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

Research output: Contribution to journalJournal articleResearchpeer-review

  • 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
  • Bojesen, Stig Egil
  • 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

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 languageEnglish
Article numbere0160316
JournalP L o S One
Issue number8
Publication statusPublished - 2016

    Research areas

  • Journal Article

ID: 167555936