A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1)

Gilles Thomas; Kevin B Jacobs; Peter Kraft; Meredith Yeager; Sholom Wacholder; David G Cox; Susan E Hankinson; Amy Hutchinson; Zhaoming Wang; Kai Yu; Nilanjan Chatterjee; Montserrat Garcia-Closas; Jesus Gonzalez-Bosquet; Ludmila Prokunina-Olsson; Nick Orr; Walter C Willett; Graham A Colditz; Regina G Ziegler; Christine D Berg; Saundra S. Buys; Catherine A McCarty; Heather Spencer Feigelson; Eugenia E Calle; Michael J Thun; Ryan Diver; Ross Prentice; Rebecca D Jackson; Charles Kooperberg; Rowan Chlebowski; Jolanta Lissowska; Beata Peplonska; Louise A Brinton; Alice Sigurdson; Michele Doody; Parveen Bhatti; Bruce H Alexander; Julie Buring; I-Min Lee; Lars J Vatten; Kristian Hveem; Merethe Kumle; Richard B Hayes; Margaret Tucker; Daniela S Gerhard; Joseph F Fraumeni; Robert N Hoover; Stephen J.  Chanock; David J Hunter

doi:10.1038/ng.353

A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1)

Gilles Thomas, Kevin B Jacobs, Peter Kraft, Meredith Yeager, Sholom Wacholder, David G Cox, Susan E Hankinson, Amy Hutchinson, Zhaoming Wang, Kai Yu, Nilanjan Chatterjee, Montserrat Garcia-Closas, Jesus Gonzalez-Bosquet, Ludmila Prokunina-Olsson, Nick Orr, Walter C Willett, Graham A Colditz, Regina G Ziegler, Christine D Berg, Saundra S. BuysCatherine A McCarty, Heather Spencer Feigelson, Eugenia E Calle, Michael J Thun, Ryan Diver, Ross Prentice, Rebecca D Jackson, Charles Kooperberg, Rowan Chlebowski, Jolanta Lissowska, Beata Peplonska, Louise A Brinton, Alice Sigurdson, Michele Doody, Parveen Bhatti, Bruce H Alexander, Julie Buring, I-Min Lee, Lars J Vatten, Kristian Hveem, Merethe Kumle, Richard B Hayes, Margaret Tucker, Daniela S Gerhard, Joseph F Fraumeni, Robert N Hoover, Stephen J. Chanock, David J Hunter

School of Medicine, Dentistry and Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

460 Citations (Scopus)

Abstract

We conducted a three-stage genome-wide association study (GWAS) of breast cancer in 9,770 cases and 10,799 controls in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. In stage 1, we genotyped 528,173 SNPs in 1,145 cases of invasive breast cancer and 1,142 controls. In stage 2, we analyzed 24,909 top SNPs in 4,547 cases and 4,434 controls. In stage 3, we investigated 21 loci in 4,078 cases and 5,223 controls. Two new loci achieved genome-wide significance. A pericentromeric SNP on chromosome 1p11.2 (rs11249433; P = 6.74 x 10(-10) adjusted genotype test, 2 degrees of freedom) resides in a large linkage disequilibrium block neighboring NOTCH2 and FCGR1B; this signal was stronger for estrogen-receptor-positive tumors. A second SNP on chromosome 14q24.1 (rs999737; P = 1.74 x 10(-7)) localizes to RAD51L1, a gene in the homologous recombination DNA repair pathway. We also confirmed associations with loci on chromosomes 2q35, 5p12, 5q11.2, 8q24, 10q26 and 16q12.1.

Original language	English
Pages (from-to)	579-84
Number of pages	6
Journal	Nature Genetics
Volume	41
Issue number	5
DOIs	https://doi.org/10.1038/ng.353
Publication status	Published - May 2009

Keywords

Alleles
Breast Neoplasms
Chromosomes, Human, Pair 1
Chromosomes, Human, Pair 14
DNA-Binding Proteins
Female
Genetic Predisposition to Disease
Genome, Human
Genome-Wide Association Study
Genotype
Humans
Linkage Disequilibrium
Polymorphism, Single Nucleotide
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.353

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Thomas, G., Jacobs, K. B., Kraft, P., Yeager, M., Wacholder, S., Cox, D. G., Hankinson, S. E., Hutchinson, A., Wang, Z., Yu, K., Chatterjee, N., Garcia-Closas, M., Gonzalez-Bosquet, J., Prokunina-Olsson, L., Orr, N., Willett, W. C., Colditz, G. A., Ziegler, R. G., Berg, C. D., ... Hunter, D. J. (2009). A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1). Nature Genetics, 41(5), 579-84. https://doi.org/10.1038/ng.353

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title = "A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1)",

abstract = "We conducted a three-stage genome-wide association study (GWAS) of breast cancer in 9,770 cases and 10,799 controls in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. In stage 1, we genotyped 528,173 SNPs in 1,145 cases of invasive breast cancer and 1,142 controls. In stage 2, we analyzed 24,909 top SNPs in 4,547 cases and 4,434 controls. In stage 3, we investigated 21 loci in 4,078 cases and 5,223 controls. Two new loci achieved genome-wide significance. A pericentromeric SNP on chromosome 1p11.2 (rs11249433; P = 6.74 x 10(-10) adjusted genotype test, 2 degrees of freedom) resides in a large linkage disequilibrium block neighboring NOTCH2 and FCGR1B; this signal was stronger for estrogen-receptor-positive tumors. A second SNP on chromosome 14q24.1 (rs999737; P = 1.74 x 10(-7)) localizes to RAD51L1, a gene in the homologous recombination DNA repair pathway. We also confirmed associations with loci on chromosomes 2q35, 5p12, 5q11.2, 8q24, 10q26 and 16q12.1.",

keywords = "Alleles, Breast Neoplasms, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 14, DNA-Binding Proteins, Female, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Genotype, Humans, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural",

author = "Gilles Thomas and Jacobs, {Kevin B} and Peter Kraft and Meredith Yeager and Sholom Wacholder and Cox, {David G} and Hankinson, {Susan E} and Amy Hutchinson and Zhaoming Wang and Kai Yu and Nilanjan Chatterjee and Montserrat Garcia-Closas and Jesus Gonzalez-Bosquet and Ludmila Prokunina-Olsson and Nick Orr and Willett, {Walter C} and Colditz, {Graham A} and Ziegler, {Regina G} and Berg, {Christine D} and Buys, {Saundra S.} and McCarty, {Catherine A} and Feigelson, {Heather Spencer} and Calle, {Eugenia E} and Thun, {Michael J} and Ryan Diver and Ross Prentice and Jackson, {Rebecca D} and Charles Kooperberg and Rowan Chlebowski and Jolanta Lissowska and Beata Peplonska and Brinton, {Louise A} and Alice Sigurdson and Michele Doody and Parveen Bhatti and Alexander, {Bruce H} and Julie Buring and I-Min Lee and Vatten, {Lars J} and Kristian Hveem and Merethe Kumle and Hayes, {Richard B} and Margaret Tucker and Gerhard, {Daniela S} and Fraumeni, {Joseph F} and Hoover, {Robert N} and Chanock, {Stephen J.} and Hunter, {David J}",

year = "2009",

month = may,

doi = "10.1038/ng.353",

language = "English",

volume = "41",

pages = "579--84",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "5",

}

Thomas, G, Jacobs, KB, Kraft, P, Yeager, M, Wacholder, S, Cox, DG, Hankinson, SE, Hutchinson, A, Wang, Z, Yu, K, Chatterjee, N, Garcia-Closas, M, Gonzalez-Bosquet, J, Prokunina-Olsson, L, Orr, N, Willett, WC, Colditz, GA, Ziegler, RG, Berg, CD, Buys, SS, McCarty, CA, Feigelson, HS, Calle, EE, Thun, MJ, Diver, R, Prentice, R, Jackson, RD, Kooperberg, C, Chlebowski, R, Lissowska, J, Peplonska, B, Brinton, LA, Sigurdson, A, Doody, M, Bhatti, P, Alexander, BH, Buring, J, Lee, I-M, Vatten, LJ, Hveem, K, Kumle, M, Hayes, RB, Tucker, M, Gerhard, DS, Fraumeni, JF, Hoover, RN, Chanock, SJ & Hunter, DJ 2009, 'A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1)', Nature Genetics, vol. 41, no. 5, pp. 579-84. https://doi.org/10.1038/ng.353

TY - JOUR

T1 - A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1)

AU - Thomas, Gilles

AU - Jacobs, Kevin B

AU - Kraft, Peter

AU - Yeager, Meredith

AU - Wacholder, Sholom

AU - Cox, David G

AU - Hankinson, Susan E

AU - Hutchinson, Amy

AU - Wang, Zhaoming

AU - Yu, Kai

AU - Chatterjee, Nilanjan

AU - Garcia-Closas, Montserrat

AU - Gonzalez-Bosquet, Jesus

AU - Prokunina-Olsson, Ludmila

AU - Orr, Nick

AU - Willett, Walter C

AU - Colditz, Graham A

AU - Ziegler, Regina G

AU - Berg, Christine D

AU - Buys, Saundra S.

AU - McCarty, Catherine A

AU - Feigelson, Heather Spencer

AU - Calle, Eugenia E

AU - Thun, Michael J

AU - Diver, Ryan

AU - Prentice, Ross

AU - Jackson, Rebecca D

AU - Kooperberg, Charles

AU - Chlebowski, Rowan

AU - Lissowska, Jolanta

AU - Peplonska, Beata

AU - Brinton, Louise A

AU - Sigurdson, Alice

AU - Doody, Michele

AU - Bhatti, Parveen

AU - Alexander, Bruce H

AU - Buring, Julie

AU - Lee, I-Min

AU - Vatten, Lars J

AU - Hveem, Kristian

AU - Kumle, Merethe

AU - Hayes, Richard B

AU - Tucker, Margaret

AU - Gerhard, Daniela S

AU - Fraumeni, Joseph F

AU - Hoover, Robert N

AU - Chanock, Stephen J.

AU - Hunter, David J

PY - 2009/5

Y1 - 2009/5

N2 - We conducted a three-stage genome-wide association study (GWAS) of breast cancer in 9,770 cases and 10,799 controls in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. In stage 1, we genotyped 528,173 SNPs in 1,145 cases of invasive breast cancer and 1,142 controls. In stage 2, we analyzed 24,909 top SNPs in 4,547 cases and 4,434 controls. In stage 3, we investigated 21 loci in 4,078 cases and 5,223 controls. Two new loci achieved genome-wide significance. A pericentromeric SNP on chromosome 1p11.2 (rs11249433; P = 6.74 x 10(-10) adjusted genotype test, 2 degrees of freedom) resides in a large linkage disequilibrium block neighboring NOTCH2 and FCGR1B; this signal was stronger for estrogen-receptor-positive tumors. A second SNP on chromosome 14q24.1 (rs999737; P = 1.74 x 10(-7)) localizes to RAD51L1, a gene in the homologous recombination DNA repair pathway. We also confirmed associations with loci on chromosomes 2q35, 5p12, 5q11.2, 8q24, 10q26 and 16q12.1.

AB - We conducted a three-stage genome-wide association study (GWAS) of breast cancer in 9,770 cases and 10,799 controls in the Cancer Genetic Markers of Susceptibility (CGEMS) initiative. In stage 1, we genotyped 528,173 SNPs in 1,145 cases of invasive breast cancer and 1,142 controls. In stage 2, we analyzed 24,909 top SNPs in 4,547 cases and 4,434 controls. In stage 3, we investigated 21 loci in 4,078 cases and 5,223 controls. Two new loci achieved genome-wide significance. A pericentromeric SNP on chromosome 1p11.2 (rs11249433; P = 6.74 x 10(-10) adjusted genotype test, 2 degrees of freedom) resides in a large linkage disequilibrium block neighboring NOTCH2 and FCGR1B; this signal was stronger for estrogen-receptor-positive tumors. A second SNP on chromosome 14q24.1 (rs999737; P = 1.74 x 10(-7)) localizes to RAD51L1, a gene in the homologous recombination DNA repair pathway. We also confirmed associations with loci on chromosomes 2q35, 5p12, 5q11.2, 8q24, 10q26 and 16q12.1.

KW - Alleles

KW - Breast Neoplasms

KW - Chromosomes, Human, Pair 1

KW - Chromosomes, Human, Pair 14

KW - DNA-Binding Proteins

KW - Female

KW - Genetic Predisposition to Disease

KW - Genome, Human

KW - Genome-Wide Association Study

KW - Genotype

KW - Humans

KW - Linkage Disequilibrium

KW - Polymorphism, Single Nucleotide

KW - Journal Article

KW - Research Support, N.I.H., Extramural

KW - Research Support, N.I.H., Intramural

U2 - 10.1038/ng.353

DO - 10.1038/ng.353

M3 - Article

C2 - 19330030

SN - 1061-4036

VL - 41

SP - 579

EP - 584

JO - Nature Genetics

JF - Nature Genetics

IS - 5

ER -

A multistage genome-wide association study in breast cancer identifies two new risk alleles at 1p11.2 and 14q24.1 (RAD51L1)

Abstract

Keywords

UN SDGs

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