Gosse-Brun S, Sauvaigo S, Daver A, Page M, Lortholary A, Larra F, Bignon Y J, Bernard-Gallon D
Laboratoire de Radioanalyse, Centre Paul Papin, Angers, France.
Anticancer Res. 1999 Nov-Dec;19(6B):5191-6.
Mutations in BRCA1 and BRCA2 genes account for the majority of familial aggregation of breast and ovarian cancers but other common genes in the population with low penetrance should be also involved in susceptibility to breast cancer. The H-ras minisatellite, located downstream of H-ras oncogene, is considered to be a likely candidate. Previous findings have estimated that as many as 1 in 11 cancers of the breast might be attributed to this region, but other studies observed inconsistent results. We propose to elucidate the potential role of H-ras locus in breast cancer, by looking at somatic alterations occurring in tumor DNAs such as the instability or the loss of heterozygosity (LOH) and by determining a potential correlation between constitutional specific H-ras alleles and clinical and/or pathological characteristics. DNA was extracted from 123 sporadic breast tumors and matched peripheral blood lymphocytes. 143 DNA samples from of peripheral blood lymphocytes from healthy donors served as a control population. The allelic diversity was determined by polymerase chain reaction analysis. Rare H-ras alleles were found to be present in about 9% of breast cancer patients while they were detected in only 1.4% of lymphocytes from healthy donors (P = 0.0044). Therefore, the risk of breast cancer is increased in patients with one or two rare alleles (odd ratio = 7.14 and 95% confidence interval = 1.94-22.27). Analyses of somatic alterations in tumor DNA have shown the lost of one allele, in general the longest, in 6.7% informative cases and an instability to H-ras locus in 6.5% tumors that appeared as a size increase of one of the two alleles. No correlation of rare H-ras alleles with clinicopathological parameters was found. Our results demonstrated an association of rare H-ras alleles with breast cancer and suggest that minisatellite H-ras may be considered as an informative marker for the breast cancer risk.
BRCA1和BRCA2基因的突变是乳腺癌和卵巢癌家族聚集性的主要原因，但人群中其他低外显率的常见基因也可能与乳腺癌易感性有关。位于H-ras癌基因下游的H-ras微卫星被认为是一个可能的候选基因。先前的研究估计，多达11分之一的乳腺癌可能归因于该区域，但其他研究观察到的结果并不一致。我们建议通过观察肿瘤DNA中发生的体细胞改变，如不稳定性或杂合性缺失（LOH），并确定构成性特异性H-ras等位基因与临床和/或病理特征之间的潜在相关性，来阐明H-ras基因座在乳腺癌中的潜在作用。从123例散发性乳腺肿瘤和匹配的外周血淋巴细胞中提取DNA。来自健康供体的143份外周血淋巴细胞DNA样本作为对照人群。通过聚合酶链反应分析确定等位基因多样性。发现约9%的乳腺癌患者存在罕见的H-ras等位基因，而在健康供体的淋巴细胞中仅检测到1.4%（P = 0.0044）。因此，携带一个或两个罕见等位基因的患者患乳腺癌的风险增加（优势比= 7.14，95%置信区间= 1.94 - 22.27）。对肿瘤DNA体细胞改变的分析显示，在6.7%的信息性病例中一个等位基因丢失，通常是最长的等位基因，在6.5%的肿瘤中H-ras基因座不稳定，表现为两个等位基因之一的大小增加。未发现罕见的H-ras等位基因与临床病理参数之间存在相关性。我们的结果表明罕见的H-ras等位基因与乳腺癌有关，并提示微卫星H-ras可被视为乳腺癌风险的一个信息性标志物。
