Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer

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Abstract

In a genome-wide scan, we show that 30 variants in 25 genomic regions are associated with risk of TN breast cancer. Women carrying many of the risk variants may have 4-fold increased risk relative to women with few variants.Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 x 10(-) (8)) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 x 10(-) (4)] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 x 10(-) (9)) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46-4.70, P = 4.8 x 10(-) (69)). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.

Details

Authors
  • Kristen S. Purrington
  • Susan Slager
  • Diana Eccles
  • Drakoulis Yannoukakos
  • Peter A. Fasching
  • Penelope Miron
  • Jane Carpenter
  • Jenny Chang-Claude
  • Nicholas G. Martin
  • Grant W. Montgomery
  • Vessela Kristensen
  • Hoda Anton-Culver
  • Paul Goodfellow
  • William J. Tapper
  • Sajjad Rafiq
  • Susan M. Gerty
  • Lorraine Durcan
  • Irene Konstantopoulou
  • Florentia Fostira
  • Athanassios Vratimos
  • Paraskevi Apostolou
  • Irene Konstanta
  • Vassiliki Kotoula
  • Sotiris Lakis
  • Meletios A. Dimopoulos
  • Dimosthenis Skarlos
  • Dimitrios Pectasides
  • George Fountzilas
  • Matthias W. Beckmann
  • Alexander Hein
  • Matthias Ruebner
  • Arif B. Ekici
  • Arndt Hartmann
  • Ruediger Schulz-Wendtland
  • Stefan P. Renner
  • Wolfgang Janni
  • Brigitte Rack
  • Christoph Scholz
  • Julia Neugebauer
  • Ulrich Andergassen
  • Michael P. Lux
  • Lothar Haeberle
  • Christine Clarke
  • Nirmala Pathmanathan
  • Anja Rudolph
  • Dieter Flesch-Janys
  • Stefan Nickels
  • Janet E. Olson
  • James N. Ingle
  • Curtis Olswold
  • Seth Slettedahl
  • Jeanette E. Eckel-Passow
  • S. Keith Anderson
  • Daniel W. Visscher
  • Victoria L. Cafourek
  • Hugues Sicotte
  • Naresh Prodduturi
  • Elisabete Weiderpass
  • Leslie Bernstein
  • Argyrios Ziogas
  • Jennifer Ivanovich
  • Graham G. Giles
  • Laura Baglietto
  • Melissa Southey
  • Veli-Matti Kosma
  • Hans-Peter Fischer
  • Malcom W. R. Reed
  • Simon S. Cross
  • Sandra Deming-Halverson
  • Martha Shrubsole
  • Qiuyin Cai
  • Xiao-Ou Shu
  • Mary Daly
  • JoEllen Weaver
  • Eric Ross
  • Jennifer Klemp
  • Priyanka Sharma
  • Diana Torres
  • Thomas Rudiger
  • Heidrun Wolfing
  • Hans-Ulrich Ulmer
  • Thaer Khoury
  • Shicha Kumar
  • Robert Pilarski
  • Charles L. Shapiro
  • Dario Greco
  • Paivi Heikkila
  • Kristiina Aittomaki
  • Carl Blomqvist
  • Astrid Irwanto
  • Jianjun Liu
  • Vernon Shane Pankratz
  • Xianshu Wang
  • Gianluca Severi
  • Arto Mannermaa
  • Douglas Easton
  • Per Hall
  • Hiltrud Brauch
  • Angela Cox
  • Wei Zheng
  • Andrew K. Godwin
  • Ute Hamann
  • Christine Ambrosone
  • Amanda Ewart Toland
  • Heli Nevanlinna
  • Celine M. Vachon
  • Fergus J. Couch
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology
Original languageEnglish
Pages (from-to)1012-1019
JournalCarcinogenesis
Volume35
Issue number5
Publication statusPublished - 2014
Publication categoryResearch
Peer-reviewedYes