Germline CDKN2A Mutation Status and Survival in Familial Melanoma Cases.
Germline mutations in CDKN2A have been associated with increased risk of melanoma and tobacco-related cancers in respiratory and upper digestive tissues. In CDKN2A wild-type (wt) melanoma families, other known high-risk, melanoma-predisposing mutations are rare, and no increased risk has been observed for nonskin cancers in this group. This study is the first to compare survival in germline CDKN2A mutated (mut) and nonmutated melanoma cases.



Melanoma-prone families participating in this study were identified through a nationwide predictive program starting in 1987. Information on cancer diagnoses (types, stages, and dates) and deaths (causes and dates) were obtained through the Swedish Cancer Registry and Cause of Death Registry. Kaplan Meier and Cox proportional hazards regression models were used to assess survival in CDKN2A(mut) (n = 96) and CDKN2A(wt) (n = 377) familial melanoma cases and in matched sporadic melanoma cases (n = 1042). All statistical tests were two-sided.



When comparing CDKN2A(mut) and CDKN2A(wt) melanoma cases, after adjusting for age, sex, and T classification, CDKN2A(mut) had worse survival than melanoma (hazard ratio [HR] = 2.50, 95% confidence interval [CI] = 1.49 to 4.21) and than nonmelanoma cancers (HR = 7.77, 95% CI = 3.65 to 16.51). Compared with matched sporadic cases, CDKN2A(mut) cases had statistically significantly worse survival from both melanoma and nonmelanoma cancers while no differences in survival were seen in CDKN2A(wt) compared with sporadic cases.



CDKN2A(mut) cases had statistically significantly worse survival than nonmelanoma cancers and, intriguingly, also from melanoma, compared with melanoma cases with no CDKN2A mutations. Further studies are required to elucidate possible mechanisms behind increased carcinogen susceptibility and the more aggressive melanoma phenotype in CDKN2A mutation carriers.
Affiliations of authors: Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden (HH, VH, RT, JH); Department of Oncology, Clinical Sciences Lund, Lund University and Skåne University Hospital (GJ, HO); Department of Dermatology, Clinical Sciences Lund, Lund University and Helsingborg Hospital (KN).
Hildur
H
Helgadottir
Affiliations of authors: Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden (HH, VH, RT, JH); Department of Oncology, Clinical Sciences Lund, Lund University and Skåne University Hospital (GJ, HO); Department of Dermatology, Clinical Sciences Lund, Lund University and Helsingborg Hospital (KN).
Veronica
V
Höiom
Affiliations of authors: Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden (HH, VH, RT, JH); Department of Oncology, Clinical Sciences Lund, Lund University and Skåne University Hospital (GJ, HO); Department of Dermatology, Clinical Sciences Lund, Lund University and Helsingborg Hospital (KN).
Rainer
R
Tuominen
Affiliations of authors: Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden (HH, VH, RT, JH); Department of Oncology, Clinical Sciences Lund, Lund University and Skåne University Hospital (GJ, HO); Department of Dermatology, Clinical Sciences Lund, Lund University and Helsingborg Hospital (KN).
Kari
K
Nielsen
Affiliations of authors: Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden (HH, VH, RT, JH); Department of Oncology, Clinical Sciences Lund, Lund University and Skåne University Hospital (GJ, HO); Department of Dermatology, Clinical Sciences Lund, Lund University and Helsingborg Hospital (KN).
Göran
G
Jönsson
Affiliations of authors: Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden (HH, VH, RT, JH); Department of Oncology, Clinical Sciences Lund, Lund University and Skåne University Hospital (GJ, HO); Department of Dermatology, Clinical Sciences Lund, Lund University and Helsingborg Hospital (KN).
Håkan
H
Olsson
Affiliations of authors: Department of Oncology-Pathology, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden (HH, VH, RT, JH); Department of Oncology, Clinical Sciences Lund, Lund University and Skåne University Hospital (GJ, HO); Department of Dermatology, Clinical Sciences Lund, Lund University and Helsingborg Hospital (KN).
Johan
J
Hansson
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000401:mortality*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000401:mortality*; D016022:Case-Control Studies; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics*; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000401:mortality*; D008875:Middle Aged; D016016:Proportional Hazards Models; D012042:Registries; D012878:Skin Neoplasms / Q000235:genetics* / Q000401:mortality*; D015996:Survival Rate; D013548:Sweden / Q000453:epidemiology; D055815:Young Adult; D000096142:Cutaneous Malignant Melanoma
C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18