Polymerase ɛ (POLE) mutations in endometrial cancer: clinical outcomes and implications for Lynch syndrome testing.
Polymerase ɛ (POLE) mutations in endometrial cancer: clinical outcomes and implications for Lynch syndrome testing.
复制标题
DOI：
10.1002/cncr.29046
复制
发表时间：
2015-02-01
期刊：
影响因子：
6.2
通讯作者：
Goodfellow, Paul J.
中科院分区：
文献类型：
--
作者：
Billingsley, Caroline C.;Cohn, David E.;Mutch, David G.;Stephens, Julie A.;Suarez, Adrian A.;Goodfellow, Paul J.
DNA聚合酶E3（POLE）外切核酸酶结构域突变是子宫内膜癌（EC）的一种亚型，其体细胞突变负荷显著增加。POLE突变型肿瘤被癌症基因组图谱描述为具有改善的无进展生存期（PFS）的分子亚型。本研究调查了类阿片样EC患者中POLE突变的频率、谱、预后意义和潜在的临床应用。采用PCR扩增和桑格测序方法检测544例肿瘤组织中POLE突变。研究了人口统计学、生存率、临床病理学和分子特征之间的关系。统计检验是双侧的。共发现30个POLE突变（5.6%）。突变与年轻年龄相关（<60岁，P= 0.001）。POLE突变在微卫星稳定（MSS）和不稳定（MSI）肿瘤中检测到的频率相似（分别为5.9%和5.2%），并且在缺乏MLH1甲基化的MSI肿瘤中最常见（P<0.001）。与PFS无关（HR=0.22，P= 0.127）。我们发现突变在MSS和MSI肿瘤中以相等的频率发生，并且在缺乏MLH1甲基化的MSI肿瘤中最常见，这对Lynch综合征筛查和突变检测具有意义。我们发现，POLE突变与一个肿瘤子集中DNA错配修复基因的体细胞突变相关。POLE突变与PFS之间不存在相关性表明POLE突变状态不太可能是临床有用的预后标志物。然而，在MSI EC中的POLE测试可以作为疾病的体细胞起源的标志物。因此，POLE肿瘤检测可能是林奇综合征基因检测的一个有价值的排除标准。
DNA polymerase epsilon (POLE) exonuclease domain mutations characterize a subtype of endometrial cancer (EC) with markedly increased somatic mutational burden. POLE mutant tumors were described as a molecular subtype with improved progression-free survival (PFS) by The Cancer Genome Atlas. This study investigates the frequency, spectrum, prognostic significance, and potential clinical application of POLE mutations in endometrioid EC patients. PCR amplification and Sanger sequencing was used to test for POLE mutation in 544 tumors. Relationships between demographic, survival, clinicopathologic and molecular features were investigated. Statistical tests were two-sided. Thirty POLE mutations (5.6%) were identified. Mutations were associated with younger age (<60 years, P=.001). POLE mutations were detected in microsatellite stable (MSS) and unstable (MSI) tumors at similar frequencies (5.9 v 5.2%, respectively) and were most common in MSI tumors lacking MLH1 methylation (P<.001). There was no association with PFS (HR=0.22, P=.127). Our discovery that mutations occur at equal frequency in MSS and MSI tumors and are most frequent in MSI tumors lacking MLH1 methylation has implications for Lynch syndrome screening and mutation testing. We show that POLE mutations are associated with somatic mutation in DNA mismatch repair genes in a subset of tumors. The absence of association between POLE mutation and PFS indicates POLE mutation status is unlikely to be a clinically useful prognostic marker. However, POLE testing in MSI ECs could serve as a marker of somatic origin of disease. As such, POLE tumor testing might be a valuable exclusionary criterion for Lynch syndrome gene testing.
登录
查看更多内容
影响因子：
2.2
作者：
Baudhuin, LM;Burgart, LJ;Thibodeau, SN
通讯作者：
Thibodeau, SN
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
19
作者：
Kunkel, Thomas A.;Burgers, Peter M.
通讯作者：
Burgers, Peter M.
影响因子：
4.5
作者：
Miyabe I;Kunkel TA;Carr AM
通讯作者：
Carr AM
影响因子：
4.7
作者：
Lancaster, Johnathan M.;Powell, C. Bethan;Herzog, Thomas J.
通讯作者：
Herzog, Thomas J.