Morra Anna, Escala-Garcia Maria, Beesley Jonathan, Keeman Renske, Canisius Sander, Ahearn Thomas U, Andrulis Irene L, Anton-Culver Hoda, Arndt Volker, Auer Paul L, Augustinsson Annelie, Beane Freeman Laura E, Becher Heiko, Beckmann Matthias W, Behrens Sabine, Bojesen Stig E, Bolla Manjeet K, Brenner Hermann, Brüning Thomas, Buys Saundra S, Caan Bette, Campa Daniele, Canzian Federico, Castelao Jose E, Chang-Claude Jenny, Chanock Stephen J, Cheng Ting-Yuan David, Clarke Christine L, Colonna Sarah V, Couch Fergus J, Cox Angela, Cross Simon S, Czene Kamila, Daly Mary B, Dennis Joe, Dörk Thilo, Dossus Laure, Dunning Alison M, Dwek Miriam, Eccles Diana M, Ekici Arif B, Eliassen A Heather, Eriksson Mikael, Evans D Gareth, Fasching Peter A, Flyger Henrik, Fritschi Lin, Gago-Dominguez Manuela, García-Sáenz José A, Giles Graham G, Grip Mervi, Guénel Pascal, Gündert Melanie, Hahnen Eric, Haiman Christopher A, Håkansson Niclas, Hall Per, Hamann Ute, Hart Steven N, Hartikainen Jaana M, Hartmann Arndt, He Wei, Hooning Maartje J, Hoppe Reiner, Hopper John L, Howell Anthony, Hunter David J, Jager Agnes, Jakubowska Anna, Janni Wolfgang, John Esther M, Jung Audrey Y, Kaaks Rudolf, Keupers Machteld, Kitahara Cari M, Koutros Stella, Kraft Peter, Kristensen Vessela N, Kurian Allison W, Lacey James V, Lambrechts Diether, Le Marchand Loic, Lindblom Annika, Linet Martha, Luben Robert N, Lubiński Jan, Lush Michael, Mannermaa Arto, Manoochehri Mehdi, Margolin Sara, Martens John W M, Martinez Maria Elena, Mavroudis Dimitrios, Michailidou Kyriaki, Milne Roger L, Mulligan Anna Marie, Muranen Taru A, Nevanlinna Heli, Newman William G, Nielsen Sune F, Nordestgaard Børge G, Olshan Andrew F, Olsson Håkan, Orr Nick, Park-Simon Tjoung-Won, Patel Alpa V, Peissel Bernard, Peterlongo Paolo, Plaseska-Karanfilska Dijana, Prajzendanc Karolina, Prentice Ross, Presneau Nadege, Rack Brigitte, Rennert Gad, Rennert Hedy S, Rhenius Valerie, Romero Atocha, Roylance Rebecca, Ruebner Matthias, Saloustros Emmanouil, Sawyer Elinor J, Schmutzler Rita K, Schneeweiss Andreas, Scott Christopher, Shah Mitul, Smichkoska Snezhana, Southey Melissa C, Stone Jennifer, Surowy Harald, Swerdlow Anthony J, Tamimi Rulla M, Tapper William J, Teras Lauren R, Terry Mary Beth, Tollenaar Rob A E M, Tomlinson Ian, Troester Melissa A, Truong Thérèse, Vachon Celine M, Wang Qin, Hurson Amber N, Winqvist Robert, Wolk Alicja, Ziogas Argyrios, Brauch Hiltrud, García-Closas Montserrat, Pharoah Paul D P, Easton Douglas F, Chenevix-Trench Georgia, Schmidt Marjanka K
Division of Molecular Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, 1066 CX, The Netherlands.
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
Breast Cancer Res. 2021 Aug 18;23(1):86. doi: 10.1186/s13058-021-01450-7.
Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients.
We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP < 0.15).
Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E-08, BFDP = 0.01, per G allele); variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E-07, BFDP = 0.09, per G allele); variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E-08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E-08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy.
We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.
鉴于乳腺肿瘤之间存在高度异质性，在未分层的乳腺癌患者群体中，特定亚组内可能存在的常见种系基因变异与生存率之间的关联可能未被发现。
我们基于预后因素（包括激素受体、肿瘤分级、年龄和全身治疗类型），在15个乳腺癌患者亚组中进行了全基因组关联分析。分析基于来自乳腺癌协会联盟的91686名欧洲血统女性患者，其中包括在中位随访8.1年期间发生的7531例乳腺癌特异性死亡病例。采用Cox回归评估常见种系变异与15年和5年乳腺癌特异性生存率的关联。我们通过贝叶斯假发现概率（BFDP<0.15）评估这些关联为真阳性的概率。
在三个患者亚组中观察到与乳腺癌特异性生存相关的证据，3级肿瘤患者中的rs5934618变异（15年风险比（HR）[95%置信区间（CI）]1.32[1.20，1.45]，P = 1.4E-08，BFDP = 0.01，每G等位基因）；接受内分泌治疗的雌激素受体（ER）阳性肿瘤患者中的rs4679741变异（15年HR[95%CI]1.18[1.11，1.26]，P = 1.6E-07，BFDP = 0.09，每G等位基因）；接受化疗的ER阴性肿瘤患者中的rs1106333变异（15年HR[95%CI]1.68[1.39，2.03]，P = 5.6E-08，BFDP = 0.12，每A等位基因）和rs78754389变异（5年HR[95%CI]1.79[1.46，2.20]，P = 1.7E-08，BFDP = 0.07，每A等位基因）。
我们在三个患者亚组中发现了四个与乳腺癌特异性生存相关的基因座的证据。在其他患者亚组中存在关联的证据有限。然而，由于事件数量较少，许多亚组的检验效能有限。即便如此，我们的结果表明常见种系基因变异对乳腺癌特异性生存的影响可能有限。
