Mutation screening of the CDKN2A promoter in melanoma families

Germline mutations of CDKN2A, at 9p21, are responsible for predisposition t o melanoma in some families. However, evidence of linkage to 9p21 has been demonstrated in a significant proportion of kindreds with no detectable mut ations in CDKN2A. It is possible that mutations in noncoding regions may be responsible for predisposition to melanoma in these families. We have anal yzed approximately 1 kb of the CDKN2A promoter upstream of the start codon in an attempt to identify causal mutations in 107 melanoma families. Four s equence variants were detected. Two of these (A-191G and A-493T) did not se gregate with disease and were present in a control population at a comparab le frequency, indicating that they are unlikely to predispose to melanoma. The A-493T variant appeared to be in linkage disequilibrium with the previo usly described CDKN2A polymorphism Ala 148Thr. The variant G-735A was detec ted in the control population, but segregation of this variant with melanom a within families could not be discounted. The fourth variant (G-34T), loca ted in the 5' UTR, creates an aberrant initiation codon. This variant appea red to segregate with melanoma and was not detected in a control population . G-34T has recently been identified in a subset of Canadian melanoma famil ies and was concluded to be associated with predisposition to melanoma. The creation of an aberrant initiation site in the 5' UTR may have an importan t role in carcinogenesis in a small percentage of families; however, mutati ons in the CDKN2A promoter appear to have a limited role in predisposition to melanoma, Genes Chromosomes Cancer 28:45-57, 2000. (C) 2000 Wiley-Liss, Inc.