Additional Breast Cancer Susceptibility Gene Identified

WESTPORT, Aug 07, 2000 (Reuters Health) - European families that have a mutation in CDKN2A, a multiple tumor suppressor gene, are at increased risk not only for melanoma and pancreatic cancer, as has been reported previously, but also for breast cancer.

Dr. Ake Borg and colleagues, from University Hospital, Lund, Sweden, collected data on 52 families with a history of two or more cases of malignant melanoma in first- and second-degree relatives. The researchers analyzed the entire CDKN2A coding region and exon 2 of the CDK4 gene from one affected member of each family.

"CDKN2A mutations were found in 10 (19%) of the 52 families," the team reports in the August 2nd issue of the Journal of the National Cancer Institute. Of these, nine had the same alteration of p16-INK4a and one had a missense mutation. An in vitro binding assay showed that the mutant p16-INK4a was unable to bind cdk4 and cdk6.

The investigators also found that in six of the families with mutant p16-INK4a, at least one member had multiple primary melanomas. These families "also had a high frequency of other malignancies--in particular, breast cancer (a total of eight cases compared with the expected 2.1) and pancreatic cancer (a total of six cases compared with the expected 0.16)."

Dr. Borg and colleagues add that the mutant p16-INK4a families with a high incidence of breast cancer also had "a propensity for multiple melanomas in females, suggesting that a sex-dependent factor may modify the phenotypic expression of CDKN2A alterations."

The results "reinforce the role of CDKN2A as a multiple tumor suppressor gene," the authors conclude, "and suggest that it should also be considered to be a breast cancer susceptibility gene. Moreover, breast cancer families with multiple cases of melanomas should be regarded as candidates for CDKN2A mutation screening."

J Natl Cancer Inst 2000;92:1260-1266.