基于人群的研究：错配修复基因变异与前列腺癌风险和结局的关联。
Population-based study of the association of variants in mismatch repair genes with prostate cancer risk and outcomes.
机构信息
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
出版信息
Cancer Epidemiol Biomarkers Prev. 2010 Jan;19(1):258-64. doi: 10.1158/1055-9965.EPI-09-0800.
BACKGROUND
Mismatch repair (MMR) gene activity may be associated with prostate cancer risk and outcomes. This study evaluated whether single nucleotide polymorphisms (SNP) in key MMR genes are related to prostate cancer outcomes.
METHODS
Data from two population-based case-control studies of prostate cancer among Caucasian and African-American men residing in King County, Washington were combined for this analysis. Cases (n = 1,458) were diagnosed with prostate cancer in 1993 to 1996 or 2002 to 2005 and were identified through the Seattle-Puget Sound Surveillance Epidemiology and End Results cancer registry. Controls (n = 1,351) were age-matched to cases and were identified through random digit dialing. Logistic regression was used to assess the relationship between haplotype-tagging SNPs and prostate cancer risk and disease aggressiveness. Cox proportional hazards regression was used to assess the relationship between SNPs and prostate cancer recurrence and prostate cancer-specific death.
RESULTS
Nineteen SNPs were evaluated in the key MMR genes: five in MLH1, 10 in MSH2, and 4 in PMS2. Among Caucasian men, one SNP in MLH1 (rs9852810) was associated with overall prostate cancer risk [odds ratio, 1.21; 95% confidence interval (95% CI), 1.02, 1.44; P = 0.03], more aggressive prostate cancer (odds ratio, 1.49; 95% CI, 1.15, 1.91; P < 0.01), and prostate cancer recurrence (hazard ratio, 1.83; 95% CI, 1.18, 2.86; P < 0.01), but not prostate cancer-specific mortality. A nonsynonymous coding SNP in MLH1, rs1799977 (I219V), was also found to be associated with more aggressive disease. These results did not remain significant after adjusting for multiple comparisons.
CONCLUSION
This population-based case-control study provides evidence for a possible association with a gene variant in MLH1 in relation to the risk of overall prostate cancer, more aggressive disease, and prostate cancer recurrence, which warrants replication.
背景
错配修复（MMR）基因的活性可能与前列腺癌的风险和结局有关。本研究评估了关键 MMR 基因中的单核苷酸多态性（SNP）是否与前列腺癌的结局有关。
方法
本分析结合了两项基于人群的、针对居住在华盛顿州金县的白种人和非裔美国男性的前列腺癌病例对照研究的数据。病例（n=1458）于 1993 年至 1996 年或 2002 年至 2005 年期间被诊断患有前列腺癌，并通过西雅图-普吉特湾监测、流行病学和最终结果癌症登记处确定。对照组（n=1351）与病例年龄匹配，并通过随机数字拨号确定。采用 logistic 回归评估单倍型标记 SNP 与前列腺癌风险和疾病侵袭性的关系。采用 Cox 比例风险回归评估 SNP 与前列腺癌复发和前列腺癌特异性死亡的关系。
结果
在关键的 MMR 基因中评估了 19 个 SNP：MLH1 中的 5 个、MSH2 中的 10 个和 PMS2 中的 4 个。在白种男性中，MLH1 中的一个 SNP（rs9852810）与总体前列腺癌风险相关[比值比，1.21；95%置信区间（95%CI），1.02，1.44；P=0.03]、侵袭性更强的前列腺癌（比值比，1.49；95%CI，1.15，1.91；P<0.01）和前列腺癌复发（风险比，1.83；95%CI，1.18，2.86；P<0.01），但与前列腺癌特异性死亡率无关。MLH1 中的一个非同义编码 SNP（rs1799977，I219V）也与更具侵袭性的疾病相关。这些结果在调整了多次比较后不再具有统计学意义。
结论
本基于人群的病例对照研究提供了证据，表明 MLH1 中的基因变异与总体前列腺癌、侵袭性更强的疾病和前列腺癌复发的风险之间可能存在关联，需要进一步研究证实。
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