Breyer Joan P, Sanders Melinda E, Airey David C, Cai Qiuyin, Yaspan Brian L, Schuyler Peggy A, Dai Qi, Boulos Fouad, Olivares Maria G, Bradley Kevin M, Gao Yu-Tang, Page David L, Dupont William D, Zheng Wei, Smith Jeffrey R
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-0275, USA.
Cancer Epidemiol Biomarkers Prev. 2009 Apr;18(4):1252-8. doi: 10.1158/1055-9965.EPI-08-1202. Epub 2009 Mar 31.
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.
乳腺癌中上皮生长因子受体基因ERBB2（HER2，NEU）的扩增与临床预后不良相关。在乳腺发育过程中，该受体在导管和小叶腺泡分化中起作用。在一项对842例经组织学确诊的浸润性乳腺癌病例和1108例来自上海乳腺癌研究的对照进行的研究中，我们对ERBB2基因的遗传变异在乳腺癌风险中的作用进行了系统调查。我们观察到ERBB2基因位于一个高连锁不平衡区域内，该区域由研究人群中的三种主要祖先单倍型组成。这些单倍型由简单串联重复序列和单核苷酸多态性标记，包括错义变体I655V和P1170A。我们在ERBB2转录起始位点上游4.4 kb的一个进化保守区域内观察到一个高度多态的简单串联重复序列具有风险修饰作用。在显性遗传模型下，年龄调整后的优势比为1.74（95%置信区间，1.27 - 2.37）。在进行多重比较校正后，其与乳腺癌以及按组织学、组织学分级和分期分层的乳腺癌的关联仍然显著。相比之下，我们未观察到ERBB2单核苷酸多态性单倍型与乳腺癌易感性之间存在关联。
