Gayther S A, Mangion J, Russell P, Seal S, Barfoot R, Ponder B A, Stratton M R, Easton D
CRC Human Cancer Genetics Research Group, Addenbrooke's Hospital, Cambridge, UK.
Nat Genet. 1997 Jan;15(1):103-5. doi: 10.1038/ng0197-103.
The breast cancer susceptibility gene BRCA2 on chromosome 13q12-13 has recently been identified. Germline mutations of BRCA2 are predicted to account for approximately 35% of families with multiple case, early onset female breast cancer, and they are also associated with an increased risk of male breast cancer, ovarian cancer, prostate cancer and pancreatic cancer. Germline mutations of a second cancer susceptibility gene BRCA1 (ref. 5), are associated with a strong predisposition to ovarian cancer as well as female breast cancer. Recent studies have suggested that the phenotype in BRCA1 families with respect to the ratio of breast to ovarian cancer varies with the location of the BRCA1 mutation. To determine whether germline mutations in BRCA2 are associated with a similar variation in phenotypic risk, we have analysed the distribution of mutations in 25 families with multiple cases of breast and/or ovarian cancer ascertained in the United Kingdom and Eire. These mutations all lead to premature truncation of BRCA2 as a result of frameshift deletions/insertions or nonsense mutations. Analysis of the mutation distribution along the length of the gene indicates a significant genotype-phenotype correlation. Truncating mutations in families with the highest risk of ovarian cancer relative to breast cancer are clustered in a region of approximately 3.3 kb in exon 11 (P = 0.0004). Published data on mutations in 45 other BRCA2-linked families provide support for this correlation.
位于13q12 - 13染色体上的乳腺癌易感基因BRCA2最近已被确定。据预测，BRCA2的种系突变约占多例、早发性女性乳腺癌家族的35%，并且它们还与男性乳腺癌、卵巢癌、前列腺癌和胰腺癌的风险增加有关。另一种癌症易感基因BRCA1（参考文献5）的种系突变与卵巢癌以及女性乳腺癌的易感性密切相关。最近的研究表明，BRCA1家族中乳腺癌与卵巢癌比例的表型随BRCA1突变的位置而变化。为了确定BRCA2中的种系突变是否与表型风险的类似变化相关，我们分析了在英国和爱尔兰确定的25个有多例乳腺癌和/或卵巢癌家族中的突变分布。这些突变均由于移码缺失/插入或无义突变导致BRCA2过早截短。对沿基因长度的突变分布分析表明存在显著的基因型 - 表型相关性。相对于乳腺癌，卵巢癌风险最高的家族中的截短突变聚集在外显子11中约3.3 kb的区域（P = 0.0004）。关于其他45个与BRCA2相关家族中的突变的已发表数据支持了这种相关性。
