Allelic variation at the 8q23.3 colorectal cancer risk locus functions as a cis-acting regulator of EIF3H.
Allelic variation at the 8q23.3 colorectal cancer risk locus functions as a cis-acting regulator of EIF3H.
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DOI：
10.1371/journal.pgen.1001126
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发表时间：
2010-09-16
期刊：
影响因子：
4.5
通讯作者：
Houlston RS
中科院分区：
文献类型：
--
作者：
Pittman AM;Naranjo S;Jalava SE;Twiss P;Ma Y;Olver B;Lloyd A;Vijayakrishnan J;Qureshi M;Broderick P;van Wezel T;Morreau H;Tuupanen S;Aaltonen LA;Alonso ME;Manzanares M;Gavilán A;Visakorpi T;Gómez-Skarmeta JL;Houlston RS
人类8q23.3的常见遗传变异与结直肠癌（CRC）风险显著相关。为了阐明这种关联的基础，我们比较了1，964例CRC病例和2，081例健康对照中8q23.3常见变异的频率。报告基因研究表明，单核苷酸多态性rs16888589作为等位基因特异性转录抑制因子。染色体构象捕获（3C）分析表明，rs16888589的基因组区域与真核生物翻译起始因子3亚基H（EIF3H）基因的启动子相互作用。我们发现EIF3H基因表达的增加增加了CRC的生长和侵袭性，从而为8q23.3相关性提供了生物学机制。这些数据为8q23.3非编码风险变异rs16888589的功能基础提供了证据，并为CRC的病因学基础提供了新的见解。人类染色体8q23上的常见遗传变异影响结直肠癌（CRC）的发生风险。为了了解这种关联的基础，我们比较了102，000例CRC病例和102，000例健康对照中8q23常见遗传变异的频率。与CRC风险密切相关的变异的功能分析显示，单核苷酸多态性rs16888589强调了8q23.3的关联。携带rs16888589的基因组区域增加真核生物翻译起始因子3亚基H的基因表达。我们发现该基因表达的增加增加了CRC的生长，从而为8q23.3相关性提供了生物学机制。这一发现对于阐明CRC的病因学基础具有特别重要的意义。
Common genetic variation at human 8q23.3 is significantly associated with colorectal cancer (CRC) risk. To elucidate the basis of this association we compared the frequency of common variants at 8q23.3 in 1,964 CRC cases and 2,081 healthy controls. Reporter gene studies showed that the single nucleotide polymorphism rs16888589 acts as an allele-specific transcriptional repressor. Chromosome conformation capture (3C) analysis demonstrated that the genomic region harboring rs16888589 interacts with the promoter of gene for eukaryotic translation initiation factor 3, subunit H (EIF3H). We show that increased expression of EIF3H gene increases CRC growth and invasiveness thereby providing a biological mechanism for the 8q23.3 association. These data provide evidence for a functional basis for the non-coding risk variant rs16888589 at 8q23.3 and provides novel insight into the etiological basis of CRC. Common inherited variation on human chromosome 8q23 influences the risk of developing colorectal cancer (CRC). To understand the basis of this association we have compared the frequency of common genetic variants at 8q23 in ∼2,000 CRC cases and ∼2,000 healthy controls. Functional analyses of variants strongly associated with CRC risk showed that the single nucleotide polymorphism rs16888589 underscores the 8q23.3 association. The region of the genome harboring rs16888589 increases the expression of the gene for eukaryotic translation initiation factor 3, subunit H. We show that increased expression of this gene increases CRC growth thereby providing a biological mechanism for the 8q23.3 association. This finding is of particular importance in elucidating the etiological basis of CRC.
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影响因子：
4.4
作者：
de Bruin EC;van de Pas S;Lips EH;van Eijk R;van der Zee MM;Lombaerts M;van Wezel T;Marijnen CA;van Krieken JH;Medema JP;van de Velde CJ;Eilers PH;Peltenburg LT
通讯作者：
Peltenburg LT
整合染色体畸变和基因表达谱以剖析直肠肿瘤发生。
影响因子：
3.8
作者：
Lips, Esther H.;van Eijk, Ronald;de Graaf, Eelco J. R.;Oosting, Jan;de Miranda, Noel F. C. C.;Karsten, Tom;de Velde, Cornelis J. van;Eilers, Paul H. C.;Tollenaar, Rob A. E. M.;van Wezel, Tom;Morreau, Hans
通讯作者：
Morreau, Hans
影响因子：
30.8
作者：
Tomlinson, Ian P. M.;Webb, Emily;Houlston, Richard S.
通讯作者：
Houlston, Richard S.
影响因子：
11.5
作者：
Aaltonen, Lauri;Johns, Louise;Houlston, Richard
通讯作者：
Houlston, Richard
DOI：
10.1097/01.wcb.0000050065.57184.bb
发表时间：
2003-04-01
影响因子：
6.3
作者：
Turkheimer, FE;Hinz, R;Cunningham, VJ
通讯作者：
Cunningham, VJ