PubMed · 9696646
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J C Bystryn. 1998-07-30. CDKN2A mutations in multiple primary melanomas.. https://doi.org/10.1056/nejm199807303390514
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Using the unique Utah Population Database, which links Utah genealogical data with Utah cancer data, we examined risks for other cancers among relatives of 4,079 melanoma cases. Age- and sex-specific rates for 35 different cancer sites were calculated, and used to estimate relative risks among relatives. In addition to the well-recognized risk for melanoma among first-degree relatives, we found significantly increased risks for prostate, breast, and colon cancers, non-Hodgkin's lymphoma, and multiple myeloma, ranging from 32 to 72% increased risk. Among second-degree relatives, in addition to increased risk for melanoma, we identified significantly increased risks for prostate cancer and multiple myeloma (27 and 53% increase, respectively). Among first-degree relatives of melanoma cases diagnosed before the age of 40 years, we found significantly elevated risks for cutaneous melanoma (380% increase) and prostate cancer (83% increase). Significantly increased risks for prostate cancer and multiple myeloma in both first- and second-degree relatives of melanoma cases are suggestive of heritable cancer syndromes. The increased risks for five additional cancer types in first-degree relatives of melanoma cases suggest that individuals with a family history of melanoma should strictly adhere to recommended screenings for all cancers.
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Germline CDKN2A mutations have been observed in approximately 20 percent of familial melanoma kindreds from North America, Europe and Australasia. There is also an increased risk of pancreatic cancer in a subset of families with mutations, however, the precise relationship between the CDKN2A gene and pancreatic cancer remains unknown. The relationships between familial melanoma, pancreatic cancer and germline CDKN2A mutations were examined using published data. There were 67 different CDKN2A mutations in 189 melanoma-prone families. Forty-two families (18 mutations) had pancreatic cancer reported. For families without reported pancreatic cancer, the most common types of mutations were missense (56%), frameshift (12%), and deletions (12%). For families with pancreatic cancer, missense (56%), splicing (17%), and frameshift (11%) mutations were most common. Seventy percent of the mutations were observed only once, while the remainder recurred in different families. Comparison of 147 melanoma-prone families without pancreatic cancer to the 42 families that had pancreatic cancer reported showed no significant differences in the types or locations of mutations. However, there was a significant difference (p=0.002) in the distribution of families across the four ankyrin repeats. This finding primarily resulted from the six most frequent mutations where the distribution of pancreatic cancer varied significantly (p=0.02) from at least 30% in c.301G>T (p.G101W), c.225_243del19 (p.P75fs), c.337_338insGTC (p.R112_L113insR), and c.377T>A (p.V126D) families to less than 10% in c.71G>C (p.R24P) and c.159G>C (p.M53I) families. Further research utilizing individual-specific data will be required to determine whether these patterns represent etiologic differences or incomplete reporting of cancer and mutation data.