Yoo Sun, Pettersson Andreas, Jordahl Kristina M, Lis Rosina T, Lindstrom Sara, Meisner Allison, Nuttall Elizabeth J, Stack Edward C, Stampfer Meir J, Kraft Peter, Brown Myles, Loda Massimo, Giovannucci Edward L, Kantoff Philip W, Mucci Lorelei A
Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
Department of Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts. Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Cancer Epidemiol Biomarkers Prev. 2014 Oct;23(10):2027-31. doi: 10.1158/1055-9965.EPI-14-0020. Epub 2014 Jun 12.
The androgen receptor (AR) is an essential gene in prostate cancer pathogenesis and progression. Genetic variation in AR exists, including a polymorphic CAG repeat sequence that is inversely associated with transcriptional activity. Experimental data suggest that heightened AR activity facilitates formation of TMPRSS2:ERG, a gene fusion present in approximately 50% of tumors of patients with prostate cancer.
We undertook a nested case-control study to investigate the hypothesis that shorter CAG repeat length would be associated with prostate cancer risk defined by TMPRSS2:ERG status. The study included 291 men with prostate cancer (147 ERG-positive) and 1,221 cancer-free controls. ORs and 95% confidence intervals (CI) were calculated using logistic regression.
Median CAG repeat length (interquartile range) among controls was 22 (20-24). Men with shorter CAG repeats had an increased risk of ERG-positive (OR, 1.07 per 1 repeat decrease; 95% CI, 1.00-1.14), but not ERG-negative prostate cancer (OR, 0.99 per 1 repeat decrease; 95% CI, 0.93-1.05).
These data suggest that shorter CAG repeats are specifically associated with development of TMPRSS2:ERG-positive prostate cancer.
Our results provide supportive evidence that androgen signaling underlies the development of prostate tumors that harbor TMPRSS2:ERG. Moreover, these results suggest that TMPRSS2:ERG may represent a unique molecular subtype of prostate cancer with an etiology distinct from TMPRSS2:ERG-negative disease.
雄激素受体（AR）是前列腺癌发病机制和进展中的一个关键基因。AR存在基因变异，包括一个多态性的CAG重复序列，该序列与转录活性呈负相关。实验数据表明，增强的AR活性促进了TMPRSS2:ERG的形成，TMPRSS2:ERG是一种基因融合体，约50%的前列腺癌患者肿瘤中存在该融合体。
我们进行了一项巢式病例对照研究，以调查CAG重复序列长度较短与由TMPRSS2:ERG状态定义的前列腺癌风险相关这一假设。该研究纳入了291名前列腺癌男性患者（147名ERG阳性）和1221名无癌对照者。使用逻辑回归计算比值比（OR）和95%置信区间（CI）。
对照者中CAG重复序列的中位数长度（四分位间距）为22（20 - 24）。CAG重复序列较短的男性患ERG阳性前列腺癌的风险增加（每减少1次重复，OR为1.07；95%CI，1.00 - 1.14），但患ERG阴性前列腺癌的风险未增加（每减少1次重复，OR为0.99；%CI，0.93 - 1.05）。
这些数据表明，较短的CAG重复序列与TMPRSS2:ERG阳性前列腺癌的发生特别相关。
我们的结果提供了支持性证据，表明雄激素信号传导是含有TMPRSS2:ERG的前列腺肿瘤发生的基础。此外，这些结果表明，TMPRSS2:ERG可能代表前列腺癌的一种独特分子亚型，其病因与TMPRSS2:ERG阴性疾病不同。
