Breast Cancer Research (Aug 2021)

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

  • Anna Morra,
  • Maria Escala-Garcia,
  • Jonathan Beesley,
  • Renske Keeman,
  • Sander Canisius,
  • Thomas U. Ahearn,
  • Irene L. Andrulis,
  • Hoda Anton-Culver,
  • Volker Arndt,
  • Paul L. Auer,
  • Annelie Augustinsson,
  • Laura E. Beane Freeman,
  • Heiko Becher,
  • Matthias W. Beckmann,
  • Sabine Behrens,
  • Stig E. Bojesen,
  • Manjeet K. Bolla,
  • Hermann Brenner,
  • Thomas Brüning,
  • Saundra S. Buys,
  • Bette Caan,
  • Daniele Campa,
  • Federico Canzian,
  • Jose E. Castelao,
  • Jenny Chang-Claude,
  • Stephen J. Chanock,
  • Ting-Yuan David Cheng,
  • Christine L. Clarke,
  • NBCS Collaborators,
  • Sarah V. Colonna,
  • Fergus J. Couch,
  • Angela Cox,
  • Simon S. Cross,
  • Kamila Czene,
  • Mary B. Daly,
  • Joe Dennis,
  • Thilo Dörk,
  • Laure Dossus,
  • Alison M. Dunning,
  • Miriam Dwek,
  • Diana M. Eccles,
  • Arif B. Ekici,
  • A. Heather Eliassen,
  • Mikael Eriksson,
  • D. Gareth Evans,
  • Peter A. Fasching,
  • Henrik Flyger,
  • Lin Fritschi,
  • Manuela Gago-Dominguez,
  • José A. García-Sáenz,
  • Graham G. Giles,
  • Mervi Grip,
  • Pascal Guénel,
  • Melanie Gündert,
  • Eric Hahnen,
  • Christopher A. Haiman,
  • Niclas Håkansson,
  • Per Hall,
  • Ute Hamann,
  • Steven N. Hart,
  • Jaana M. Hartikainen,
  • Arndt Hartmann,
  • Wei He,
  • Maartje J. Hooning,
  • Reiner Hoppe,
  • John L. Hopper,
  • Anthony Howell,
  • David J. Hunter,
  • ABCTB Investigators,
  • kConFab Investigators,
  • Agnes Jager,
  • Anna Jakubowska,
  • Wolfgang Janni,
  • Esther M. John,
  • Audrey Y. Jung,
  • Rudolf Kaaks,
  • Machteld Keupers,
  • Cari M. Kitahara,
  • Stella Koutros,
  • Peter Kraft,
  • Vessela N. Kristensen,
  • Allison W. Kurian,
  • James V. Lacey,
  • Diether Lambrechts,
  • Loic Le Marchand,
  • Annika Lindblom,
  • Martha Linet,
  • Robert N. Luben,
  • Jan Lubiński,
  • Michael Lush,
  • Arto Mannermaa,
  • Mehdi Manoochehri,
  • Sara Margolin,
  • John W. M. Martens,
  • Maria Elena Martinez,
  • Dimitrios Mavroudis,
  • Kyriaki Michailidou,
  • Roger L. Milne,
  • Anna Marie Mulligan,
  • Taru A. Muranen,
  • Heli Nevanlinna,
  • William G. Newman,
  • Sune F. Nielsen,
  • Børge G. Nordestgaard,
  • Andrew F. Olshan,
  • Håkan Olsson,
  • Nick Orr,
  • Tjoung-Won Park-Simon,
  • Alpa V. Patel,
  • Bernard Peissel,
  • Paolo Peterlongo,
  • Dijana Plaseska-Karanfilska,
  • Karolina Prajzendanc,
  • Ross Prentice,
  • Nadege Presneau,
  • Brigitte Rack,
  • Gad Rennert,
  • Hedy S. Rennert,
  • Valerie Rhenius,
  • Atocha Romero,
  • Rebecca Roylance,
  • Matthias Ruebner,
  • Emmanouil Saloustros,
  • Elinor J. Sawyer,
  • Rita K. Schmutzler,
  • Andreas Schneeweiss,
  • Christopher Scott,
  • Mitul Shah,
  • Snezhana Smichkoska,
  • Melissa C. Southey,
  • Jennifer Stone,
  • Harald Surowy,
  • Anthony J. Swerdlow,
  • Rulla M. Tamimi,
  • William J. Tapper,
  • Lauren R. Teras,
  • Mary Beth Terry,
  • Rob A. E. M. Tollenaar,
  • Ian Tomlinson,
  • Melissa A. Troester,
  • Thérèse Truong,
  • Celine M. Vachon,
  • Qin Wang,
  • Amber N. Hurson,
  • Robert Winqvist,
  • Alicja Wolk,
  • Argyrios Ziogas,
  • Hiltrud Brauch,
  • Montserrat García-Closas,
  • Paul D. P. Pharoah,
  • Douglas F. Easton,
  • Georgia Chenevix-Trench,
  • Marjanka K. Schmidt

DOI
https://doi.org/10.1186/s13058-021-01450-7
Journal volume & issue
Vol. 23, no. 1
pp. 1 – 18

Abstract

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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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