ONLINE MUTATION REPORT Identification of a splice acceptor site mutation in p16/p14 within a breast cancer, melanoma, neurofibroma prone kindred

Epidemiological studies estimate that at least 10% of all cancer cases, including breast cancer, can be attributed to inherited susceptibility. Two hereditary breast cancer genes, BRCA1 and BRCA2, have been identified and women who inherit a mutated copy of either gene have a raised lifetime risk of breast and ovarian cancer. More than 80% of families with multiple cases of breast cancer and ovarian cancer and most very large families with multiple cases of breast cancer carry mutations in either BRCA1 or BRCA2. However, only one third of families with only four or five cases of breast cancer and no cases of ovarian cancer carry mutations in either BRCA1 or BRCA2. 8 Large scale screening studies for BRCA1 and BRCA2 mutations have shown that the percentage of high risk breast cancer families carrying a predisposing mutation in either gene is likely to be overestimated and depending on the criteria used to define the syndrome is likely to be greatly overestimated. 9 10 Therefore, additional BRCA genes remain to be identified. Inactivation of the INK4a/ARF locus on human chromosome 9p21 by point mutation, deletion, or hypermethylation is observed in many cancers. Accumulating evidence now suggests that the frequency of involvement of the INK4a/ARF locus in human cancers may be second only to that of TP53, underscoring its broad importance in tumorigenesis. The INK4a/ARF locus encodes for two distinct tumour suppressor genes, p16 and p14, which have alternative first exons (1α or 1β) and common exons 2 and 3; p16 is encoded by three exons (designated 1α, 2, and 3), whereas p14 is encoded by a unique first exon (exon 1β) which splices into the INK4A exon 2, but is translated into an alternative reading frame (ARF). Germline mutations of p16 have been identified in a proportion of familial melanomas. Many of these mutations are also predicted to inactivate p14 19 20 and, in addition, mutations in exon 1β of p14 have recently been identified in hereditary melanoma families. Interestingly, a high frequency of other carcinomas, particularly pancreatic tumours, nervous system tumours, head and neck tumours, and also breast carcinomas, has been reported in INK4a/ARF mutation positive melanoma families. 22 24–29 In this study, we have evaluated members of 31 BRCA1 and BRCA2 mutation negative families presenting with multiple cases of early onset breast cancer, and in some cases malignant melanoma and pancreatic cancer, for germline mutations in p16 and p14.