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

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 - Ven den Berg, David

AU - Smeets, Ann

AU - Zhao, Hui

AU - Chang-Claude, Jenny

AU - Rudolph, Anja

AU - Radice, Paolo

AU - Barile, Monica

AU - Couch, Fergus J

AU - Vachon, Celine

AU - Giles, Graham

AU - Milne, Roger L

AU - Haiman, Christopher A

AU - Marchand, Loic Le

AU - Goldberg, Mark S

AU - Teo, Soo-Hwang

AU - Taib, Nur Aishah Mohd

AU - Kristensen, Vessela

AU - Borresen-Dale, Anne-Lise

AU - Zheng, Wei

AU - Shrubsole, Martha

AU - Winqvist, Robert

AU - Jukkola-Vuorinen, Arja

AU - Andrulis, Irene L

AU - Knight, Julia A

AU - Devilee, Peter

AU - Seynaeve, Caroline

AU - García-Closas, Montserrat

AU - Czene, Kamila

AU - Darabi, Hatef

AU - Hollestelle, Antoinette

AU - Martens, John W M

AU - Li, Jingmei

AU - Lu, Wei

AU - Shu, Xiao-Ou

AU - Cox, Angela

AU - Cross, Simon S

AU - Blot, William J

AU - Cai, Qiuyin

AU - Shah, Mitul

AU - Luccarini, Craig

AU - Baynes, Caroline

AU - Harrington, Patricia

AU - Kang, Daehee

AU - Choi, Ji-Yeob

AU - Hartman, Mikael

AU - Chia, Kee Seng

AU - Kabisch, Maria

AU - Torres, Diana

AU - Jakubowska, Anna

AU - Lubinski, Jan

AU - Sangrajrang, Suleeporn

AU - Brennan, Paul

AU - Slager, Susan

AU - Yannoukakos, Drakoulis

AU - Shen, Chen-Yang

AU - Hou, Ming-Feng

AU - Swerdlow, Anthony

AU - Orr, Nick

AU - Simard, Jacques

AU - Hall, Per

AU - Pharoah, Paul D P

AU - Easton, Douglas F

AU - Chanock, Stephen J

AU - Dunning, Alison M

AU - Figueroa, Jonine D

AU - kConFab/AOCS Investigators

PY - 2016

Y1 - 2016

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 - Journal Article

U2 - 10.1371/journal.pone.0160316

DO - 10.1371/journal.pone.0160316

M3 - SCORING: Journal article

C2 - 27556229

VL - 11

SP - e0160316

JO - PLOS ONE

JF - PLOS ONE

SN - 1932-6203

IS - 8

ER -