A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes.
A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes.
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DOI：
10.1038/sj.bjc.6600008
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发表时间：
2002-01-07
影响因子：
8.8
通讯作者：
Easton, D F
中科院分区：
文献类型：
--
作者：
Antoniou, A C;Pharoah, P D P;McMullan, G;Day, N E;Stratton, M R;Peto, J;Ponder, B J;Easton, D F
在计算一名妇女是BRCA 1或BRCA 2携带者的概率以进行遗传咨询时，重要的是要考虑到可能存在其他乳腺癌易感基因。我们使用了来自英国一系列基于人群的乳腺癌病例和高风险家庭的数据，以及BRCA 1和BRCA 2突变状态的信息，以调查可以最好地解释BRCA 1和BRCA 2家族以外的家族性乳腺癌的遗传模型。我们还评估了BRCA 1和BRCA 2携带者中风险修饰因子的证据。我们估计了BRCA 1，BRCA 2，第三个假设基因“BRCA 3”的同时效应，以及使用分离分析的多基因效应。超几何多基因模型被用来近似多基因遗传和风险修饰的影响。BRCA 1和BRCA 2不能解释所有观察到的家族聚集性。残留家族性乳腺癌的最佳拟合模型是多基因模型，尽管具有单个隐性等位基因的模型产生了类似的拟合。也有重要的证据表明，其他基因对BRCA 1和BRCA 2突变携带者患乳腺癌的风险具有修饰作用。在该模型下，BRCA 1的频率估计为0.051%（95% CI：0.021-0.125%），BRCA 2的频率估计为0.068%（95% CI：0.033-0.141%）。根据所有修饰物的平均发病率，70岁时的乳腺癌风险估计为BRCA 1为35.3%，BRCA 2为50.3%。BRCA 1和BRCA 2的相应卵巢癌风险分别为25.9%和9.1%。研究结果表明，几个常见的，低突变率的基因与风险的乘法效应可能会导致乳腺癌的残留非BRCA 1/2家族聚集。修正效应可以解释先前报道的基于人群的BRCA 1/2突变率估计值与基于高危家庭的估计值之间的差异。英国癌症杂志（2002）86，76-83。DOI：10.1038/sj/bjc/6600008 www.bjcancer.com © 2002癌症研究运动
In computing the probability that a woman is a BRCA1 or BRCA2 carrier for genetic counselling purposes, it is important to allow for the fact that other breast cancer susceptibility genes may exist. We used data from both a population based series of breast cancer cases and high risk families in the UK, with information on BRCA1 and BRCA2 mutation status, to investigate the genetic models that can best explain familial breast cancer outside BRCA1 and BRCA2 families. We also evaluated the evidence for risk modifiers in BRCA1 and BRCA2 carriers. We estimated the simultaneous effects of BRCA1, BRCA2, a third hypothetical gene ‘BRCA3’, and a polygenic effect using segregation analysis. The hypergeometric polygenic model was used to approximate polygenic inheritance and the effect of risk modifiers. BRCA1 and BRCA2 could not explain all the observed familial clustering. The best fitting model for the residual familial breast cancer was the polygenic, although a model with a single recessive allele produced a similar fit. There was also significant evidence for a modifying effect of other genes on the risks of breast cancer in BRCA1 and BRCA2 mutation carriers. Under this model, the frequency of BRCA1 was estimated to be 0.051% (95% CI: 0.021–0.125%) and of BRCA2 0.068% (95% CI: 0.033–0.141%). The breast cancer risk by age 70 years, based on the average incidence over all modifiers was estimated to be 35.3% for BRCA1 and 50.3% for BRCA2. The corresponding ovarian cancer risks were 25.9% for BRCA1 and 9.1% for BRCA2. The findings suggest that several common, low penetrance genes with multiplicative effects on risk may account for the residual non-BRCA1/2 familial aggregation of breast cancer. The modifying effect may explain the previously reported differences between population based estimates for BRCA1/2 penetrance and estimates based on high-risk families. British Journal of Cancer (2002) 86, 76–83. DOI: 10.1038/sj/bjc/6600008 www.bjcancer.com © 2002 The Cancer Research Campaign