Frequency of breast cancer attributable to BRCA1 in a population-based series of American women
Frequency of breast cancer attributable to BRCA1 in a population-based series of American women
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DOI：
10.1001/jama.279.12.915
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发表时间：
1998-03-25
影响因子：
120.7
通讯作者：
King, MC
中科院分区：
文献类型：
--
作者：
Newman, B;Mu, H;King, MC
上下文。-先前对BRCA1突变患病率的研究是基于高危人群的，得出的估计并不能反映美国乳腺癌患者的一般人群的经历。目的：确定BRCA1中已知疾病相关突变和其他变异的患病率，以及在以人群为基础的未选择家族史的白人和黑人乳腺癌患者样本中，BRCA1在种族、诊断年龄和家族史状况方面的差异。病例对照study.Setting。-北卡罗莱纳中部和东部的24个县。病例为在1993年5月至1996年6月期间首次确诊为浸润性乳腺癌的20至74岁妇女。对照组按5岁年龄范围和种族与病例频率匹配。本报告包括前211例病例和188例对照，以及随后的99例病例和108例非裔美国人血统对照。主要结果测量。-病例分析BRCA1基因编码序列、剪接、5′非翻译区、3′非翻译区任意位点的种系变异，对照组分析选定的变异。使用多重单链构象分析进行筛选，所有潜在的变异都使用基因组测序确认。211例乳腺癌患者中有3例BRCA1有疾病相关变异，均为蛋白截断突变。在对抽样概率进行调整后，患有疾病相关变异的乳腺癌患者比例在白人女性中为3.3%(95%可信区间，0%-7.2%)，在黑人女性中为0%。在白人女性中，有卵巢癌家族史的遗传突变发生率为23%，至少有4例乳腺癌伴或不伴卵巢癌的家庭中遗传突变发生率为13%，同时患有乳腺癌和卵巢癌且至少有4名患病亲属的家庭中遗传突变发生率为33%。由于这些结果是基于少数处于最高风险水平的家庭，因此这些估计的置信区间很宽。另外5例患者有罕见的错义突变或单个氨基酸缺失，其生物学意义尚不清楚。在黑人女性中，3'非翻译区变异在病例中比在对照组中更常见。这些数据表明，在美国普通人群中，BRCA1的广泛筛查是没有必要的。相比之下，BRCA1突变在患有乳腺癌和卵巢癌的家庭中足够频繁，或者至少有4例乳腺癌（任何年龄），可能需要考虑基因分型。BRCA1群体遗传学的新图景涉及家族史、年龄和遗传祖先的复杂相互作用，在考虑测试或解释结果时应考虑所有这些因素。
Context.-Previous studies of BRCA1 mutation prevalence have been based on high-risk groups, yielding estimates that do not reflect the experience of the general population of US patients with breast cancer.Objective.-To determine prevalence of known disease-related mutations and other variants in BRCA1 and how it differs by race, age at diagnosis, and family history status in a population-based sample of white and black patients with breast cancer unselected for family history,Design.-Case-control study.Setting.-A 24-county area of central and eastern North Carolina.Participants.-Cases were women aged 20 to 74 years diagnosed as having a first invasive breast cancer between May 1993 and June 1996. Controls were frequency matched to cases by 5-year age range and race. The first 211 cases and 188 controls regardless of race and the subsequent 99 cases and 108 controls of African American ancestry are included in this report.Main Outcome Measure.-Germline variants at any site in the coding sequence, splice junctions, 5' untranslated region, or 3' untranslated region of the BRCA1 gene were analyzed in cases, and selected variants were analyzed in controls. Screening was performed using multiplex single-strand conformation analysis, with all potential variants confirmed using genomic sequencing.Results.-Three of 211 patients with breast cancer had disease-related variants at BRCA1, all of which were protein-truncating mutations. After adjustment for sampling probabilities, the proportion of patients with breast cancer with disease-related variants was 3.3% (95% confidence interval, 0%-7.2%) in white women and 0% in black women. Young age at diagnosis alone did not predict BRCA1 carrier status in this population, In white women, prevalence of inherited mutation was 23% for cases with family history of ovarian cancer, 13% for cases from families with at least 4 cases of breast cancer with or without ovarian cancer, and 33% for cases from families with both breast and ovarian cancer and at least 4 affected relatives. Because these results are based on few families at the highest levels of risk, confidence intervals around these estimates are wide. An additional 5 patients had rare missense mutations or a single amino acid deletion, the biological significance of which is unknown, In black women, a variant in the 3' untranslated region was statistically significantly more common in cases than in controls.Conclusions.-These data suggest that in the general US population, widespread screening of BRCA1 is not warranted. In contrast, BRCA1 mutations are sufficiently frequent in families with both breast and ovarian cancer, or at least 4 cases of breast cancer (at any age), that genotyping might be considered. The emerging picture of BRCA1 population genetics involves complex interactions of family history, age, and genetic ancestry, all of which should be taken into account when considering testing or interpreting results.