Impact of E27X, a novel CDKN2A germ line mutation, on p16 and p14ARF expression in Italian melanoma families displaying pancreatic cancer and neuroblastoma.
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 1alpha provides interesting insights towards clarifying the mechanisms by which the CDKN2A/ARF locus is involved in cancer predisposition.
Ghiorzo
Paola
P
Department of Oncology, Biology and Genetics/Medical Genetics Service, University of Genoa, and Dermatology Unit, San Martino Hospital, Italy. paola.ghiorzo@unige.it
Gargiulo
Sara
S
Pastorino
Lorenza
L
Nasti
Sabina
S
Cusano
Roberto
R
Bruno
William
W
Gliori
Sara
S
Sertoli
Mario R
MR
Burroni
Anna
A
Savarino
Vincenzo
V
Gensini
Francesca
F
Sestini
Roberta
R
Queirolo
Paola
P
Goldstein
Alisa M
AM
Scarrà
Giovanna Bianchi
GB
D000328:Adult; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D005260:Female; D019942:Genes, p16; D005838:Genotype; D018095:Germ-Line Mutation; D006239:Haplotypes; D006801:Humans; D007558:Italy; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D017354:Point Mutation; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics* / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF