Colorectal cancer risk and patients' survival: influence of polymorphisms in genes somatically mutated in colorectal tumors
Colorectal cancer risk and patients' survival: influence of polymorphisms in genes somatically mutated in colorectal tumors
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DOI：
10.1007/s10552-014-0379-1
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发表时间：
2014-06-01
影响因子：
2.3
通讯作者：
Foersti, Asta
中科院分区：
文献类型：
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作者：
Huhn, Stefanie;Bevier, Melanie;Foersti, Asta
最初的两项研究旨在高通量鉴定结直肠癌(CRC)肿瘤的体细胞突变谱，分别于2006年和2007年发表。利用外显子组测序，他们分别描述了69个和140个候选癌症基因(CaN基因)。在排除了公认的CRC基因APC、KRAS、TP53和ABCA1后，我们利用Koscience竞争性等位基因欧洲特异性PCR(TM)基因分型技术分析了10个CAN基因(OBSCN、MLL3、PKHD1、SYNE1、ERCC6、FBXW7、EPHB6/TRPV6、ELAC1/Smad4、EphA3和ADAMTSL3)中35个潜在功能的单核苷酸多态(SNPs)。除了CRC风险(1,399例CRC病例，838例对照)，我们还考虑了SNPs对患者生存的影响(406例)。尽管我们的计算机分析表明研究的基因和SNPs具有功能相关性，但我们的数据并不支持所研究的生殖系变异对CRC风险和生存的强烈影响。ML3基因与结直肠癌风险和生存率的相关性最强(rs64211，OR1.50，p=0.002，显性模型；hr2.12，p=0.020，隐性模型)。EPHB6/TRPV6(显性模式)中的两个SNP与生存率呈边缘相关(分别为rs4987622 Hr0.58p=0.028和rs6947538 Hr0.64，p=0.036)。尽管在几项下一代测序或表达分析中，CaN基因的体细胞突变与各种类型癌症的发生和进展有关，但我们的研究表明，所研究的潜在功能种系变异不太可能影响结直肠癌的风险或生存。
The first two studies aiming for the high-throughput identification of the somatic mutation spectrum of colorectal cancer (CRC) tumors were published in 2006 and 2007. Using exome sequencing, they described 69 and 140 candidate cancer genes (CAN genes), respectively. We hypothesized that germline variants in these genes may influence CRC risk, similar to APC, which is causing CRC through germline and somatic mutations.After excluding the well-established CRC genes APC, KRAS, TP53, and ABCA1, we analyzed 35 potentially functional single-nucleotide polymorphisms (SNPs) in 10 CAN genes (OBSCN, MLL3, PKHD1, SYNE1, ERCC6, FBXW7, EPHB6/TRPV6, ELAC1/SMAD4, EPHA3, and ADAMTSL3) using KBiosciences Competitive AlleleaEuroSpecific PCR (TM) genotyping assays. In addition to CRC risk (1,399 CRC cases, 838 controls), we also considered the influence of the SNPs on patients' survival (406 cases).In spite of the fact that our in silico analyses suggested functional relevance for the studied genes and SNPs, our data did not support a strong influence of the studied germline variants on CRC risk and survival. The strongest association with CRC risk and survival was found for MLL3 (rs6464211, OR 1.50, p = 0.002, dominant model; HR 2.12, p = 0.020, recessive model). Two SNPs in EPHB6/TRPV6 (dominant model) showed marginal associations with survival (rs4987622 HR 0.58 p = 0.028 and rs6947538 HR 0.64, p = 0.036, respectively).Although somatic mutations in the CAN genes have been related to the development and progression of various types of cancers in several next-generation sequencing or expression analyses, our study suggests that the studied potentially functional germline variants are not likely to affect CRC risk or survival.