title: CDKN2a mutation-negative melanoma families have increased risk exclusively for skin cancers but not for other malignancies.
abstract: 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.
authors.affiliation: Department of Oncology Pathology, Karolinska Institutet and Karolinska University Hospital, Solna, 171 76, Stockholm, Sweden.
authors.forename: Hildur
authors.initials: H
authors.lastname: Helgadottir
authors.affiliation: Department of Oncology Pathology, Karolinska Institutet and Karolinska University Hospital, Solna, 171 76, Stockholm, Sweden.
authors.forename: Veronica
authors.initials: V
authors.lastname: Höiom
authors.affiliation: Department of Oncology Pathology, Karolinska Institutet and Karolinska University Hospital, Solna, 171 76, Stockholm, Sweden.
authors.forename: Rainer
authors.initials: R
authors.lastname: Tuominen
authors.affiliation: Department of Oncology, Lund University and Skåne University Hospital, Malmö, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Jönsson
authors.affiliation: Department of Oncology Pathology, Karolinska Institutet and Karolinska University Hospital, Solna, 171 76, Stockholm, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Månsson-Brahme
authors.affiliation: Department of Oncology, Lund University and Skåne University Hospital, Malmö, Sweden.
authors.forename: Håkan
authors.initials: H
authors.lastname: Olsson
authors.affiliation: Department of Oncology Pathology, Karolinska Institutet and Karolinska University Hospital, Solna, 171 76, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Hansson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008545:Melanoma / Q000201:enzymology / Q000235:genetics*; D008875:Middle Aged; D011446:Prospective Studies; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics*; D012306:Risk; D012878:Skin Neoplasms / Q000201:enzymology / Q000235:genetics*; D055815:Young Adult
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D044102:Receptor, Melanocortin, Type 1
keywords: CDKN2A; MC1R; genetic counseling; melanoma; squamous cell skin cancer