Prognostic significance of POLE proofreading mutations in endometrial cancer.
Prognostic significance of POLE proofreading mutations in endometrial cancer.
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DOI：
10.1093/jnci/dju402
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发表时间：
2015-01
期刊：
影响因子：
--
通讯作者：
Bosse T
中科院分区：
文献类型：
--
作者：
Church DN;Stelloo E;Nout RA;Valtcheva N;Depreeuw J;ter Haar N;Noske A;Amant F;Tomlinson IP;Wild PJ;Lambrechts D;Jürgenliemk-Schulz IM;Jobsen JJ;Smit VT;Creutzberg CL;Bosse T
目前子宫内膜癌（EC）的风险分层导致辅助治疗经常过度和不足，并且可以通过新型生物标志物来改善。我们检查了 POLE 校对突变（最近报道约 7% 的 EC 中存在）是否可以预测预后。我们对 PORTEC-1 和 -2 试验 (n = 788) 的 EC 进行了靶向 POLE 测序，并根据 POLE 状态分析了临床结果。我们通过荟萃分析将这些结果与另外三个系列 (n = 628) 的结果相结合，生成 POLE 突变 EC 的无复发生存 (RFS) 和癌症特异性生存 (CSS) 的多变量调整、汇总风险比 (HR)。所有统计检验都是双面的。 在 PORTEC-1 和 2 的 788 个 EC 中的 48 个 (6.1%) 中检测到 POLE 突变，并且与高肿瘤级别相关 (P < .001)。患有 POLE 突变 EC 的女性复发率（6.2% vs 14.1%）和 EC 死亡率（2.3% vs 9.7%）较少，但在整个 PORTEC 队列中，RFS 和 CSS 的差异没有统计学意义（多变量调整 HR = 0.43，95% CI = 0.13 至 1.37，P = 0.15；HR = 0.19，95% CI = 0.03 至 1.44，P = 0.11 分别）。然而，在 109 个 3 级肿瘤中，15 个 POLE 突变型 EC 中有 0 个复发，而 94 个 POLE 野生型癌症中有 29 个复发（30.9%）；反映在统计学上显着更高的 RFS（多变量调整 HR = 0.11，95% CI = 0.001 至 0.84，P = .03）。在其他系列中，33 个 POLE 突变 EC 中的任何一个都没有发生 EC 相关事件，导致 RFS 的多变量调整汇总 HR 为 0.33（95% CI = 0.12 至 0.91，P = .03），CSS 为 0.26（95% CI = 0.06 至 1.08，P = .06）。 POLE 校对突变可预测良好的 EC 预后，独立于其他临床病理学变量，在高级别肿瘤中效果最大。这种新型生物标志物可能有助于减少 EC 的过度治疗。
Current risk stratification in endometrial cancer (EC) results in frequent over- and underuse of adjuvant therapy, and may be improved by novel biomarkers. We examined whether POLE proofreading mutations, recently reported in about 7% of ECs, predict prognosis. We performed targeted POLE sequencing in ECs from the PORTEC-1 and -2 trials (n = 788), and analyzed clinical outcome according to POLE status. We combined these results with those from three additional series (n = 628) by meta-analysis to generate multivariable-adjusted, pooled hazard ratios (HRs) for recurrence-free survival (RFS) and cancer-specific survival (CSS) of POLE-mutant ECs. All statistical tests were two-sided. POLE mutations were detected in 48 of 788 (6.1%) ECs from PORTEC-1 and-2 and were associated with high tumor grade (P < .001). Women with POLE-mutant ECs had fewer recurrences (6.2% vs 14.1%) and EC deaths (2.3% vs 9.7%), though, in the total PORTEC cohort, differences in RFS and CSS were not statistically significant (multivariable-adjusted HR = 0.43, 95% CI = 0.13 to 1.37, P = .15; HR = 0.19, 95% CI = 0.03 to 1.44, P = .11 respectively). However, of 109 grade 3 tumors, 0 of 15 POLE-mutant ECs recurred, compared with 29 of 94 (30.9%) POLE wild-type cancers; reflected in statistically significantly greater RFS (multivariable-adjusted HR = 0.11, 95% CI = 0.001 to 0.84, P = .03). In the additional series, there were no EC-related events in any of 33 POLE-mutant ECs, resulting in a multivariable-adjusted, pooled HR of 0.33 for RFS (95% CI = 0.12 to 0.91, P = .03) and 0.26 for CSS (95% CI = 0.06 to 1.08, P = .06). POLE proofreading mutations predict favorable EC prognosis, independently of other clinicopathological variables, with the greatest effect seen in high-grade tumors. This novel biomarker may help to reduce overtreatment in EC.
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影响因子：
64.8
作者：
通讯作者：
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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.
常见的与癌症相关的DNA聚合酶ε突变会导致异常强的突变器表型，表明富达缺陷与校对丧失不同。
影响因子：
11.2
作者：
Kane DP;Shcherbakova PV
通讯作者：
Shcherbakova PV
影响因子：
8.4
作者：
Hogberg, Thomas;Signorelli, Mauro;de Oliveira, Carlos Freire;Fossati, Roldano;Lissoni, Andrea Alberto;Sorbe, Bengt;Andersson, Hakan;Grenman, Seija;Lundgren, Caroline;Rosenberg, Per;Boman, Karin;Tholander, Bengt;Scambia, Giovanni;Reed, Nicholas;Cormio, Gennaro;Tognon, Germana;Clarke, Jackie;Sawicki, Tomasz;Zola, Paolo;Kristensen, Gunnar
通讯作者：
Kristensen, Gunnar
影响因子：
3.5
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
通讯作者：
Tomlinson IP