DNA polymerase ε and δ exonuclease domain mutations in endometrial cancer.
DNA polymerase ε and δ exonuclease domain mutations in endometrial cancer.
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DOI：
10.1093/hmg/ddt131
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发表时间：
2013-07-15
影响因子：
3.5
通讯作者：
Tomlinson IP
中科院分区：
文献类型：
--
作者：
Church DN;Briggs SE;Palles C;Domingo E;Kearsey SJ;Grimes JM;Gorman M;Martin L;Howarth KM;Hodgson SV;NSECG Collaborators;Kaur K;Taylor J;Tomlinson IP
在细胞分裂之前DNA的精确复制对于抑制诱变和肿瘤发展是必不可少的。真核生物DNA复制的高保真度是由于DNA聚合酶将核苷酸准确掺入新生DNA链、DNA聚合酶δ和δ的核酸外切酶活性识别和去除错配核苷酸（校正）以及错配修复（MMR）装置对新合成DNA的复制后监视和修复的组合。虽然缺陷MMR对肿瘤形成的贡献是公认的，但缺陷DNA聚合酶活性在癌症发展中重要的证据有限。我们最近发现，生殖系POLE和POLD 1核酸外切酶结构域突变（EDM）易患结直肠癌（CRC），在后者的情况下，子宫内膜癌（EC）。体细胞POLE突变也发生在5-10%的散发性CRC中，并且是超变、微卫星稳定分子表型的基础。我们假设散发性EC也可能获得体细胞POLE和/或POLD 1突变。在这里，我们发现，尽管POLD 1 EDM并不常见，但在173例子宫内膜癌中，有7%的患者存在具有良好致病作用证据的错义POLE EDM。POLE突变定位于高度保守的残基，并强烈预测会影响校对。与此一致，POLE突变型肿瘤是高度突变的，具有高频率的碱基置换，以及特别大的相对过量的G：C>T：A颠换。所有的POLE EDM肿瘤都是微卫星稳定的，这表明DNA校对或MMR的缺陷提供了实现基因组不稳定和肿瘤发生的替代机制。
Accurate duplication of DNA prior to cell division is essential to suppress mutagenesis and tumour development. The high fidelity of eukaryotic DNA replication is due to a combination of accurate incorporation of nucleotides into the nascent DNA strand by DNA polymerases, the recognition and removal of mispaired nucleotides (proofreading) by the exonuclease activity of DNA polymerases δ and ɛ, and post-replication surveillance and repair of newly synthesized DNA by the mismatch repair (MMR) apparatus. While the contribution of defective MMR to neoplasia is well recognized, evidence that faulty DNA polymerase activity is important in cancer development has been limited. We have recently shown that germline POLE and POLD1 exonuclease domain mutations (EDMs) predispose to colorectal cancer (CRC) and, in the latter case, to endometrial cancer (EC). Somatic POLE mutations also occur in 5–10% of sporadic CRCs and underlie a hypermutator, microsatellite-stable molecular phenotype. We hypothesized that sporadic ECs might also acquire somatic POLE and/or POLD1 mutations. Here, we have found that missense POLE EDMs with good evidence of pathogenic effects are present in 7% of a set of 173 endometrial cancers, although POLD1 EDMs are uncommon. The POLE mutations localized to highly conserved residues and were strongly predicted to affect proofreading. Consistent with this, POLE-mutant tumours were hypermutated, with a high frequency of base substitutions, and an especially large relative excess of G:C>T:A transversions. All POLE EDM tumours were microsatellite stable, suggesting that defects in either DNA proofreading or MMR provide alternative mechanisms to achieve genomic instability and tumourigenesis.
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影响因子：
64.8
作者：
Seshagiri, Somasekar;Stawiski, Eric W.;Durinck, Steffen;Modrusan, Zora;Storm, Elaine E.;Conboy, Caitlin B.;Chaudhuri, Subhra;Guan, Yinghui;Janakiraman, Vasantharajan;Jaiswal, Bijay S.;Guillory, Joseph;Ha, Connie;Dijkgraaf, Gerrit J. P.;Stinson, Jeremy;Gnad, Florian;Huntley, Melanie A.;Degenhardt, Jeremiah D.;Haverty, Peter M.;Bourgon, Richard;Wang, Weiru;Koeppen, Hartmut;Gentleman, Robert;Starr, Timothy K.;Zhang, Zemin;Largaespada, David A.;Wu, Thomas D.;de Sauvage, Frederic J.
通讯作者：
de Sauvage, Frederic J.
影响因子：
4.5
作者：
Miyabe I;Kunkel TA;Carr AM
通讯作者：
Carr AM
DOI：
10.1073/pnas.88.21.9473
发表时间：
1991-11-01
影响因子：
11.1
作者：
MORRISON, A;BELL, JB;SUGINO, A
通讯作者：
SUGINO, A
影响因子：
45.3
作者：
Bertagnolli, Monica M.;Redston, Mark;Warren, Robert S.
通讯作者：
Warren, Robert S.
影响因子：
2.9
作者：
Wang, J;Yu, P;Steitz, TA
通讯作者：
Steitz, TA