Germline p16INK4A mutation and protein dysfunction in a family with inherited melanoma
Liu, L.; Lassam, N.J.; Slingerland, J.M.; Bailey, D.; Cole, D.; Jenkins, R.; Hogg, D.
Oncogene 11(2): 405-412
1995
ISSN/ISBN: 0950-9232 PMID: 7624155 Document Number: 444274
The gene encoding the cell cycle inhibitor p16-INK4A (also known as p16, MTS1, CDKN2 and INK4) has been mapped to human chromosome band 9p21, a region that also contains a putative melanoma susceptibility gene. Although germline mutations in the coding region of the p16-INK4A gene have been detected in some families with inherited melanoma, many other families show no evidence of such mutations and hence the role of p16-INK4A the development of this tumor is still unclear. In this report, we describe a family with inherited melanoma in which a novel mutation in exon 2 of the p16-INK4A gene segregates with the disease. The mutant gene encodes a protein with an in-frame deletion of two amino acids (Asp96 and Leu97). We show that the mutant protein is functionally abnormal: it is unable to bind cdk4 in vitro and does not inhibit colony formation in tertiary passage rat embryo fibroblasts. Moreover, in a metastatic lesion from one patient the wild type p16-INK4A allele was deleted and the mutant allele retained. We conclude that family members carrying this germline mutation in the p16-INK4A gene are predisposed to melanoma. By extension, these findings implicate the p16-INK4A gene in the development of some cases of familial melanoma.