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

grantor: University of TorontoGermline 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.M.Sc