Association of Germline Genetic Variants with Breast Cancer-Specific Survival in Patient Subgroups Defined by Clinic-Pathological Variables Related to Tumor Biology and Type of Systemic Treatment

Morra Anna,Escala-Garcia Maria,Beesley Jonathan,Keeman Renske,Canisius Sander,Ahearn Thomas U., University of Toronto,Anton-Culver Hoda,Arndt Volker, University of Wisconsin-Milwaukee,Augustinsson Annelie,Beane Freeman Laura E.,Becher Heiko,Beckmann Matthias W.,Behrens Sabine, University of Copenhagen,Bolla Manjeet K., German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK),Brüning Thomas,Buys Saundra S.,Caan Bette, University of Pisa,Canzian Federico,Castelao Jose E., University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf,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., Harvard T.H. Chan School of Public Health,Eriksson Mikael, University of California at Los Angeles, David Geffen School of Medicine,Flyger Henrik,Fritschi Lin, University of California San Diego, Moores Cancer Center,García-Sáenz José A., Monash University,Grip Mervi,Guénel Pascal, Helmholtz Zentrum München,Hahnen Eric,Haiman Christopher A.,Håkansson Niclas, Södersjukhuset,Hamann Ute,Hart Steven N.,Hartikainen Jaana M.,Hartmann Arndt,He Wei,Hooning Maartje J., University of Tübingen,Hopper John L.,Howell Anthony, University of Oxford,Jager Agnes,Jakubowska Anna,Janni Wolfgang, Stanford Cancer Institute, Stanford University School of Medicine,Jung Audrey Y.,Kaaks Rudolf,Keupers Machteld,Kitahara Cari M.,Koutros Stella,Kraft Peter, Oslo University Hospital and University of Oslo,Lacey James V., University of Leuven,Le Marchand Loic, Karolinska University Hospital,Linet Martha,Luben Robert N.,Lubiński Jan,Lush Michael, Kuopio University Hospital, Biobank of Eastern Finland,Manoochehri Mehdi, Karolinska Institutet,Martens John W. M., University of California San Diego,Mavroudis Dimitrios, The Cyprus Institute of Neurology & Genetics, Cyprus School of Molecular Medicine, University Health Network, Laboratory Medicine Program,Muranen Taru A.,Nevanlinna Heli, Copenhagen University Hospital,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., University of Cologne, Center for Molecular Medicine Cologne (CMMC), University Hospital and German Cancer Research Center, National Center for Tumor Diseases,Scott Christopher,Shah Mitul,Smichkoska Snezhana, The University of Melbourne, University of Western Australia, University of Heidelberg,Swerdlow Anthony J., Weill Cornell Medicine,Tapper William J.,Teras Lauren R.,Terry Mary Beth,Tollenaar Rob A. E. M.,Troester Melissa A.,Truong Thérèse,Vachon Celine M.,Wang Qin,Hurson Amber N., Northern Finland Laboratory Centre Oulu, Uppsala University,Ziogas Argyrios, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK) Partner Site Tübingen,García-Closas Montserrat,Pharoah Paul D. P.,Easton Douglas F.,Chenevix-Trench Georgia,Schmidt Marjanka K.

Carolina Digital Repository (University of North Carolina at Chapel Hill)（2021）

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Abstract

Background 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. Methods 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). Results 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. Conclusions 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.

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Key words

Common germline genetic variants,Breast cancer-specific survival,Patient subgroups,Tumor biology,Systemic treatment

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