CDKN2A MUTATIONS IN MULTIPLE PRIMARY MELANOMAS

Background Germ-line mutations in the CDKN2A tumor-suppressor gene (al so known as p16, p16(INK4a), and MTS1) have been linked to the develop ment of melanoma in some families with inherited melanoma. Whether mut ations in CDKN2A confer a predisposition to sporadic (nonfamilial) mel anoma is not known. In some patients with sporadic melanoma, one or mo re additional primary lesions develop, suggesting that some of these p atients have an un derlying genetic susceptibility to the cancer. We h ypothesized that this predisposition might be due to germ-line CDKN2A mutations. Methods We used the polymerase chain reaction, single-stran d conformation polymorphism analysis, and direct DNA sequencing to ide ntify germ-line mutations in the CDKN2A gene in patients with multiple primary melanomas who did not have family histories of the disease. A quantitative yeast two-hybrid assay was used to evaluate the function al importance of the CDKN2A variants. Results Of 33 patients with mult iple primary melanomas, 5 (15 percent; 95 percent confidence interval, 4 percent to 27 percent) had germ-line CDKN2A mutations. These includ ed a 24-bp insertion at the 5' end of the coding sequence, three misse nse mutations (Arg24Pro, Met53lle, and Ser56lle), and a 2-bp deletion at position 307 to 308 (resulting in a truncated CDKN2A protein). In t hree families, CDKN2A mutations identical to those in the probands wer e found in other family members. In two families with mutations, we un covered previously unknown evidence of family histories of melanoma. C onclusions Some patients with multiple primary melanomas but without f amily histories of the disease have germ-line mutations of the CDKN2A gene. The presence of multiple primary melanomas may signal a genetic susceptibility to melanoma not only in the index patient but also in f amily members, who may benefit from melanoma-surveillance programs. (C ) 1998, Massachusetts Medical Society.