Human Molecular Genetics Advance Access originally published online on August 7, 2006
Human Molecular Genetics 2006 15(18):2682-2689; doi:10.1093/hmg/ddl199
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Impact of E27X, a novel CDKN2A germ line mutation, on p16 and p14ARF expression in Italian melanoma families displaying pancreatic cancer and neuroblastoma
1 Department of Oncology, Biology and Genetics/Medical Genetics Service and 2 Department of Internal Medicine, University of Genoa, Italy, 3 National Cancer Institute, Genoa, Italy, 4 Dermatology Unit, San Martino Hospital, Genoa, Italy, 5 Department of Clinical Pathophysiology/Medical Genetics Service, University of Florence, Florence, Italy and 6 Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Bethesda, USA
* To whom correspondence should be addressed at: Department of Oncology, Biology and Genetics V.le Benedetto XV, 6 16129 Italy. Tel: +39 010 3538982; Fax: +39 0103538978; Email: paola.ghiorzo{at}unige.it
Received June 1, 2006; Accepted July 27, 2006
Mutations in the CDKN2A gene underlie melanoma susceptibility in as many as 50% of melanoma kindreds in selected populations, and several CDKN2A founder mutations have been described. Inherited mutations in CDKN2A have been found to be associated with other, non-melanoma cancers including pancreatic cancer (PC) and neural system tumors (NST). Here we report a novel germline mutation in exon 1 of the CDKN2A gene, E27X, which we first detected in melanoma patients living in or originally from a small geographic area bordering Liguria in north-western Italy. A subset of melanoma kindreds positive for this mutation displayed PC and neuroblastoma. E27X generates a premature stop codon, leading to dramatically reduced protein levels of p16 and leaving p14ARF unaltered. As PC and NSTs have been postulated to be preferentially associated with CDKN2A mutations located in exon 2 and/or affecting p14ARF alone, the position of E27X in exon 1
provides interesting insights towards clarifying the mechanisms by which the CDKN2A/ARF locus is involved in cancer predisposition.
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.
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