Rosenthal Eric, Moyes Kelsey, Arnell Christopher, Evans Brent, Wenstrup Richard J
Myriad Genetic Laboratories, Inc., 320 Wakara Way, Salt Lake City, UT, 84108, USA,
Breast Cancer Res Treat. 2015 Jan;149(1):223-7. doi: 10.1007/s10549-014-3218-x. Epub 2014 Dec 6.
An estimated 1:40 individuals of Ashkenazi Jewish (AJ) ancestry carry one of three common founder mutations in BRCA1 or BRCA2, resulting in the inherited cancer condition, Hereditary Breast and Ovarian Cancer (HBOC) syndrome. Targeted testing for these three mutations (BRCA1 187delAG, BRCA1 5385insC, and BRCA2 6174delT) is therefore recommended for all AJ breast and ovarian cancer patients, regardless of age of diagnosis or family history. Comprehensive analysis of both genes is recommended for a subset of AJ patients in whom founder mutations are not identified, but estimates of the yield from comprehensive analysis in this population vary widely. We sought to determine the proportion of non-founder mutations as a percentage of all mutations in BRCA1 and BRCA2 among AJ patients to inform decisions about HBOC testing strategies in this population. We analyzed the genetic testing results for 37,952 AJ patients for whom clinical testing of BRCA1 and BRCA2 was performed at Myriad Genetic Laboratories from January 2006 through August 2013. Analysis was limited to AJ-only patients for whom the initial test order was either (1) comprehensive testing, or (2) founder mutation testing with instructions to automatically "reflex" to comprehensive analysis if negative. Cases were excluded if a separate follow-up order was placed to reflex to comprehensive analysis only after the founder mutation testing was reported out as negative. Among all BRCA1 and BRCA2 mutations detected in these groups, the percentage of non-founder mutations was 13 % (104/802) and 7.2 % (198/2,769). One-hundred and eighty-nine unique non-founder mutations were detected, 76 in BRCA1 and 113 in BRCA2. Non-founder mutations make up between 7.2 and 13.0 % of all BRCA1 and BRCA2 mutations in Ashkenazi Jews. A wide range of mutations are present, most of which are also seen in non-AJ individuals.
据估计，每40名有阿什肯纳兹犹太（AJ）血统的人中就有1人携带BRCA1或BRCA2中三种常见的奠基者突变之一，从而导致遗传性癌症疾病——遗传性乳腺癌和卵巢癌（HBOC）综合征。因此，建议对所有AJ乳腺癌和卵巢癌患者进行这三种突变（BRCA1 187delAG、BRCA1 5385insC和BRCA2 6174delT）的靶向检测，无论诊断年龄或家族史如何。对于未检测到奠基者突变的一部分AJ患者，建议对这两个基因进行全面分析，但该人群中全面分析的检出率估计差异很大。我们试图确定AJ患者中BRCA1和BRCA2所有突变中非奠基者突变的比例，以便为该人群HBOC检测策略的决策提供依据。我们分析了2006年1月至2013年8月在Myriad遗传实验室对37952名AJ患者进行BRCA1和BRCA2临床检测的基因检测结果。分析仅限于仅AJ患者，其初始检测指令要么是（1）全面检测，要么是（2）奠基者突变检测，并指示如果检测结果为阴性则自动“追溯”到全面分析。如果仅在奠基者突变检测报告为阴性后才下达单独的后续指令以追溯到全面分析，则将病例排除。在这些组中检测到的所有BRCA1和BRCA2突变中，非奠基者突变的比例分别为13%（104/802）和7.2%（198/2769）。共检测到189种独特的非奠基者突变，其中BRCA1有76种，BRCA2有113种。非奠基者突变占阿什肯纳兹犹太人所有BRCA1和BRCA2突变的7.2%至13.0%。存在多种突变，其中大多数在非AJ个体中也可见。
