Are the so-called low penetrance breast cancer genes, ATM, BRIP1, PALB2 and CHEK2, high risk for women with strong family histories?
Are the so-called low penetrance breast cancer genes, ATM, BRIP1, PALB2 and CHEK2, high risk for women with strong family histories?
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所谓的低渗透率乳腺癌基因，ATM，BRIP1，PALB2和CHEK2是否对拥有较强家庭历史的女性高风险？
DOI：
10.1186/bcr2099
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Hopper JL
中科院分区：
文献类型：
--
作者：
Byrnes GB;Southey MC;Hopper JL
一个女人通常提出遗传咨询，因为她有一个强大的家族史，并有兴趣知道她将在未来发展疾病的概率;也就是说，她的绝对风险。给定因素的相对风险是指与人口平均风险（意义a）或与没有该因素时的风险（意义B）相比的风险，所有其他因素保持不变。不理解这三个不同的概念可能会导致无法正确理解临床基因检测研究的后果。几项研究发现，ATM、BRIP 1、PALB 2和CHEK 2的突变频率在有强烈家族史的病例中比对照组高出许多倍。为了解释选定的病例抽样（确定），应用了一个统计模型，该模型假设任何测量变量的影响乘以未测量变量的影响。这种乘法多基因模型实际上估计了意义B的相对风险，而不是意义a，并发现它在1.7至2.4的范围内。作者得出结论，这些变体是“低突变率”。他们没有注意到，他们的模型拟合预测，对于一些女性来说，绝对风险可能与BRCA 2突变携带者一样高。这是因为相对风险乘以多基因风险，而后者是由家族史预测的。因此，对有家族史的女性进行这些基因的突变检测，特别是如果它是早发性的，可能与BRCA 1和BRCA 2一样具有临床相关性。
A woman typically presents for genetic counselling because she has a strong family history and is interested in knowing the probability she will develop disease in the future; that is, her absolute risk. Relative risk for a given factor refers to risk compared with either population average risk (sense a), or risk when not having the factor, with all other factors held constant (sense b). Not understanding that these are three distinct concepts can result in failure to correctly appreciate the consequences of studies on clinical genetic testing. Several studies found that the frequencies of mutations in ATM, BRIP1, PALB2 and CHEK2 were many times greater for cases with a strong family history than for controls. To account for the selected case sampling (ascertainment), a statistical model that assumes that the effect of any measured variant multiplies the effect of unmeasured variants was applied. This multiplicative polygenic model in effect estimated the relative risk in the sense b, not sense a, and found it was in the range of 1.7 to 2.4. The authors concluded that the variants are "low penetrance". They failed to note that their model fits predicted that, for some women, absolute risk may be as high as for BRCA2 mutation carriers. This is because the relative risk multiplies polygenic risk, and the latter is predicted by family history. Therefore, mutation testing of these genes for women with a strong family history, especially if it is of early onset, may be as clinically relevant as it is for BRCA1 and BRCA2.
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影响因子：
64.8
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