CDKN2A mutation in a non-FAMMM kindred with cancers at multiple sites results in a functionally abnormal protein

Sun, Sophie, Pollock, Pamela M., Liu, Ling, Karimi, Sepideh, Jothy, Serge, Milner, Benedict J., Renwick, Andrew, Lassam, Norman J., Hayward, Nicholas K., Hogg, David, Narod, Steven A., & Foulkes, William D. (1997) CDKN2A mutation in a non-FAMMM kindred with cancers at multiple sites results in a functionally abnormal protein. International Journal of Cancer, 73(4), pp. 531-536.

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The CDKN2A gene encodes p16 (CDKN2A), a cell-cycle inhibitor protein which prevents inappropriate cell cycling and, hence, proliferation. Germ-line mutations in CDKN2A predispose to the familial atypical multiple-mole melanoma (FAMMM) syndrome but also have been seen in rare families in which only 1 or 2 individuals are affected by cutaneous malignant melanoma (CMM). We therefore sequenced exons 1alpha and 2 of CDKN2A using lymphocyte DNA isolated from index cases from 67 families with cancers at multiple sites, where the patterns of cancer did not resemble those attributable to known genes such as hMLH1, hMLH2, BRCA1, BRCA2, TP53 or other cancer susceptibility genes. We found one mutation, a mis-sense mutation resulting in a methionine to isoleucine change at codon 53 (M531) of exon 2. The individual tested had developed 2 CMMs but had no dysplastic nevi and lacked a family history of dysplastic nevi or CMM. Other family members had been diagnosed with oral cancer (2 persons), bladder cancer (1 person) and possibly gall-bladder cancer. While this mutation has been reported in Australian and North American melanoma kindreds, we did not observe it in 618 chromosomes from Scottish and Canadian controls. Functional studies revealed that the CDKN2A variant carrying the M531 change was unable to bind effectively to CDK4, showing that this mutation is of pathological significance. Our results have confirmed that CDKN2A mutations are not limited to FAMMM kindreds but also demonstrate that multi-site cancer families without melanoma are very unlikely to contain CDKN2A mutations.

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38 citations in Web of Science®
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ID Code: 45812
Item Type: Journal Article
Refereed: Yes
Keywords: Adolescent, Adult, Aged, Cyclin-Dependent Kinase Inhibitor p16/ genetics, Female, Genes, Tumor Suppressor/ genetics, Germ-Line Mutation/ genetics, Humans, Male, Melanoma/genetics, Middle Aged, Neoplasms, Multiple Primary/ genetics, Pedigree, Syndrome
DOI: 10.1002/(SICI)1097-0215(19971114)73:4<531::AID-IJC13>3.0.CO;2-C
ISSN: 0020-7136
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > ONCOLOGY AND CARCINOGENESIS (111200) > Cancer Cell Biology (111201)
Divisions: Past > QUT Faculties & Divisions > Faculty of Science and Technology
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 1997 John Wiley & Sons, Inc.
Deposited On: 09 Sep 2011 01:08
Last Modified: 14 Jul 2017 09:01

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