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; kConFab/AOCS Investigators; Anna H Wu; David Ven den Berg

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, kConFab/AOCS Investigators, Anna H Wu, David Ven den Berg

Department of Clinical Medicine

8 Citations (Scopus)

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). Perallelic 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
Article number	e0160316
Journal	P L o S One
Volume	11
Issue number	8
ISSN	1932-6203
DOIs	https://doi.org/10.1371/journal.pone.0160316
Publication status	Published - Aug 2016

Keywords

Journal Article

UN SDGs

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

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10.1371/journal.pone.0160316

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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., ... Ven den Berg, D. (2016). Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus. P L o S One, 11(8), Article e0160316. https://doi.org/10.1371/journal.pone.0160316

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, kConFab/AOCS Investigators, Wu, AH & Ven den Berg, D 2016, 'Fine-Mapping of the 1p11.2 Breast Cancer Susceptibility Locus', P L o S One, vol. 11, no. 8, e0160316. https://doi.org/10.1371/journal.pone.0160316

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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). Perallelic 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.",

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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 - kConFab/AOCS Investigators

AU - Wu, Anna H

AU - Ven den Berg, David

PY - 2016/8

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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). Perallelic 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). Perallelic 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 - Journal Article

U2 - 10.1371/journal.pone.0160316

DO - 10.1371/journal.pone.0160316

M3 - Journal article

C2 - 27556229

SN - 1932-6203

VL - 11

JO - P L o S One

JF - P L o S One

IS - 8

M1 - e0160316

ER -

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

Abstract

Keywords

UN SDGs

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