Mitochondrial DNA sequence variation and risk of pancreatic cancer.
Mitochondrial DNA sequence variation and risk of pancreatic cancer.
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DOI：
10.1158/0008-5472.can-11-1682
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发表时间：
2012-02-01
期刊：
影响因子：
11.2
通讯作者：
Tranah GJ
中科院分区：
文献类型：
--
作者：
Lam ET;Bracci PM;Holly EA;Chu C;Poon A;Wan E;White K;Kwok PY;Pawlikowska L;Tranah GJ
虽然线粒体基因组表现出高突变率，但常见的线粒体DNA（mtDNA）变异并不总是与胰腺癌相关。在这里，我们通过对旧金山弗朗西斯科湾区胰腺癌病例对照研究中参与者（病例=286，对照=283）的mtDNA进行测序，全面检查了线粒体基因组变异。五种常见变异与胰腺癌相关，具有名义统计学显著性（p<0.05），其中ND 2基因中的mt5460 g的发现最强（比值比（OR）=3.9，95%置信区间（CI）=1.5-10; p=0.004），其编码A331 T置换。与最常见的单倍群H相比，单倍群K与胰腺癌风险降低名义上相关（OR = 0.32，CI=0.13-0.76; p=0.01）。共有19个单倍型组特异性罕见变异与胰腺癌风险产生名义上的统计学显著相关性（p<0.05），其中大多数在参与氧化磷酸化的基因中观察到。使用加权和统计来确定22种线粒体tRNA中的变体对胰腺癌风险的总体影响（p=0.02）。虽然HV 2和12 S RNA区域中的单细胞变异的负担在欧洲单倍群N病例中比对照组高3倍，但在非洲单倍群L病例中ND 4和ND 5中的单细胞变异的患病率比对照组高2至3倍。总之，这项研究的结果提供了证据，表明聚集的常见和罕见变异以及单细胞变异的积累是胰腺癌风险的重要贡献者。
Although the mitochondrial genome exhibits high mutation rates, common mitochondrial DNA (mtDNA) variation has not been consistently associated with pancreatic cancer. Here, we comprehensively examined mitochondrial genomic variation by sequencing the mtDNA of participants (cases=286, controls=283) in a San Francisco Bay Area pancreatic cancer case-control study. Five common variants were associated with pancreatic cancer at nominal statistical significance (p<0.05) with the strongest finding for mt5460g in the ND2 gene (odds ratio (OR)=3.9, 95% confidence interval (CI)=1.5–10; p=0.004) which encodes an A331T substitution. Haplogroup K was nominally associated with reduced pancreatic cancer risk (OR = 0.32, CI=0.13–0.76; p=0.01) when compared with the most common haplogroup, H. A total of 19 haplogroup-specific rare variants yielded nominal statistically significant associations (p<0.05) with pancreatic cancer risk, with the majority observed in genes involved in oxidative phosphorylation. Weighted-sum statistics were used to identify an aggregate effect of variants in the 22 mitochondrial tRNAs on pancreatic cancer risk (p=0.02). While the burden of singleton variants in the HV2 and 12S RNA regions was three times higher among European haplogroup N cases than controls, the prevalence of singleton variants in ND4 and ND5 was two to three times higher among African haplogroup L cases than in controls. Together, the results of this study provide evidence that aggregated common and rare variants and the accumulation of singleton variants are important contributors to pancreatic cancer risk.