BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing.-猫眼课题宝

DOI：

10.1001/jama.1997.03550150046034

发表时间：

1997-10

期刊：

JAMA

影响因子：

通讯作者：

中科院分区：

其他

文献类型：

作者：

D. Shattuck-Eidens;A. Oliphant;M. Mcclure;Celeste McBride;J. Gupte;T. Rubano;D. Pruss;S. Tavtigian;D. Teng;N. Adey;Mark Staebell;Kathryn Gumpper;R. Lundstrom;M. Hulick;Mark Kelly;J. Holmen;B. Lingenfelter;S. Manley;F. Fujimura;M. Luce;B. Ward;L. Cannon-Albright;L. Steele;K. Offit;T. Gilewski;Larry Norton;K. T. Brown;Charlene J. Schulz;H. Hampel;A. Schluger;E. Giulotto;W. Zoli;A. Ravaioli;H. Nevanlinna;S. Pyrhonen;P. Rowley;S. Loader;M. Osborne;M. Daly;I. Tepler;P. L. Weinstein;Jennifer Scalia;Richard Michaelson;Rodney J. Scott;P. Radice;M. Pierotti;J. Garber;C. Isaacs;B. Peshkin;M. Lippman;M. Dosik;M. Caligo;R. Greenstein;R. Pilarski;Barbara L. Weber;R. Burgemeister;T. S. Frank;M. Skolnick;Alun Thomas

背景：BRCA1基因突变可能会导致乳腺癌和/或卵巢癌的重大风险。然而，关于所有可能的突变以及风险因素与突变之间的关系的知识是不完整的。目的鉴定乳腺癌和/或卵巢癌患者中BRCA1突变，并确定最能预测有害BRCA1突变存在的因素。来自美国、意大利、德国、芬兰和瑞士的研究机构对798名女性进行了BRCA1编码序列和侧翼内含子区域的完整序列分析。研究机构选择了798名代表家庭的人员（每个家庭一人），这些家庭被认为由于潜在的危险因素（如多例乳腺癌、早期乳腺癌诊断和卵巢癌病例）而具有较高的BRCA1突变先验风险。没有参与者来自遗传标记显示与BRCA1位点相关的家庭。主要结果测量在该样本中检测到的序列变异，以及旨在确定BRCA1突变检测阳性的预测特征的分析。结果102例（12.8%）女性检测到明显的有害突变。发现了50个新的遗传改变，包括24个有害突变，24个未知意义的变异和2个罕见的多态性。在71名德系犹太妇女的一个亚群中，只发现了两种不同的有害突变：185delAG（17例）和532insc（7例）。揭示了先前报道的外显子11突变的偏倚。患者的特定诊断特征（单侧或双侧乳腺癌，伴或不伴卵巢癌）、早期诊断年龄、德系犹太人种族和癌症家族史与携带有害BRCA1突变的可能性呈正相关。结论：通过逻辑回归分析，我们提供了一种评估女性携带有害BRCA1突变的概率的方法，这可以成为临床医生将遗传易感性检测纳入其医疗实践的重要工具。

CONTEXT A mutation in the BRCA1 gene may confer substantial risk for breast and/or ovarian cancer. However, knowledge regarding all possible mutations and the relationship between risk factors and mutations is incomplete. OBJECTIVES To identify BRCA1 mutations and to determine factors that best predict presence of a deleterious BRCA1 mutation in patients with breast and/or ovarian cancer. DESIGN A complete sequence analysis of the BRCA1 coding sequence and flanking intronic regions was performed in 798 women in a collaborative effort involving institutions from the United States, Italy, Germany, Finland, and Switzerland. PARTICIPANTS Institutions selected 798 persons representing families (1 person for each family) thought to be at elevated a priori risk of BRCA1 mutation due to potential risk factors, such as multiple cases of breast cancer, early age of breast cancer diagnosis, and cases of ovarian cancer. No participant was from a family in which genetic markers showed linkage to the BRCA1 locus. MAJOR OUTCOME MEASURES Sequence variants detected in this sample are presented along with analyses designed to determine predictive characteristics of those testing positive for BRCA1 mutations. RESULTS In 102 women (12.8%), clearly deleterious mutations were detected. Fifty new genetic alterations were found including 24 deleterious mutations, 24 variants of unknown significance, and 2 rare polymorphisms. In a subset of 71 Ashkenazi Jewish women, only 2 distinct deleterious mutations were found: 185delAG in 17 cases and 5382insC in 7 cases. A bias in prior reports for mutations in exon 11 was revealed. Characteristics of a patient's specific diagnosis (unilateral or bilateral breast cancer, with or without ovarian cancer), early age at diagnosis, Ashkenazi Jewish ethnicity, and family history of cancer were positively associated with the probability of her carrying a deleterious BRCA1 mutation. CONCLUSIONS Using logistic regression analysis, we provide a method for evaluating the probability of a woman's carrying a deleterious BRCA1 mutation for a wide range of cases, which can be an important tool for clinicians as they incorporate genetic susceptibility testing into their medical practice.

BRCA1 sequence analysis in women at high risk for susceptibility mutations. Risk factor analysis and implications for genetic testing.

文献摘要

被引文献

相似文献