Distelman-Menachem Tal, Shapira Tal, Laitman Yael, Kaufman Bella, Barak Frida, Tavtigian Sean, Friedman Eitan
Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, Tel-Hashomer, Israel.
Fam Cancer. 2009;8(2):127-33. doi: 10.1007/s10689-008-9216-6. Epub 2008 Sep 17.
Three mutations in BRCA1 (185delAG 5382InsC) and BRCA2 (6174delT) can be detected in a substantial proportion of Jewish Ashkenazi breast/ovarian cancer families. Family-specific pathogenic mutations in both genes can be detected in up to 5% of high risk Ashkenazim. The contribution of major gene rearrangements and seemingly pathogenic missense mutations to inherited breast cancer predisposition has never been systematically evaluated in Ashkenazim.
High risk, Jewish Ashkenazi women, non-carriers of the predominant Jewish BRCA1/BRCA2 mutations, were genotyped for major gene rearrangements in BRCA1/BRCA2 using Multiplex ligation-dependent probe amplification (MLPA), and for the occurrence rate of 6 seemingly pathogenic missense mutations in BRCA1 (R866C, R331S, R841W, Y179C, C61G, M1008I) using a modified restriction enzyme assay.
Overall, 105 Jewish Ashkenazi high risk women, participated in the study: 104 with breast cancer [age at diagnosis (mean +/- SD) 51.05 +/- 11.13 years], one was affected with ovarian cancer (61 years). Two were found to carry the M1008I mutation in BRCA1 and none harbored any of the other missense mutations. MLPA reveled four changes (amplifications of exons 5, 17, 19 and 21) in BRCA1 in five patients, and six patients exhibited 4 MLPA-detectable abnormalities in BRCA2 (amplifications in exons 1b, 2, and deletions in exons 11a and 25). None of these abnormalities could be confirmed using quantitative PCR (qPCR) analysis.
Major gene rearrangements involving BRCA1 BRCA2 contribute little to the burden of inherited predisposition of breast cancer in Ashkenazi Jews.
在相当一部分犹太裔阿什肯纳兹乳腺癌/卵巢癌家族中可检测到BRCA1基因的三种突变（185delAG、5382InsC）和BRCA2基因的一种突变（6174delT）。在高达5%的高危阿什肯纳兹人中可检测到这两个基因的家族特异性致病突变。在阿什肯纳兹人中，主要基因重排和看似致病的错义突变对遗传性乳腺癌易感性的贡献从未得到系统评估。
对未携带主要犹太BRCA1/BRCA2突变的高危犹太裔阿什肯纳兹女性，使用多重连接依赖探针扩增技术（MLPA）对BRCA1/BRCA2中的主要基因重排进行基因分型，并使用改良的限制性内切酶分析法对BRCA1中6种看似致病的错义突变（R866C、R331S、R841W、Y179C、C61G、M1008I）的发生率进行检测。
总体而言，105名犹太裔阿什肯纳兹高危女性参与了该研究：104名患有乳腺癌[诊断时年龄（均值±标准差）为51.05±11.13岁]，1名患有卵巢癌（61岁）。发现两名患者携带BRCA1基因的M1008I突变，未发现携带任何其他错义突变。MLPA检测发现5例患者的BRCA1基因有4处变化（外显子5、17、19和21的扩增），6例患者的BRCA2基因有4处可通过MLPA检测到的异常（外显子1b、2的扩增以及外显子11a和25的缺失）。使用定量PCR（qPCR）分析无法确认这些异常情况。
涉及BRCA1和BRCA2的主要基因重排对犹太裔阿什肯纳兹犹太人遗传性乳腺癌易感性负担的贡献很小。
