美国国立癌症研究所乳腺癌与前列腺癌队列联盟中雌激素受体β的序列变异与前列腺癌风险
Sequence variants of estrogen receptor beta and risk of prostate cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium.
作者信息
Chen Yen-Ching, Kraft Peter, Bretsky Philip, Ketkar Shamika, Hunter David J, Albanes Demetrius, Altshuler David, Andriole Gerald, Berg Christine D, Boeing Heiner, Burtt Noel, Bueno-de-Mesquita Bas, Cann Howard, Canzian Federico, Chanock Stephen, Dunning Alison, Feigelson Heather S, Freedman Matthew, Gaziano J Michael, Giovannucci Edward, Sánchez Maria-Jose, Haiman Christopher A, Hallmans Göran, Hayes Richard B, Henderson Brian E, Hirschhorn Joel, Kaaks Rudolf, Key Timothy J, Kolonel Laurence N, LeMarchand Loic, Ma Jing, Overvad Kim, Palli Domenico, Pharaoh Paul, Pike Malcolm, Riboli Eliot, Rodriguez Carmen, Setiawan V Wendy, Stampfer Meir, Stram Daniel O, Thomas Gilles, Thun Michael J, Travis Ruth C, Virtamo Jarmo, Trichopoulou Antonia, Wacholder Sholom, Weinstein Stephanie J
机构信息
Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115, USA.
出版信息
Cancer Epidemiol Biomarkers Prev. 2007 Oct;16(10):1973-81. doi: 10.1158/1055-9965.EPI-07-0431.
BACKGROUND
Estrogen receptor beta (ESR2) may play a role in modulating prostate carcinogenesis through the regulation of genes related to cell proliferation and apoptosis.
METHODS
We conducted nested case-control studies in the Breast and Prostate Cancer Cohort Consortium (BPC3) that pooled 8,323 prostate cancer cases and 9,412 controls from seven cohorts. Whites were the predominant ethnic group. We characterized genetic variation in ESR2 by resequencing exons in 190 breast and prostate cancer cases and genotyping a dense set of single nucleotide polymorphisms (SNP) spanning the locus in a multiethnic panel of 349 cancer-free subjects. We selected four haplotype-tagging SNPs (htSNP) to capture common ESR2 variation in Whites; these htSNPs were then genotyped in all cohorts. Conditional logistic regression models were used to assess the association between sequence variants of ESR2 and the risk of prostate cancer. We also investigated the effect modification by age, body mass index, and family history, as well as the association between sequence variants of ESR2 and advanced-stage (>or=T3b, N1, or M1) and high-grade (Gleason sum >or=8) prostate cancer, respectively.
RESULTS
The four tag SNPs in ESR2 were not significantly associated with prostate cancer risk, individually. The global test for the influence of any haplotype on the risk of prostate cancer was not significant (P = 0.31). However, we observed that men carrying two copies of one of the variant haplotypes (TACC) had a 1.46-fold increased risk of prostate cancer (99% confidence interval, 1.06-2.01) compared with men carrying zero copies of this variant haplotype. No SNPs or haplotypes were associated with advanced stage or high grade of prostate cancer.
CONCLUSION
In our analysis focused on genetic variation common in Whites, we observed little evidence for any substantial association of inherited variation in ESR2 with risk of prostate cancer. A nominally significant (P < 0.01) association between the TACC haplotype and prostate cancer risk under the recessive model could be a chance finding and, in any event, would seem to contribute only slightly to the overall burden of prostate cancer.
背景
雌激素受体β（ESR2）可能通过调节与细胞增殖和凋亡相关的基因，在前列腺癌发生过程中发挥作用。
方法
我们在乳腺癌和前列腺癌队列联盟（BPC3）中开展了巢式病例对照研究，该联盟汇集了来自7个队列的8323例前列腺癌病例和9412例对照。白人是主要种族群体。我们通过对190例乳腺癌和前列腺癌病例的外显子进行重测序，并在349名无癌受试者的多民族样本中对跨越该基因座的一组密集单核苷酸多态性（SNP）进行基因分型，来表征ESR2的遗传变异。我们选择了4个单倍型标签SNP（htSNP）来捕获白人中常见的ESR2变异；然后在所有队列中对这些htSNP进行基因分型。使用条件逻辑回归模型来评估ESR2序列变异与前列腺癌风险之间的关联。我们还研究了年龄、体重指数和家族史的效应修正，以及ESR2序列变异与晚期（≥T3b、N1或M1）和高级别（Gleason评分≥8）前列腺癌之间的关联。
结果
ESR2中的4个标签SNP单独与前列腺癌风险均无显著关联。对任何单倍型对前列腺癌风险影响的全局检验无显著性（P = 0.31）。然而，我们观察到，携带其中一种变异单倍型（TACC）两份拷贝的男性患前列腺癌的风险比携带该变异单倍型零份拷贝的男性高1.46倍（99%置信区间，1.06 - 2.01）。没有SNP或单倍型与前列腺癌的晚期或高级别相关。
结论
在我们针对白人中常见遗传变异的分析中，几乎没有证据表明ESR2的遗传变异与前列腺癌风险存在任何实质性关联。在隐性模型下，TACC单倍型与前列腺癌风险之间名义上显著（P < 0.01）的关联可能是偶然发现，无论如何，似乎对前列腺癌的总体负担贡献不大。
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