Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT

BACKGROUND:Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5%-40% of melanoma cases reported in melanoma-prone families. We sought to determine whether MELPREDICT was generalizable to a global series of families with melanoma and whether performance improvements can be achieved.METHODS:In total, 2116 familial melanoma cases were ascertained by the international GenoMEL Consortium. We recapitulated the MELPREDICT model within our data (GenoMELPREDICT) to assess performance improvements by adding phenotypic risk factors and history of pancreatic cancer. We report areas under the curve (AUC) with 95% confidence intervals (CIs) along with net reclassification indices (NRIs) as performance metrics.RESULTS:MELPREDICT performed well (AUC 0.752, 95% CI 0.730-0.775), and GenoMELPREDICT performance was similar (AUC 0.748, 95% CI 0.726-0.771). Adding a reported history of pancreatic cancer yielded discriminatory improvement (P < .0001) in GenoMELPREDICT (AUC 0.772, 95% CI 0.750-0.793, NRI 0.40). Including phenotypic risk factors did not improve performance.CONCLUSION:The MELPREDICT model functioned well in a global data set of familial melanoma cases. Adding pancreatic cancer history improved model prediction. GenoMELPREDICT is a simple tool for predicting CDKN2A mutational status among melanoma patients from melanoma-prone families and can aid in directing these patients to receive genetic testing or cancer risk counseling(AU)

Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families

Germline mutations in CDKN2A are frequently identified among melanoma kindreds and are associated with increased atypical nevus counts. However, a clear relationship between pathogenic CDKN2A mutation carriage and other nevus phenotypes including counts of common acquired nevi has not yet been established. Using data from GenoMEL, we investigated the relationships between CDKN2A mutation carriage and 2-mm, 5-mm, and atypical nevus counts among blood-related members of melanoma families. Compared with individuals without a pathogenic mutation, those who carried one had an overall higher prevalence of atypical (odds ratio = 1.64; 95% confidence interval = 1.18-2.28) nevi but not 2-mm nevi (odds ratio = 1.06; 95% confidence interval = 0.92-1.21) or 5-mm nevi (odds ratio = 1.26; 95% confidence interval = 0.94-1.70). Stratification by case status showed more pronounced positive associations among non-case family members, who were nearly three times (odds ratio = 2.91; 95% confidence interval = 1.75-4.82) as likely to exhibit nevus counts at or above the median in all three nevus categories simultaneously when harboring a pathogenic mutation (vs. not harboring one). Our results support the hypothesis that unidentified nevogenic genes are co-inherited with CDKN2A and may influence carcinogenesis(AU)

Hereditary breast cancer associated with a germline BRCA2 mutation in identical female twins with similar disease expression

The relative contribution of heritable and nonheritable factors to disease expresion in BRCA2 mutation carriers is largely unknown. This report describes a familial breast cancer syndrome in a pair of identical female twins. These twins showed an extremely high concordance in their clinical histories: both twins exhibited similar cancer-related risk factors, and developed breast cancer at the same age with the same disease stage and identical histological features. No differences were detected in hormone receptors status, p53, bcl-2, erbB-2 and LI Ki67 expression by immunohistochemistry. A BRCA2 exon 11 protein truncation test showed a lower molecular weight band tha the one expected for a norma allele, in both twins. Sequence analysis of DNA showed a 6 bp insertion between nucleotides 4359-4360, which resulted in a premature stop codon at position 1378. The remarkable disease similarity oberved in the identical twin pair is in accordance with an important role for heritable factores in disease expression among patients carrying BRCA germline mutations