MELPREDICT: a logistic regression model to estimate CDKN2A carrier probability

Abstract

Background: Heritable alterations in CDKN2A account for a subset of familial melanoma cases although no robust method exists to identify those at risk of being a mutation carrier. Methods: We set out to construct a model for estimating CDKN2A mutation carrier probability using a cohort of 116 consecutive familial cutaneous melanoma patients evaluated at Massachusetts General Hospital Pigmented Lesion Center between April 2001 and September 2004. Germline CDKN2A and CDK4 status on the familial melanoma cases and clinical features associated with mutational status were then used to build a multiple logistic regression model to predict carrier probability and performance of model on external validation. Results: From the 116 kindreds prone to melanoma in the Boston area, 13 CDKN2A mutation carriers were identified and 12 were subsequently used in the modeling. Proband age at diagnosis, number of proband primaries, and number of additional family primaries were most closely associated with germline mutations. The estimated probability of the proband being a mutation carrier based on the logistic

Familial melanoma: Clinical factors associated with germline CDKN2A mutations according to the number of patients affected by melanoma in a family

“…The prevalence of CDKN2A mutations in the F31 families (32%) was more than double that in the F2 families (13%), and was similar to that reported in the GenoMEL study of families with 3 or more melanoma cases (frequency of 39% and 95% CI overlapping with that estimated in F31 families). 5,6 The prevalence of CDKN2A mutations in the F2 families was higher than that estimated in the international population-based study 10 (point estimate of 4%) but was between 2 point estimates obtained from similar clinical studies restricted to first-degree relatives (7% in a North American sample 19 and 23% in an Italian sample). 20 Forty CDKN2A mutations were identified in the current sample of which 35 had been previously described.…”

Genetic risk factors for melanoma

“…Indeed, the GenoMEL study (Goldstein et al 2007) as well as three other studies Eliason et al 2006;Niendorf et al 2006) have shown that the probability of Wnding a CDKN2A mutation increases with the number of recorded patients with melanoma in a family. Thus, estimates of the penetrance of CDKN2A mutations derived from multiple-case studies may not be representative of CDKN2A mutation carrier risks in the general population.…”

Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma-prone families from three continents

“…1 Several variables have individually been reported to be associated with an increased frequency of CDKN2A mutations, including increased number of patients with melanoma, early median age at melanoma diagnosis, the occurrence of pancreatic cancer in a family and the occurrence of multiple melanoma tumours in a patient. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] These four features have been assessed separately. However, it has not been previously possible to compare the four factors across geographical regions, nor to examine them simultaneously.…”