Garcia-Closas M, Couch FJ, Lindstrom S, Michailidou K, Schmidt MK, Brook MN, Orr N, Rhie SK, Riboli E, Feigelson HS, Le Marchand L, Buring JE, Eccles D, Miron P, Fasching PA, Brauch H, Chang-Claude J, Carpenter J, Godwin AK, Nevanlinna H, Giles GG, Cox A, Hopper JL, Bolla MK, Wang Q, Dennis J, Dicks E, Howat WJ, Schoof N, Bojesen SE, Lambrechts D, Broeks A, Andrulis IL, Guénel P, Burwinkel B, Sawyer EJ, Hollestelle A, Fletcher O, Winqvist R, Brenner H, Mannermaa A, Hamann U, Meindl A, Lindblom A, Zheng W, Devillee P, Goldberg MS, Lubinski J, Kristensen V, Swerdlow A, Anton-Culver H, Dörk T, Muir K, Matsuo K, Wu AH, Radice P, Teo SH, Shu XO, Blot W, Kang D, Hartman M, Sangrajrang S, Shen CY, Southey MC, Park DJ, Hammet F, Stone J, Veer LJ, Rutgers EJ, Lophatananon A, Stewart-Brown S, Siriwanarangsan P, Peto J, Schrauder MG, Ekici AB, Beckmann MW, Dos Santos Silva I, Johnson N, Warren H, Tomlinson I, Kerin MJ, Miller N, Marme F, Schneeweiss A, Sohn C, Truong T, Laurent-Puig P, Kerbrat P, Nordestgaard BG, Nielsen SF, Flyger H, Milne RL, Perez JI, Menéndez P, Müller H, Arndt V, Stegmaier C, Lichtner P, Lochmann M, Justenhoven C, Ko YD, Gene ENvironmental Interaction and breast CAncer GENICA Network, Muranen TA, Aittomäki K, Blomqvist C, Greco D, Heikkinen T, Ito H, Iwata H, Yatabe Y, Antonenkova NN, Margolin S, Kataja V, Kosma VM, Hartikainen JM, Balleine R, kConFab Investigators, Tseng CC, Berg DV, Stram DO, Neven P, Dieudonné AS, Leunen K, Rudolph A, Nickels S, Flesch-Janys D, Peterlongo P, Peissel B, Bernard L, Olson JE, Wang X, Stevens K, Severi G, Baglietto L, McLean C, Coetzee GA, Feng Y, Henderson BE, Schumacher F, Bogdanova NV, Labrèche F, Dumont M, Yip CH, Taib NA, Cheng CY, Shrubsole M, Long J, Pylkäs K, Jukkola-Vuorinen A, Kauppila S, Knight JA, Glendon G, Mulligan AM, Tollenaar RA, Seynaeve CM, Kriege M, Hooning MJ, van den Ouweland AM, van Deurzen CH, Lu W, Gao YT, Cai H, Balasubramanian SP, Cross SS, Reed MW, Signorello L, Cai Q, Shah M, Miao H, Chan CW, Chia KS, Jakubowska A, Jaworska K, Durda K, Hsiung CN, Wu PE, Yu JC, Ashworth A, Jones M, Tessier DC, González-Neira A, Pita G, Alonso MR, Vincent D, Bacot F, Ambrosone CB, Bandera EV, John EM, Chen GK, Hu JJ, Rodriguez-Gil JL, Bernstein L, Press MF, Ziegler RG, Millikan RM, Deming-Halverson SL, Nyante S, Ingles SA, Waisfisz Q, Tsimiklis H, Makalic E, Schmidt D, Bui M, Gibson L, Müller-Myhsok B, Schmutzler RK, Hein R, Dahmen N, Beckmann L, Aaltonen K, Czene K, Irwanto A, Liu J, Turnbull C, Familial Breast Cancer Study FBCS, Rahman N, Meijers-Heijboer H, Uitterlinden AG, Rivadeneira F, Australian Breast Cancer Tissue Bank ABCTB Investigators, Olswold C, Slager S, Pilarski R, Ademuyiwa F, Konstantopoulou I, Martin NG, Montgomery GW, Slamon DJ, Rauh C, Lux MP, Jud SM, Bruning T, Weaver J, Sharma P, Pathak H, Tapper W, Gerty S, Durcan L, Trichopoulos D, Tumino R, Peeters PH, Kaaks R, Campa D, Canzian F, Weiderpass E, Johansson M, Khaw KT, Travis R, Clavel-Chapelon F, Kolonel LN, Chen C, Beck A, Hankinson SE, Berg CD, Hoover RN, Lissowska J, Figueroa JD, Chasman DI, Gaudet MM, Diver WR, Willett WC, Hunter DJ, Simard J, Benitez J, Dunning AM, Sherman ME, Chenevix-Trench G, Chanock SJ, Hall P, Pharoah PD, Vachon C, Easton DF, Haiman CA, Kraft P
Abstract
Estrogen receptor (ER)-negative tumors represent 20-30% of all breast cancers, with a higher proportion occurring in younger women and women of African ancestry. The etiology and clinical behavior of ER-negative tumors are different from those of tumors expressing ER (ER positive), including differences in genetic predisposition. To identify susceptibility loci specific to ER-negative disease, we combined in a meta-analysis 3 genome-wide association studies of 4,193 ER-negative breast cancer cases and 35,194 controls with a series of 40 follow-up studies (6,514 cases and 41,455 controls), genotyped using a custom Illumina array, iCOGS, developed by the Collaborative Oncological Gene-environment Study (COGS). SNPs at four loci, 1q32.1 (MDM4, P = 2.1 × 10(-12) and LGR6, P = 1.4 × 10(-8)), 2p24.1 (P = 4.6 × 10(-8)) and 16q12.2 (FTO, P = 4.0 × 10(-8)), were associated with ER-negative but not ER-positive breast cancer (P > 0.05). These findings provide further evidence for distinct etiological pathways associated with invasive ER-positive and ER-negative breast cancers.
MeSH Terms
Breast Neoplasms/etiology,metabolism,pathologyCase-Control StudiesCooperative BehaviorFemaleGenetic Loci/geneticsGenetic Predisposition to DiseaseGenome-Wide Association StudyGenotypeHumansMeta-Analysis as TopicOligonucleotide Array Sequence AnalysisPolymorphism, Single Nucleotide/geneticsReceptors, Estrogen/genetics,metabolismRisk Factors
Chemicals
Receptors, Estrogen
Authors & Affiliations
274 authors, click to expand affiliations / ORCID
Garcia-Closas Montserrat
1] Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, UK. [2] Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK. [3].
Couch Fergus J
Lindstrom Sara
Michailidou Kyriaki
Schmidt Marjanka K
Brook Mark N
Orr Nick
Rhie Suhn Kyong
Riboli Elio
Feigelson Heather S
Le Marchand Loic
Buring Julie E
Eccles Diana
Miron Penelope
Fasching Peter A
Brauch Hiltrud
Chang-Claude Jenny
Carpenter Jane
Godwin Andrew K
Nevanlinna Heli
Giles Graham G
Cox Angela
Hopper John L
Bolla Manjeet K
Wang Qin
Dennis Joe
Dicks Ed
Howat Will J
Schoof Nils
Bojesen Stig E
Lambrechts Diether
Broeks Annegien
Andrulis Irene L
Guénel Pascal
Burwinkel Barbara
Sawyer Elinor J
Hollestelle Antoinette
Fletcher Olivia
Winqvist Robert
Brenner Hermann
Mannermaa Arto
Hamann Ute
Meindl Alfons
Lindblom Annika
Zheng Wei
Devillee Peter
Goldberg Mark S
Lubinski Jan
Kristensen Vessela
Swerdlow Anthony
Anton-Culver Hoda
Dörk Thilo
Muir Kenneth
Matsuo Keitaro
Wu Anna H
Radice Paolo
Teo Soo Hwang
Shu Xiao-Ou
Blot William
Kang Daehee
Hartman Mikael
Sangrajrang Suleeporn
Shen Chen-Yang
Southey Melissa C
Park Daniel J
Hammet Fleur
Stone Jennifer
Veer Laura J Van't
Rutgers Emiel J
Lophatananon Artitaya
Stewart-Brown Sarah
Siriwanarangsan Pornthep
Peto Julian
Schrauder Michael G
Ekici Arif B
Beckmann Matthias W
Dos Santos Silva Isabel
Johnson Nichola
Warren Helen
Tomlinson Ian
Kerin Michael J
Miller Nicola
Marme Federick
Schneeweiss Andreas
Sohn Christof
Truong Therese
Laurent-Puig Pierre
Kerbrat Pierre
Nordestgaard Børge G
Nielsen Sune F
Flyger Henrik
Milne Roger L
Perez Jose Ignacio Arias
Menéndez Primitiva
Müller Heiko
Arndt Volker
Stegmaier Christa
Lichtner Peter
Lochmann Magdalena
Justenhoven Christina
Ko Yon-Dschun
Gene ENvironmental Interaction and breast CAncer (GENICA) Network
Muranen Taru A
Aittomäki Kristiina
Blomqvist Carl
Greco Dario
Heikkinen Tuomas
Ito Hidemi
Iwata Hiroji
Yatabe Yasushi
Antonenkova Natalia N
Margolin Sara
Kataja Vesa
Kosma Veli-Matti
Hartikainen Jaana M
Balleine Rosemary
kConFab Investigators
Tseng Chiu-Chen
Berg David Van Den
Stram Daniel O
Neven Patrick
Dieudonné Anne-Sophie
Leunen Karin
Rudolph Anja
Nickels Stefan
Flesch-Janys Dieter
Peterlongo Paolo
Peissel Bernard
Bernard Loris
Olson Janet E
Wang Xianshu
Stevens Kristen
Severi Gianluca
Baglietto Laura
McLean Catriona
Coetzee Gerhard A
Feng Ye
Henderson Brian E
Schumacher Fredrick
Bogdanova Natalia V
Labrèche France
Dumont Martine
Yip Cheng Har
Taib Nur Aishah Mohd
Cheng Ching-Yu
Shrubsole Martha
Long Jirong
Pylkäs Katri
Jukkola-Vuorinen Arja
Kauppila Saila
Knight Julia A
Glendon Gord
Mulligan Anna Marie
Tollenaar Robertus A E M
Seynaeve Caroline M
Kriege Mieke
Hooning Maartje J
van den Ouweland Ans M W
van Deurzen Carolien H M
Lu Wei
Gao Yu-Tang
Cai Hui
Balasubramanian Sabapathy P
Cross Simon S
Reed Malcolm W R
Signorello Lisa
Cai Qiuyin
Shah Mitul
Miao Hui
Chan Ching Wan
Chia Kee Seng
Jakubowska Anna
Jaworska Katarzyna
Durda Katarzyna
Hsiung Chia-Ni
Wu Pei-Ei
Yu Jyh-Cherng
Ashworth Alan
Jones Michael
Tessier Daniel C
González-Neira Anna
Pita Guillermo
Alonso M Rosario
Vincent Daniel
Bacot Francois
Ambrosone Christine B
Bandera Elisa V
John Esther M
Chen Gary K
Hu Jennifer J
Rodriguez-Gil Jorge L
Bernstein Leslie
Press Michael F
Ziegler Regina G
Millikan Robert M
Deming-Halverson Sandra L
Nyante Sarah
Ingles Sue A
Waisfisz Quinten
Tsimiklis Helen
Makalic Enes
Schmidt Daniel
Bui Minh
Gibson Lorna
Müller-Myhsok Bertram
Schmutzler Rita K
Hein Rebecca
Dahmen Norbert
Beckmann Lars
Aaltonen Kirsimari
Czene Kamila
Irwanto Astrid
Liu Jianjun
Turnbull Clare
Familial Breast Cancer Study (FBCS)
Rahman Nazneen
Meijers-Heijboer Hanne
Uitterlinden Andre G
Rivadeneira Fernando
Australian Breast Cancer Tissue Bank (ABCTB) Investigators
Olswold Curtis
Slager Susan
Pilarski Robert
Ademuyiwa Foluso
Konstantopoulou Irene
Martin Nicholas G
Montgomery Grant W
Slamon Dennis J
Rauh Claudia
Lux Michael P
Jud Sebastian M
Bruning Thomas
Weaver Joellen
Sharma Priyanka
Pathak Harsh
Tapper Will
Gerty Sue
Durcan Lorraine
Trichopoulos Dimitrios
Tumino Rosario
Peeters Petra H
Kaaks Rudolf
Campa Daniele
Canzian Federico
Weiderpass Elisabete
Johansson Mattias
Khaw Kay-Tee
Travis Ruth
Clavel-Chapelon Françoise
Kolonel Laurence N
Chen Constance
Beck Andy
Hankinson Susan E
Berg Christine D
Hoover Robert N
Lissowska Jolanta
Figueroa Jonine D
Chasman Daniel I
Gaudet Mia M
Diver W Ryan
Willett Walter C
Hunter David J
Simard Jacques
Benitez Javier
Dunning Alison M
Sherman Mark E
Chenevix-Trench Georgia
Chanock Stephen J
Hall Per
Pharoah Paul D P
Vachon Celine
Easton Douglas F
Haiman Christopher A
Kraft Peter
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Garcia-Closas(M),Couch(FJ),Lindstrom(S),Michailidou(K),Schmidt(MK),Brook(MN),Orr(N),Rhie(SK),Riboli(E),Feigelson(HS),Le Marchand(L),Buring(JE),Eccles(D),Miron(P),Fasching(PA),Brauch(H),Chang-Claude(J),Carpenter(J),Godwin(AK),Nevanlinna(H),Giles(GG),Cox(A),Hopper(JL),Bolla(MK),Wang(Q),Dennis(J),Dicks(E),Howat(WJ),Schoof(N),Bojesen(SE),Lambrechts(D),Broeks(A),Andrulis(IL),Guénel(P),Burwinkel(B),Sawyer(EJ),Hollestelle(A),Fletcher(O),Winqvist(R),Brenner(H),Mannermaa(A),Hamann(U),Meindl(A),Lindblom(A),Zheng(W),Devillee(P),Goldberg(MS),Lubinski(J),Kristensen(V),Swerdlow(A),Anton-Culver(H),Dörk(T),Muir(K),Matsuo(K),Wu(AH),Radice(P),Teo(SH),Shu(XO),Blot(W),Kang(D),Hartman(M),Sangrajrang(S),Shen(CY),Southey(MC),Park(DJ),Hammet(F),Stone(J),Veer(LJ),Rutgers(EJ),Lophatananon(A),Stewart-Brown(S),Siriwanarangsan(P),Peto(J),Schrauder(MG),Ekici(AB),Beckmann(MW),Dos Santos Silva(I),Johnson(N),Warren(H),Tomlinson(I),Kerin(MJ),Miller(N),Marme(F),Schneeweiss(A),Sohn(C),Truong(T),Laurent-Puig(P),Kerbrat(P),Nordestgaard(BG),Nielsen(SF),Flyger(H),Milne(RL),Perez(JI),Menéndez(P),Müller(H),Arndt(V),Stegmaier(C),Lichtner(P),Lochmann(M),Justenhoven(C),Ko(YD),Gene ENvironmental Interaction and breast CAncer (GENICA) Network,Muranen(TA),Aittomäki(K),Blomqvist(C),Greco(D),Heikkinen(T),Ito(H),Iwata(H),Yatabe(Y),Antonenkova(NN),Margolin(S),Kataja(V),Kosma(VM),Hartikainen(JM),Balleine(R),kConFab Investigators,Tseng(CC),Berg(DV),Stram(DO),Neven(P),Dieudonné(AS),Leunen(K),Rudolph(A),Nickels(S),Flesch-Janys(D),Peterlongo(P),Peissel(B),Bernard(L),Olson(JE),Wang(X),Stevens(K),Severi(G),Baglietto(L),McLean(C),Coetzee(GA),Feng(Y),Henderson(BE),Schumacher(F),Bogdanova(NV),Labrèche(F),Dumont(M),Yip(CH),Taib(NA),Cheng(CY),Shrubsole(M),Long(J),Pylkäs(K),Jukkola-Vuorinen(A),Kauppila(S),Knight(JA),Glendon(G),Mulligan(AM),Tollenaar(RA),Seynaeve(CM),Kriege(M),Hooning(MJ),van den Ouweland(AM),van Deurzen(CH),Lu(W),Gao(YT),Cai(H),Balasubramanian(SP),Cross(SS),Reed(MW),Signorello(L),Cai(Q),Shah(M),Miao(H),Chan(CW),Chia(KS),Jakubowska(A),Jaworska(K),Durda(K),Hsiung(CN),Wu(PE),Yu(JC),Ashworth(A),Jones(M),Tessier(DC),González-Neira(A),Pita(G),Alonso(MR),Vincent(D),Bacot(F),Ambrosone(CB),Bandera(EV),John(EM),Chen(GK),Hu(JJ),Rodriguez-Gil(JL),Bernstein(L),Press(MF),Ziegler(RG),Millikan(RM),Deming-Halverson(SL),Nyante(S),Ingles(SA),Waisfisz(Q),Tsimiklis(H),Makalic(E),Schmidt(D),Bui(M),Gibson(L),Müller-Myhsok(B),Schmutzler(RK),Hein(R),Dahmen(N),Beckmann(L),Aaltonen(K),Czene(K),Irwanto(A),Liu(J),Turnbull(C),Familial Breast Cancer Study (FBCS),Rahman(N),Meijers-Heijboer(H),Uitterlinden(AG),Rivadeneira(F),Australian Breast Cancer Tissue Bank (ABCTB) Investigators,Olswold(C),Slager(S),Pilarski(R),Ademuyiwa(F),Konstantopoulou(I),Martin(NG),Montgomery(GW),Slamon(DJ),Rauh(C),Lux(MP),Jud(SM),Bruning(T),Weaver(J),Sharma(P),Pathak(H),Tapper(W),Gerty(S),Durcan(L),Trichopoulos(D),Tumino(R),Peeters(PH),Kaaks(R),Campa(D),Canzian(F),Weiderpass(E),Johansson(M),Khaw(KT),Travis(R),Clavel-Chapelon(F),Kolonel(LN),Chen(C),Beck(A),Hankinson(SE),Berg(CD),Hoover(RN),Lissowska(J),Figueroa(JD),Chasman(DI),Gaudet(MM),Diver(WR),Willett(WC),Hunter(DJ),Simard(J),Benitez(J),Dunning(AM),Sherman(ME),Chenevix-Trench(G),Chanock(SJ),Hall(P),Pharoah(PD),Vachon(C),Easton(DF),Haiman(CA),Kraft(P)Genome-wide association studies identify four ER negative-specific breast cancer risk loci.Nature geneticsNone45410.1038/ng.2561