Shattuck-Eidens D, Oliphant A, McClure M, McBride C, Gupte J, Rubano T, Pruss D, Tavtigian S V, Teng D H, Adey N, Staebell M, Gumpper K, Lundstrom R, Hulick M, Kelly M, Holmen J, Lingenfelter B, Manley S, Fujimura F, Luce M, Ward B, Cannon-Albright L, Steele L, Offit K, Thomas A
Myriad Genetics, Inc, Salt Lake City, Utah, USA.
JAMA. 1997 Oct 15;278(15):1242-50.
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.
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.
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.
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.
Sequence variants detected in this sample are presented along with analyses designed to determine predictive characteristics of those testing positive for BRCA1 mutations.
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.
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基因的突变可能会使患乳腺癌和/或卵巢癌的风险大幅增加。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认识并不完整。
识别BRCA1突变，并确定最能预测乳腺癌和/或卵巢癌患者存在有害BRCA1突变的因素。
在美国、意大利、德国、芬兰和瑞士的机构共同参与下，对798名女性的BRCA1编码序列和侧翼内含子区域进行了完整的序列分析。
各机构挑选了798人（每个家庭1人），这些人所代表的家庭因潜在风险因素（如多例乳腺癌、乳腺癌诊断时年龄较小以及卵巢癌病例）被认为BRCA1突变的先验风险较高。没有参与者来自遗传标记显示与BRCA1基因座连锁的家庭。
展示该样本中检测到的序列变异，并进行分析以确定BRCA1突变检测呈阳性者的预测特征。
在102名女性（12.8%）中检测到明显有害的突变。发现了50种新的基因改变，包括24种有害突变、24种意义不明的变异和2种罕见的多态性。在71名阿什肯纳兹犹太女性亚组中，仅发现2种不同的有害突变：17例为185delAG，7例为5382insC。揭示了先前报告中外显子11突变的偏差。患者的特定诊断特征（单侧或双侧乳腺癌，有无卵巢癌）、诊断时年龄较小、阿什肯纳兹犹太种族以及癌症家族史与她携带有害BRCA1突变的概率呈正相关。
通过逻辑回归分析，我们提供了一种方法来评估广泛病例中女性携带有害BRCA1突变的概率，这对于临床医生将遗传易感性检测纳入医疗实践可能是一个重要工具。
