CHEK2*1100delC相关乳腺癌风险的基因修饰因子。
Genetic modifiers of CHEK2*1100delC-associated breast cancer risk.
作者信息
Muranen Taru A, Greco Dario, Blomqvist Carl, Aittomäki Kristiina, Khan Sofia, Hogervorst Frans, Verhoef Senno, Pharoah Paul D P, Dunning Alison M, Shah Mitul, Luben Robert, Bojesen Stig E, Nordestgaard Børge G, Schoemaker Minouk, Swerdlow Anthony, García-Closas Montserrat, Figueroa Jonine, Dörk Thilo, Bogdanova Natalia V, Hall Per, Li Jingmei, Khusnutdinova Elza, Bermisheva Marina, Kristensen Vessela, Borresen-Dale Anne-Lise, Peto Julian, Dos Santos Silva Isabel, Couch Fergus J, Olson Janet E, Hillemans Peter, Park-Simon Tjoung-Won, Brauch Hiltrud, Hamann Ute, Burwinkel Barbara, Marme Frederik, Meindl Alfons, Schmutzler Rita K, Cox Angela, Cross Simon S, Sawyer Elinor J, Tomlinson Ian, Lambrechts Diether, Moisse Matthieu, Lindblom Annika, Margolin Sara, Hollestelle Antoinette, Martens John W M, Fasching Peter A, Beckmann Matthias W, Andrulis Irene L, Knight Julia A, Anton-Culver Hoda, Ziogas Argyrios, Giles Graham G, Milne Roger L, Brenner Hermann, Arndt Volker, Mannermaa Arto, Kosma Veli-Matti, Chang-Claude Jenny, Rudolph Anja, Devilee Peter, Seynaeve Caroline, Hopper John L, Southey Melissa C, John Esther M, Whittemore Alice S, Bolla Manjeet K, Wang Qin, Michailidou Kyriaki, Dennis Joe, Easton Douglas F, Schmidt Marjanka K, Nevanlinna Heli
机构信息
Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
Unit of Systems Toxicology, Finnish Institute of Occupational Health, Helsinki, Finland.
出版信息
Genet Med. 2017 May;19(5):599-603. doi: 10.1038/gim.2016.147. Epub 2016 Oct 6.
PURPOSE
CHEK21100delC is a founder variant in European populations that confers a two- to threefold increased risk of breast cancer (BC). Epidemiologic and family studies have suggested that the risk associated with CHEK21100delC is modified by other genetic factors in a multiplicative fashion. We have investigated this empirically using data from the Breast Cancer Association Consortium (BCAC).
METHODS
Using genotype data from 39,139 (624 1100delC carriers) BC patients and 40,063 (224) healthy controls from 32 BCAC studies, we analyzed the combined risk effects of CHEK2*1100delC and 77 common variants in terms of a polygenic risk score (PRS) and pairwise interaction.
RESULTS
The PRS conferred odds ratios (OR) of 1.59 (95% CI: 1.21-2.09) per standard deviation for BC for CHEK21100delC carriers and 1.58 (1.55-1.62) for noncarriers. No evidence of deviation from the multiplicative model was found. The OR for the highest quintile of the PRS was 2.03 (0.86-4.78) for CHEK21100delC carriers, placing them in the high risk category according to UK NICE guidelines. The OR for the lowest quintile was 0.52 (0.16-1.74), indicating a lifetime risk close to the population average.
CONCLUSION
Our results confirm the multiplicative nature of risk effects conferred by CHEK2*1100delC and the common susceptibility variants. Furthermore, the PRS could identify carriers at a high lifetime risk for clinical actions.Genet Med advance online publication 06 October 2016.
目的
CHEK21100delC是欧洲人群中的一个始祖变异，它使患乳腺癌（BC）的风险增加两到三倍。流行病学和家族研究表明，与CHEK21100delC相关的风险会以乘法方式被其他遗传因素所改变。我们利用乳腺癌协会联盟（BCAC）的数据对此进行了实证研究。
方法
我们使用了来自32项BCAC研究的39139例（624例携带1100delC）乳腺癌患者和40063例（224例）健康对照的基因型数据，从多基因风险评分（PRS）和成对相互作用方面分析了CHEK2*1100delC和77个常见变异的联合风险效应。
结果
对于携带CHEK21100delC的个体，PRS每增加一个标准差，患BC的优势比（OR）为1.59（95%可信区间：1.21 - 2.09），对于非携带者为1.58（1.55 - 1.62）。未发现偏离乘法模型的证据。对于携带CHEK21100delC的个体，PRS最高五分位数的OR为2.03（0.86 - 4.78），根据英国国家卫生与临床优化研究所（NICE）指南，他们属于高风险类别。最低五分位数的OR为0.52（0.16 - 1.74），表明终生风险接近人群平均水平。
结论
我们的结果证实了CHEK2*1100delC和常见易感性变异所赋予的风险效应的乘法性质。此外，PRS可以识别出终生风险高的携带者以便采取临床行动。《遗传医学》于2016年10月6日在线优先发表。
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