The role of germline CDKN2A mutations in the development of melanoma and other malignancies

Germline mutations in the CDKN2A tumor suppressor gene have been linked with the development of inherited melanoma in some families. Studies of inherited melanoma have revealed two apparent discrepancies. First, many families that are linked to the chromosome region containing the CDKN2A gene do not harbor CDKN2A coding mutations. I have shown that several melanoma families possess a CDKN2A non-coding mutation resulting in loss of wild-type CDKN2A expression. The discovery of this mutation suggests that non-coding mutations in CDKN2A are important in melanoma predisposition. Second, in contrast with the predominance of CDKN2A dysfunction in sporadic tumors, germline CDKN2A mutations are associated with a narrow spectrum of malignancy. I performed loss of heterozygosity studies on malignant cells obtained from a multiple myeloma patient harboring a germline CDKN2A mutation. I observed loss of the wild-type allele in the malignant population suggesting that germline CDKN2A mutations may also predispose to multiple myeloma in some individuals.