乳腺癌风险与显示不同等位基因表达的基因变异的关联：4q21处一个新的乳腺癌易感位点的鉴定。
Association of breast cancer risk with genetic variants showing differential allelic expression: Identification of a novel breast cancer susceptibility locus at 4q21.
作者信息
Hamdi Yosr, Soucy Penny, Adoue Véronique, Michailidou Kyriaki, Canisius Sander, Lemaçon Audrey, Droit Arnaud, Andrulis Irene L, Anton-Culver Hoda, Arndt Volker, Baynes Caroline, Blomqvist Carl, Bogdanova Natalia V, Bojesen Stig E, Bolla Manjeet K, Bonanni Bernardo, Borresen-Dale Anne-Lise, Brand Judith S, Brauch Hiltrud, Brenner Hermann, Broeks Annegien, Burwinkel Barbara, Chang-Claude Jenny, Couch Fergus J, Cox Angela, Cross Simon S, Czene Kamila, Darabi Hatef, Dennis Joe, Devilee Peter, Dörk Thilo, Dos-Santos-Silva Isabel, Eriksson Mikael, Fasching Peter A, Figueroa Jonine, Flyger Henrik, García-Closas Montserrat, Giles Graham G, Goldberg Mark S, González-Neira Anna, Grenaker-Alnæs Grethe, Guénel Pascal, Haeberle Lothar, Haiman Christopher A, Hamann Ute, Hallberg Emily, Hooning Maartje J, Hopper John L, Jakubowska Anna, Jones Michael, Kabisch Maria, Kataja Vesa, Lambrechts Diether, Le Marchand Loic, Lindblom Annika, Lubinski Jan, Mannermaa Arto, Maranian Mel, Margolin Sara, Marme Frederik, Milne Roger L, Neuhausen Susan L, Nevanlinna Heli, Neven Patrick, Olswold Curtis, Peto Julian, Plaseska-Karanfilska Dijana, Pylkäs Katri, Radice Paolo, Rudolph Anja, Sawyer Elinor J, Schmidt Marjanka K, Shu Xiao-Ou, Southey Melissa C, Swerdlow Anthony, Tollenaar Rob A E M, Tomlinson Ian, Torres Diana, Truong Thérèse, Vachon Celine, Van Den Ouweland Ans M W, Wang Qin, Winqvist Robert, Zheng Wei, Benitez Javier, Chenevix-Trench Georgia, Dunning Alison M, Pharoah Paul D P, Kristensen Vessela, Hall Per, Easton Douglas F, Pastinen Tomi, Nord Silje, Simard Jacques
机构信息
Genomics Center, Centre Hospitalier Universitaire de Québec Research Center, Laval University, Quebec, Canada.
Institut National de la Santé et de la Recherche Médicale U1043, Toulouse, France.
出版信息
Oncotarget. 2016 Dec 6;7(49):80140-80163. doi: 10.18632/oncotarget.12818.
There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas.
基因表达水平存在显著的个体间差异。通过调节基因表达，顺式作用变异代表了表型变异的一个重要来源。因此，与差异等位基因表达相关的顺式调控单核苷酸多态性（SNP）是作为致病变异进行进一步研究的功能候选者。为了研究与差异等位基因表达相关的常见变异是否参与乳腺癌易感性，基于基因参与癌症相关途径和/或机制建立了一份基因列表。此后，利用来自全基因组等位基因表达相关SNP图谱的数据，选择了313个基因变异，然后在46451例乳腺癌病例和42599例欧洲血统对照中评估它们与乳腺癌风险的关联，这些对照来自参与乳腺癌协会联盟的41项研究。评估了这些关联与总体乳腺癌风险以及雌激素受体阴性和阳性疾病的关系。在4q21上鉴定出一个新的乳腺癌易感位点（rs11099601）（比值比=1.05，P=5.6×10−6）。rs11099601位于一个135kb的连锁不平衡区域，该区域包含几个基因，包括编码蛋白质HEL308（一种参与DNA修复的DNA依赖性ATP酶和DNA解旋酶）的HELQ、编码线粒体核糖体蛋白S18C的MRPS18C以及编码参与DNA损伤反应和双链断裂（DSB）修复的BRCA1 BRCT结构域相互作用蛋白的FAM175A（ABRAXAS）。乳腺癌组织中的表达数量性状位点（eQTL）分析显示，rs11099601与HELQ（P=8.28×10−14）、MRPS18C（P=1.94×10−27）和FAM175A（P=3.83×10−3）相关，分别解释了这些基因在乳腺癌中表达变异的约20%、14%和1%。
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