Lee Andrew J, Cunningham Alex P, Tischkowitz Marc, Simard Jacques, Pharoah Paul D, Easton Douglas F, Antoniou Antonis C
Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, The University of Cambridge, Strangeways Research Laboratory, Cambridge, UK.
Department of Medical Genetics and National Institute for Health Research, Cambridge Biomedical Research Centre, The University of Cambridge, Cambridge, UK.
Genet Med. 2016 Dec;18(12):1190-1198. doi: 10.1038/gim.2016.31. Epub 2016 Apr 14.
The proliferation of gene panel testing precipitates the need for a breast cancer (BC) risk model that incorporates the effects of mutations in several genes and family history (FH). We extended the BOADICEA model to incorporate the effects of truncating variants in PALB2, CHEK2, and ATM.
The BC incidence was modeled via the explicit effects of truncating variants in BRCA1/2, PALB2, CHEK2, and ATM and other unobserved genetic effects using segregation analysis methods.
The predicted average BC risk by age 80 for an ATM mutation carrier is 28%, 30% for CHEK2, 50% for PALB2, and 74% for BRCA1 and BRCA2. However, the BC risks are predicted to increase with FH burden. In families with mutations, predicted risks for mutation-negative members depend on both FH and the specific mutation. The reduction in BC risk after negative predictive testing is greatest when a BRCA1 mutation is identified in the family, but for women whose relatives carry a CHEK2 or ATM mutation, the risks decrease slightly.
The model may be a valuable tool for counseling women who have undergone gene panel testing for providing consistent risks and harmonizing their clinical management. A Web application can be used to obtain BC risks in clinical practice (http://ccge.medschl.cam.ac.uk/boadicea/).Genet Med 18 12, 1190-1198.
基因检测组合的激增促使人们需要一种乳腺癌（BC）风险模型，该模型要纳入多个基因的突变效应和家族史（FH）。我们扩展了BOADICEA模型，以纳入PALB2、CHEK2和ATM基因截短变异的效应。
采用分离分析方法，通过BRCA1/2、PALB2、CHEK2和ATM基因截短变异的明确效应以及其他未观察到的遗传效应来模拟BC发病率。
ATM突变携带者到80岁时预测的平均BC风险为28%，CHEK2为30%，PALB2为50%，BRCA1和BRCA2为74%。然而，BC风险预计会随着FH负担的增加而升高。在有突变的家族中，突变阴性成员的预测风险取决于FH和具体的突变。当家族中检测到BRCA1突变时，阴性预测检测后BC风险的降低幅度最大，但对于亲属携带CHEK2或ATM突变的女性，风险略有降低。
该模型可能是一种有价值的工具，可为接受基因检测组合的女性提供咨询，以提供一致的风险并协调其临床管理。可使用一个网络应用程序在临床实践中获取BC风险（http://ccge.medschl.cam.ac.uk/boadicea/）。《遗传医学》第18卷第12期，1190 - 1198页。
