title: Heritable variation of ERBB2 and breast cancer risk.
abstract: Amplification of the epithelial growth factor receptor gene ERBB2 (HER2, NEU) in breast cancer is associated with a poor clinical prognosis. In mammary gland development, this receptor plays a role in ductal and lobuloalveolar differentiation. We conducted a systematic investigation of the role of genetic variation of the ERBB2 gene in breast cancer risk in a study of 842 histologically confirmed invasive breast cancer cases and 1,108 controls from the Shanghai Breast Cancer Study. We observed that the ERBB2 gene resides within a locus of high linkage disequilibrium, composed of three major ancestral haplotypes in the study population. These haplotypes are marked by simple tandem repeat and single nucleotide polymorphisms, including the missense variants I655V and P1170A. We observed a risk-modifying effect of a highly polymorphic simple tandem repeat within an evolutionarily conserved region, 4.4 kb upstream from the ERBB2 transcription start site. Under a dominant genetic model, the age-adjusted odds ratio was 1.74 (95% confidence interval, 1.27-2.37). Its association with breast cancer, and with breast cancer stratified by histology, by histologic grade, and by stage, remained significant after correction for multiple comparisons. In contrast, we observed no association of ERBB2 single nucleotide polymorphism haplotypes with breast cancer predisposition.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-0275, USA. jeffrey.smith@vanderbilt.edu
authors.forename: Joan P
authors.initials: JP
authors.lastname: Breyer
authors.forename: Melinda E
authors.initials: ME
authors.lastname: Sanders
authors.forename: David C
authors.initials: DC
authors.lastname: Airey
authors.forename: Qiuyin
authors.initials: Q
authors.lastname: Cai
authors.forename: Brian L
authors.initials: BL
authors.lastname: Yaspan
authors.forename: Peggy A
authors.initials: PA
authors.lastname: Schuyler
authors.forename: Qi
authors.initials: Q
authors.lastname: Dai
authors.forename: Fouad
authors.initials: F
authors.lastname: Boulos
authors.forename: Maria G
authors.initials: MG
authors.lastname: Olivares
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Bradley
authors.forename: Yu-Tang
authors.initials: YT
authors.lastname: Gao
authors.forename: David L
authors.initials: DL
authors.lastname: Page
authors.forename: William D
authors.initials: WD
authors.lastname: Dupont
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Smith