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Patients with both pancreatic adenocarcinoma and melanoma may harbor germline CDKN2A mutations

✍ Scribed by Geeta Lal; Ling Liu; David Hogg; Norman J. Lassam; Mark S. Redston; Steven Gallinger

Publisher: John Wiley and Sons
Year: 2000
Tongue: English
Weight: 73 KB
Volume: 27
Category: Article
ISSN: 1045-2257
DOI: 10.1002/(sici)1098-2264(200004)27:4<358::aid-gcc4>3.0.co;2-o

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✦ Synopsis

Germline mutations of the CDKN2A tumor suppressor gene have been identified in melanoma kindreds linked to 9p21, and pancreatic adenocarcinoma is the second most common malignancy in some of these families. We hypothesized that unselected patients with both primary cancers, i.e., pancreatic cancer and malignant melanoma, have a genetic predisposition to tumor development, and that this susceptibility may be due to germline CDKN2A mutations. Fourteen patients, with both pathologically verified pancreatic adenocarcinoma and melanoma, were assessed for germline CDKN2A mutations by polymerase chain reaction amplification and sequencing of six overlapping fragments encompassing exons 1␣ and 2. A yeast two-hybrid assay was used to assess the functional consequences of CDKN2A variants. Germline CDKN2A mutations were identified in 2/14 patients: I49S, a novel substitution in exon 1␣, and M53I, a previously reported missense mutation in exon 2. Both variants lead to compromised CDKN2A function. We conclude that the occurrence of both pancreatic cancer and melanoma, in the same patient, signals an inherited susceptibility to cancer, and that this predisposition is, in some cases, due to germline CDKN2A mutations. This finding has important implications not only for the proband, but also for other family members.

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