposing to pancreatic cancer, with published data from selected melanoma kindreds. 8,14 Therefore, we performed a study in an unselected series of pancreatic adenocarcinoma patients from the Mayo Clinic Biospecimen Resource for Pancreas Research.…”

Prospective risk of cancer and the influence of tobacco use in carriers of the p16-Leiden germline variant

“…A previous retrospective study by de Snoo et al 6 also found significantly increased risks for these tumours in a cohort of p16-Leiden variant carriers. Oldenburg et al 15 described a p16-Leiden variant-positive family in which many relatives had developed lung cancer and head and neck tumours.…”

“…5 Several studies reported an increased risk of tumours other than melanoma and pancreatic cancers for various CDKN2A germline variants. [6][7][8][9][10] However, these studies have used a variety of methodological approaches and some have been limited by inclusion of heterogeneous groups or by failure to determine individual mutation status. In addition, the influence of environmental factors (for example, smoking) on the phenotypic variability in FAMMM syndrome is yet to be elucidated.…”