CM-Score: a validated scoring system to predict <i>CDKN2A</i> germline mutations in melanoma families from Northern Europe.

Abstract

Several factors have been reported that influence the probability of a germline <i>CDKN2A</i> mutation in a melanoma family. Our goal was to create a scoring system to estimate this probability, based on a set of clinical features present in the patient and his or her family. Five clinical features and their association with <i>CDKN2A</i> mutations were investigated in a training cohort of 1227 Dutch melanoma families (13.7% with <i>CDKN2A</i> mutation) using multivariate logistic regression. Predefined features included number of family members with melanoma and with multiple primary melanomas, median age at diagnosis and presence of pancreatic cancer or upper airway cancer in a family member. Based on these five features, a scoring system (<i>CDKN2A Mutation</i>(<i>CM</i>)<i>-Score</i>) was developed and subsequently validated in a combined Swedish and Dutch familial melanoma cohort (n=421 families; 9.0% with <i>CDKN2A</i> mutation). All five features were significantly associated (p<0.05) with a <i>CDKN2A</i> mutation. At a CM-Score of 16 out of 49 possible points, the threshold of 10% mutation probability is approximated (9.9%; 95% CI 9.8 to 10.1). This probability further increased to >90% for families with ≥36 points. A CM-Score under 16 points was associated with a low mutation probability (≤4%). CM-Score performed well in both the training cohort (area under the curve (AUC) 0.89; 95% CI 0.86 to 0.92) and the external validation cohort (AUC 0.94; 95% CI 0.90 to 0.98). We developed a practical scoring system to predict <i>CDKN2A</i> mutation status among melanoma-prone families. We suggest that <i>CDKN2A</i> analysis should be recommended to families with a CM-Score of ≥16 points.