Although the CDKN2A gene has been shown to be the major genetic determinant governing high-penetrance susceptibility to melanoma, there remains a significant proportion of melanoma pedigrees in which germline mutations of CDKN2A have not been identified. We have therefore studied the prevalence of germline 9p deletions encompassing the CDKN2 locus in melanoma pedigrees, using multiplex ligation-dependent probe amplification. Germline deletions were found in 3 of 93 UK pedigrees, with no previously identified CDKN2A mutations. A hemizygous deletion of CDKN2A exon 1beta previously reported by this group was confirmed in one family and identified in a second. Microsatellite analysis determined that these two families were ancestrally related. In the third family, a novel p16 hemizygous deletion involving CDKN2A exons 1alpha, 2, and 3 was detected. An additional 9p21 deletion reported previously in a USA melanoma-neural system tumor family was shown to involve CDKN2A exon 1beta, and not p16. The CDKN2A exon 1beta deletions provide further evidence that this tumor suppressor gene is important in melanoma-neural system tumor susceptibility, but do not exclude the possibility of a novel gene or regulatory element also being deleted in this region. Deletions at 9p21 are rare and explain only a small proportion of melanoma susceptibility. This study is the first to comprehensively exclude deletions in melanoma-prone families with no previously identified CDKN2A mutations.
(c) 2005 Wiley-Liss, Inc.