Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus

Hisani N Horne; Charles C Chung; Han Zhang; Kai Yu; Ludmila Prokunina-Olsson; Kyriaki Michailidou; Manjeet K Bolla; Qin Wang; Joe Dennis; John L Hopper; Melissa C Southey; Marjanka K Schmidt; Annegien Broeks; Kenneth Muir; Artitaya Lophatananon; Peter A Fasching; Matthias W Beckmann; Olivia Fletcher; Nichola Johnson; Elinor J Sawyer; Ian Tomlinson; Barbara Burwinkel; Frederik Marme; Pascal Guénel; Thérèse Truong; Stig E Bojesen; Henrik Flyger; Javier Benitez; Anna González-Neira; Hoda Anton-Culver; Susan L Neuhausen; Hermann Brenner; Volker Arndt; Alfons Meindl; Rita K Schmutzler; Hiltrud Brauch; Ute Hamann; Heli Nevanlinna; Sofia Khan; Keitaro Matsuo; Hiroji Iwata; Thilo Dörk; Natalia V Bogdanova; Annika Lindblom; Sara Margolin; Arto Mannermaa; Veli-Matti Kosma; Georgia Chenevix-Trench; Anna H Wu; Wei Lu; kConFab/AOCS Investigators

doi:10.1371/journal.pone.0160316

Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus

Hisani N Horne, Charles C Chung, Han Zhang, Kai Yu, Ludmila Prokunina-Olsson, Kyriaki Michailidou, Manjeet K Bolla, Qin Wang, Joe Dennis, John L Hopper, Melissa C Southey, Marjanka K Schmidt, Annegien Broeks, Kenneth Muir, Artitaya Lophatananon, Peter A Fasching, Matthias W Beckmann, Olivia Fletcher, Nichola Johnson, Elinor J SawyerIan Tomlinson, Barbara Burwinkel, Frederik Marme, Pascal Guénel, Thérèse Truong, Stig E Bojesen, Henrik Flyger, Javier Benitez, Anna González-Neira, Hoda Anton-Culver, Susan L Neuhausen, Hermann Brenner, Volker Arndt, Alfons Meindl, Rita K Schmutzler, Hiltrud Brauch, Ute Hamann, Heli Nevanlinna, Sofia Khan, Keitaro Matsuo, Hiroji Iwata, Thilo Dörk, Natalia V Bogdanova, Annika Lindblom, Sara Margolin, Arto Mannermaa, Veli-Matti Kosma, Georgia Chenevix-Trench, Anna H Wu, Wei Lu, kConFab/AOCS Investigators

Division of Population Health, Health Services Research & Primary Care (L5)

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

Abstract

The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.

Original language	English
Pages (from-to)	e0160316
Journal	P L o S One
Volume	11
Issue number	8
DOIs	https://doi.org/10.1371/journal.pone.0160316
Publication status	Published - 24 Aug 2016

Keywords

Alleles
Breast Neoplasms
Case-Control Studies
Chromosome Mapping
Chromosomes, Human, Pair 1
Computational Biology
Female
Gene Frequency
Genetic Association Studies
Genetic Predisposition to Disease
Genotype
Humans
Linkage Disequilibrium
Neoplasm Grading
Polymorphism, Single Nucleotide
Population Surveillance
Quantitative Trait Loci
Risk Assessment
Journal Article

UN SDGs

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

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10.1371/journal.pone.0160316

Cite this

Horne, H. N., Chung, C. C., Zhang, H., Yu, K., Prokunina-Olsson, L., Michailidou, K., Bolla, M. K., Wang, Q., Dennis, J., Hopper, J. L., Southey, M. C., Schmidt, M. K., Broeks, A., Muir, K., Lophatananon, A., Fasching, P. A., Beckmann, M. W., Fletcher, O., Johnson, N., ... kConFab/AOCS Investigators (2016). Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus. P L o S One, 11(8), e0160316. https://doi.org/10.1371/journal.pone.0160316

@article{65e086129af54aafa270b2c172b39017,

title = "Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus",

abstract = "The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.",

keywords = "Alleles, Breast Neoplasms, Case-Control Studies, Chromosome Mapping, Chromosomes, Human, Pair 1, Computational Biology, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Humans, Linkage Disequilibrium, Neoplasm Grading, Polymorphism, Single Nucleotide, Population Surveillance, Quantitative Trait Loci, Risk Assessment, Journal Article",

author = "Horne, {Hisani N} and Chung, {Charles C} and Han Zhang and Kai Yu and Ludmila Prokunina-Olsson and Kyriaki Michailidou and Bolla, {Manjeet K} and Qin Wang and Joe Dennis and Hopper, {John L} and Southey, {Melissa C} and Schmidt, {Marjanka K} and Annegien Broeks and Kenneth Muir and Artitaya Lophatananon and Fasching, {Peter A} and Beckmann, {Matthias W} and Olivia Fletcher and Nichola Johnson and Sawyer, {Elinor J} and Ian Tomlinson and Barbara Burwinkel and Frederik Marme and Pascal Gu{\'e}nel and Th{\'e}r{\`e}se Truong and Bojesen, {Stig E} and Henrik Flyger and Javier Benitez and Anna Gonz{\'a}lez-Neira and Hoda Anton-Culver and Neuhausen, {Susan L} and Hermann Brenner and Volker Arndt and Alfons Meindl and Schmutzler, {Rita K} and Hiltrud Brauch and Ute Hamann and Heli Nevanlinna and Sofia Khan and Keitaro Matsuo and Hiroji Iwata and Thilo D{\"o}rk and Bogdanova, {Natalia V} and Annika Lindblom and Sara Margolin and Arto Mannermaa and Veli-Matti Kosma and Georgia Chenevix-Trench and Wu, {Anna H} and Wei Lu and {kConFab/AOCS Investigators}",

year = "2016",

month = aug,

day = "24",

doi = "10.1371/journal.pone.0160316",

language = "English",

volume = "11",

pages = "e0160316",

journal = "P L o S One",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "8",

}

Horne, HN, Chung, CC, Zhang, H, Yu, K, Prokunina-Olsson, L, Michailidou, K, Bolla, MK, Wang, Q, Dennis, J, Hopper, JL, Southey, MC, Schmidt, MK, Broeks, A, Muir, K , Lophatananon, A, Fasching, PA, Beckmann, MW, Fletcher, O, Johnson, N, Sawyer, EJ, Tomlinson, I, Burwinkel, B, Marme, F, Guénel, P, Truong, T, Bojesen, SE, Flyger, H, Benitez, J, González-Neira, A, Anton-Culver, H, Neuhausen, SL, Brenner, H, Arndt, V, Meindl, A, Schmutzler, RK, Brauch, H, Hamann, U, Nevanlinna, H, Khan, S, Matsuo, K, Iwata, H, Dörk, T, Bogdanova, NV, Lindblom, A, Margolin, S, Mannermaa, A, Kosma, V-M, Chenevix-Trench, G, Wu, AH, Lu, W & kConFab/AOCS Investigators 2016, 'Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus', P L o S One, vol. 11, no. 8, pp. e0160316. https://doi.org/10.1371/journal.pone.0160316

TY - JOUR

T1 - Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus

AU - Horne, Hisani N

AU - Chung, Charles C

AU - Zhang, Han

AU - Yu, Kai

AU - Prokunina-Olsson, Ludmila

AU - Michailidou, Kyriaki

AU - Bolla, Manjeet K

AU - Wang, Qin

AU - Dennis, Joe

AU - Hopper, John L

AU - Southey, Melissa C

AU - Schmidt, Marjanka K

AU - Broeks, Annegien

AU - Muir, Kenneth

AU - Lophatananon, Artitaya

AU - Fasching, Peter A

AU - Beckmann, Matthias W

AU - Fletcher, Olivia

AU - Johnson, Nichola

AU - Sawyer, Elinor J

AU - Tomlinson, Ian

AU - Burwinkel, Barbara

AU - Marme, Frederik

AU - Guénel, Pascal

AU - Truong, Thérèse

AU - Bojesen, Stig E

AU - Flyger, Henrik

AU - Benitez, Javier

AU - González-Neira, Anna

AU - Anton-Culver, Hoda

AU - Neuhausen, Susan L

AU - Brenner, Hermann

AU - Arndt, Volker

AU - Meindl, Alfons

AU - Schmutzler, Rita K

AU - Brauch, Hiltrud

AU - Hamann, Ute

AU - Nevanlinna, Heli

AU - Khan, Sofia

AU - Matsuo, Keitaro

AU - Iwata, Hiroji

AU - Dörk, Thilo

AU - Bogdanova, Natalia V

AU - Lindblom, Annika

AU - Margolin, Sara

AU - Mannermaa, Arto

AU - Kosma, Veli-Matti

AU - Chenevix-Trench, Georgia

AU - Wu, Anna H

AU - Lu, Wei

AU - kConFab/AOCS Investigators

PY - 2016/8/24

Y1 - 2016/8/24

N2 - The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.

AB - The Cancer Genetic Markers of Susceptibility genome-wide association study (GWAS) originally identified a single nucleotide polymorphism (SNP) rs11249433 at 1p11.2 associated with breast cancer risk. To fine-map this locus, we genotyped 92 SNPs in a 900kb region (120,505,799-121,481,132) flanking rs11249433 in 45,276 breast cancer cases and 48,998 controls of European, Asian and African ancestry from 50 studies in the Breast Cancer Association Consortium. Genotyping was done using iCOGS, a custom-built array. Due to the complicated nature of the region on chr1p11.2: 120,300,000-120,505,798, that lies near the centromere and contains seven duplicated genomic segments, we restricted analyses to 429 SNPs excluding the duplicated regions (42 genotyped and 387 imputed). Per-allelic associations with breast cancer risk were estimated using logistic regression models adjusting for study and ancestry-specific principal components. The strongest association observed was with the original identified index SNP rs11249433 (minor allele frequency (MAF) 0.402; per-allele odds ratio (OR) = 1.10, 95% confidence interval (CI) 1.08-1.13, P = 1.49 x 10-21). The association for rs11249433 was limited to ER-positive breast cancers (test for heterogeneity P≤8.41 x 10-5). Additional analyses by other tumor characteristics showed stronger associations with moderately/well differentiated tumors and tumors of lobular histology. Although no significant eQTL associations were observed, in silico analyses showed that rs11249433 was located in a region that is likely a weak enhancer/promoter. Fine-mapping analysis of the 1p11.2 breast cancer susceptibility locus confirms this region to be limited to risk to cancers that are ER-positive.

KW - Alleles

KW - Breast Neoplasms

KW - Case-Control Studies

KW - Chromosome Mapping

KW - Chromosomes, Human, Pair 1

KW - Computational Biology

KW - Female

KW - Gene Frequency

KW - Genetic Association Studies

KW - Genetic Predisposition to Disease

KW - Genotype

KW - Humans

KW - Linkage Disequilibrium

KW - Neoplasm Grading

KW - Polymorphism, Single Nucleotide

KW - Population Surveillance

KW - Quantitative Trait Loci

KW - Risk Assessment

KW - Journal Article

U2 - 10.1371/journal.pone.0160316

DO - 10.1371/journal.pone.0160316

M3 - Article

C2 - 27556229

SN - 1932-6203

VL - 11

SP - e0160316

JO - P L o S One

JF - P L o S One

IS - 8

ER -

Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus

Abstract

Keywords

UN SDGs

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