评估AURKA-HMMR-TPX2-TUBG1功能模块与BRCA1/2突变携带者患乳腺癌风险之间的关联。
Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.
作者信息
Blanco Ignacio, Kuchenbaecker Karoline, Cuadras Daniel, Wang Xianshu, Barrowdale Daniel, de Garibay Gorka Ruiz, Librado Pablo, Sánchez-Gracia Alejandro, Rozas Julio, Bonifaci Núria, McGuffog Lesley, Pankratz Vernon S, Islam Abul, Mateo Francesca, Berenguer Antoni, Petit Anna, Català Isabel, Brunet Joan, Feliubadaló Lidia, Tornero Eva, Benítez Javier, Osorio Ana, Ramón y Cajal Teresa, Nevanlinna Heli, Aittomäki Kristiina, Arun Banu K, Toland Amanda E, Karlan Beth Y, Walsh Christine, Lester Jenny, Greene Mark H, Mai Phuong L, Nussbaum Robert L, Andrulis Irene L, Domchek Susan M, Nathanson Katherine L, Rebbeck Timothy R, Barkardottir Rosa B, Jakubowska Anna, Lubinski Jan, Durda Katarzyna, Jaworska-Bieniek Katarzyna, Claes Kathleen, Van Maerken Tom, Díez Orland, Hansen Thomas V, Jønson Lars, Gerdes Anne-Marie, Ejlertsen Bent, de la Hoya Miguel, Caldés Trinidad, Dunning Alison M, Oliver Clare, Fineberg Elena, Cook Margaret, Peock Susan, McCann Emma, Murray Alex, Jacobs Chris, Pichert Gabriella, Lalloo Fiona, Chu Carol, Dorkins Huw, Paterson Joan, Ong Kai-Ren, Teixeira Manuel R, Hogervorst Frans B L, van der Hout Annemarie H, Seynaeve Caroline, van der Luijt Rob B, Ligtenberg Marjolijn J L, Devilee Peter, Wijnen Juul T, Rookus Matti A, Meijers-Heijboer Hanne E J, Blok Marinus J, van den Ouweland Ans M W, Aalfs Cora M, Rodriguez Gustavo C, Phillips Kelly-Anne A, Piedmonte Marion, Nerenstone Stacy R, Bae-Jump Victoria L, O'Malley David M, Ratner Elena S, Schmutzler Rita K, Wappenschmidt Barbara, Rhiem Kerstin, Engel Christoph, Meindl Alfons, Ditsch Nina, Arnold Norbert, Plendl Hansjoerg J, Niederacher Dieter, Sutter Christian, Wang-Gohrke Shan, Steinemann Doris, Preisler-Adams Sabine, Kast Karin, Varon-Mateeva Raymonda, Gehrig Andrea, Bojesen Anders, Pedersen Inge Sokilde, Sunde Lone, Jensen Uffe Birk, Thomassen Mads, Kruse Torben A, Foretova Lenka, Peterlongo Paolo, Bernard Loris, Peissel Bernard, Scuvera Giulietta, Manoukian Siranoush, Radice Paolo, Ottini Laura, Montagna Marco, Agata Simona, Maugard Christine, Simard Jacques, Soucy Penny, Berger Andreas, Fink-Retter Anneliese, Singer Christian F, Rappaport Christine, Geschwantler-Kaulich Daphne, Tea Muy-Kheng, Pfeiler Georg, John Esther M, Miron Alex, Neuhausen Susan L, Terry Mary Beth, Chung Wendy K, Daly Mary B, Goldgar David E, Janavicius Ramunas, Dorfling Cecilia M, van Rensburg Elisabeth J, Fostira Florentia, Konstantopoulou Irene, Garber Judy, Godwin Andrew K, Olah Edith, Narod Steven A, Rennert Gad, Paluch Shani Shimon, Laitman Yael, Friedman Eitan, Liljegren Annelie, Rantala Johanna, Stenmark-Askmalm Marie, Loman Niklas, Imyanitov Evgeny N, Hamann Ute, Spurdle Amanda B, Healey Sue, Weitzel Jeffrey N, Herzog Josef, Margileth David, Gorrini Chiara, Esteller Manel, Gómez Antonio, Sayols Sergi, Vidal Enrique, Heyn Holger, Stoppa-Lyonnet Dominique, Léoné Melanie, Barjhoux Laure, Fassy-Colcombet Marion, de Pauw Antoine, Lasset Christine, Ferrer Sandra Fert, Castera Laurent, Berthet Pascaline, Cornelis François, Bignon Yves-Jean, Damiola Francesca, Mazoyer Sylvie, Sinilnikova Olga M, Maxwell Christopher A, Vijai Joseph, Robson Mark, Kauff Noah, Corines Marina J, Villano Danylko, Cunningham Julie, Lee Adam, Lindor Noralane, Lázaro Conxi, Easton Douglas F, Offit Kenneth, Chenevix-Trench Georgia, Couch Fergus J, Antoniou Antonis C, Pujana Miguel Angel
机构信息
Hereditary Cancer Program, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, Catalonia, Spain.
Epidemiological Study of Familial Breast Cancer (EMBRACE), Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom.
出版信息
PLoS One. 2015 Apr 1;10(4):e0120020. doi: 10.1371/journal.pone.0120020. eCollection 2015.
While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach. The association of HMMR rs299290 with breast cancer risk in BRCA1 mutation carriers was confirmed: per-allele hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.04-1.15, p = 1.9 x 10(-4) (false discovery rate (FDR)-adjusted p = 0.043). Variation in CSTF1, located next to AURKA, was also found to be associated with breast cancer risk in BRCA2 mutation carriers: rs2426618 per-allele HR = 1.10, 95% CI 1.03-1.16, p = 0.005 (FDR-adjusted p = 0.045). Assessment of pairwise interactions provided suggestions (FDR-adjusted pinteraction values > 0.05) for deviations from the multiplicative model for rs299290 and CSTF1 rs6064391, and rs299290 and TUBG1 rs11649877 in both BRCA1 and BRCA2 mutation carriers. Following these suggestions, the expression of HMMR and AURKA or TUBG1 in sporadic breast tumors was found to potentially interact, influencing patients' survival. Together, the results of this study support the hypothesis of a causative link between altered function of AURKA-HMMR-TPX2-TUBG1 and breast carcinogenesis in BRCA1/2 mutation carriers.
虽然BRCA1与AURKA-RHAMM-TPX2-TUBG1之间的相互作用调节乳腺上皮细胞极化，但HMMR（基因产物RHAMM）的常见基因变异可能与BRCA1突变携带者患乳腺癌的风险相关。基于这些观察结果，我们进一步评估了AURKA-HMMR-TPX2-TUBG1功能模块与BRCA1或BRCA2突变携带者患乳腺癌风险之间的联系。对15252名BRCA1突变携带者和8211名BRCA2突变携带者的41个单核苷酸多态性（SNP）进行了基因分型，随后采用回顾性似然法进行分析。BRCA1突变携带者中HMMR rs299290与乳腺癌风险的关联得到证实：每等位基因风险比（HR）=1.10，95%置信区间（CI）1.04-1.15，p = 1.9×10⁻⁴（错误发现率（FDR）调整后p = 0.043）。还发现位于AURKA旁边的CSTF1变异与BRCA2突变携带者患乳腺癌的风险相关：rs2426618每等位基因HR = 1.10，95%CI 1.03-1.16，p = 0.005（FDR调整后p = 0.045）。对成对相互作用的评估为BRCA1和BRCA2突变携带者中rs299290与CSTF1 rs6064391以及rs299290与TUBG1 rs11649877偏离乘法模型提供了提示（FDR调整后p相互作用值>0.05）。遵循这些提示，发现散发性乳腺肿瘤中HMMR与AURKA或TUBG1的表达可能相互作用，影响患者的生存。总之，本研究结果支持AURKA-HMMR-TPX2-TUBG1功能改变与BRCA1/2突变携带者乳腺癌发生之间存在因果联系的假设。
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