High prevalence of the G101W germline mutation in the CDKN2A (P16ink4a) gene in 62 Italian malignant melanoma families

Abstract

CDKN2A germline mutation frequency estimates are commonly based on families with several melanoma cases. When we started counseling in a research setting on gene susceptibility analysis in northern and central Italy, however, we mostly found small families with few cases. Here we briefly characterize those kindred, estimate CDKN2A/CDK4 mutation test yields, and provide indications on the possibility of implementing formal DNA testing for melanoma-prone families in Italy. In September 1995 we started genetic counseling in a research setting at our Medical Genetics Center. Screening for CDKN2A/CDK4 mutations was performed on families with two melanoma patients, one of whom was younger than 50 years at onset, the other complying with one of the following: 1) being a first-degree relative, 2) having an additional relative with pancreatic cancer, or 3) having multiple primary melanomas. Sixty-two of 67 (80%) melanoma cases met our criteria. Four previously described CDKN2A mutations (G101W, R24P, V126D, and N71S) were found in 21 of the 62 families (34%) with a high prevalence of G101W (18/21). The percentage of families with two melanoma cases/family harboring a mutation was low (7%, 2/27), but rose to 45% (9/20) if one of the melanoma patients carried multiple melanomas or if pancreatic cancer was present in that family. In the 15 families with three melanoma cases the presence of a mutation was higher (67%, 10/15) and reached 100% in the 4 families with four or more melanoma cases. Our results suggest that CDKN2A/CDK4 counseling-based mutational analysis may be reasonably efficient also for families with two melanoma cases, if one patient carries multiple melanomas or if pancreatic cancer is present in the family.

Clinical genetic testing for familial melanoma in Italy: A cooperative study

“…The frequency of mutations increased significantly with the number of patients with MPM in the family and reached 100% in the families with two or more MPM, confirming that the number of cases with MPM increases the likelihood of detecting a germline CDKN2A mutation in a family. 10,[37][38][39] In a very recent hospital-based study of single primary melanoma and MPM, 20 we found that the frequency of CDKN2A mutations in MPM cases was 32.6%. The MPM cases had a 4-fold higher likelihood of carrying a CDKN2A mutation than the single primary melanoma cases (odds ratio = 4.27; 95% confidence interval 2.43-7.53), independent of a family history of the disease, which suggests that the SIGU recommendations may be modified in the future to include the presence of MPM as a criterion for candidacy to genetic testing.…”

Prevalence of CDKN2A mutations in pancreatic cancer patients: implications for genetic counseling

“…Published recommendations for CDKN2A screening include patients with multiple (Z3) primary melanomas, or families with at least one melanoma and two other instances of melanoma or pancreatic cancer in the family, with mutation detection rates of 20-40% in this setting. [36][37][38] Under these recommendations, two of the seven (29%) families meeting criteria were determined to carry a mutation in this study, and we believe this is a reasonable proportion for discriminating candidates for genetic testing. However, it should also be noted that the majority of mutations would not have been identified with this approach.…”

Multiple primary melanomas (MPMs) and criteria for genetic assessment: MultiMEL, a multicenter study of the Italian Melanoma Intergroup

“…12,13 Leachman et al 13 proposed that 2 cancer events, including pancreatic cancer, either in the patient or in a family member, are criteria enough to best identify which patients would benefit from genetic testing in low melanoma incidence areas. Italy was included among these areas on the basis of mutation prevalence data from the Ligurian population 12,[14][15][16][17][18] where CDKN2A founder mutations were prevalent in up to 40% of melanoma families in concert with a strong association with pancreatic cancer. 19,20 The Italian study based on the Italian Society of Human Genetics (SIGU) protocol for melanoma families found that 33% of the families overall and 25% of those with only 2 affected members carried CDKN2A mutations.…”