The genetic landscape of endometrial clear cell carcinomas.
The genetic landscape of endometrial clear cell carcinomas.
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DOI：
10.1002/path.4947
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发表时间：
2017-10
期刊：
影响因子：
--
通讯作者：
Weigelt B
中科院分区：
文献类型：
--
作者：
DeLair DF;Burke KA;Selenica P;Lim RS;Scott SN;Middha S;Mohanty AS;Cheng DT;Berger MF;Soslow RA;Weigelt B
子宫内膜透明细胞癌是一种罕见的子宫内膜癌，通常与侵袭性临床行为相关。在这里，我们试图定义子宫内膜透明细胞癌（ECCs）的体细胞遗传学改变的剧目，以及ECCs是否可以被分类为子宫内膜浆液性癌和浆液性癌的分子亚型。我们针对32个纯EC的300个癌症相关基因进行了严格的组织病理学审查、免疫组织化学分析和大规模平行测序。分别有11例（34%）、7例（22%）和6例（19%）内皮细胞出现p53、ARID 1A和至少一种DNA错配修复蛋白的异常表达。从本研究中包括的32个ECC中的30个获得靶向测序数据，其显示两个ECC（7%）是超突变的，并且具有影响POLE的核酸外切酶结构域的突变。在POLE野生型ECC中，TP 53（46%），PIK 3CA（36%），PPP 2 R1 A（36%），FBXW 7（25%），ARID 1A（21%），PIK 3R 1（18%）和SPOP（18%）是最常受突变影响的基因，18%和11%分别具有CCNE 1和ERBB 2扩增，而11%显示DAXX纯合缺失。与癌症基因组图谱（TCGA）中的非POLE类乳腺癌相比，ECCs较少发生影响CTNNB 1和PTEN的突变，但PPP 2 R1 A和TP 53突变更频繁。与子宫内膜浆液性癌（TCGA）相比，ECCs较少发生TP 53突变。使用基于分子的TCGA分类的替代模型，所有以前在子宫内膜浆液性癌和浆液性癌中鉴定的分子亚型都存在于所研究的ECCs中，包括POLE、MMR缺陷、拷贝数高（浆液性）/p53异常和拷贝数低（浆液性）/p53野生型，这些在单变量分析中与无病生存率显著相关。这些发现表明，ECCs是一组具有不同结局的组织学和遗传异质性肿瘤。此外，我们的数据表明，分类为一般的“高级别”或“II型”肿瘤的ECC可能是没有道理的。
Clear cell carcinoma of the endometrium is a rare type of endometrial cancer generally associated with an aggressive clinical behavior. Here we sought to define the repertoire of somatic genetic alterations in endometrial clear cell carcinomas (ECCs) and whether ECCs could be classified into the molecular subtypes described for endometrial endometrioid and serous carcinomas. We performed a rigorous histopathological review, immunohistochemical analysis and massively parallel sequencing targeting 300 cancer-related genes of 32 pure ECCs. Eleven (34%), seven (22%) and six (19%) ECCs displayed abnormal expression patterns of p53, ARID1A and at least one DNA mismatch repair protein, respectively. Targeted sequencing data were obtained from 30 of the 32 ECCs included in this study, which revealed that two ECCs (7%) were ultramutated and harbored mutations affecting the exonuclease domain of POLE. In POLE wild-type ECCs, TP53 (46%), PIK3CA (36%), PPP2R1A (36%), FBXW7 (25%), ARID1A (21%), PIK3R1 (18%) and SPOP (18%) were the genes most commonly affected by mutations, and 18% and 11% harbored CCNE1 and ERBB2 amplifications, respectively, while 11% showed DAXX homozygous deletions. In comparison to non-POLE endometrioid carcinomas from The Cancer Genome Atlas (TCGA), ECCs less frequently harbored mutations affecting CTNNB1 and PTEN but more frequently PPP2R1A and TP53 mutations. Compared to endometrial serous carcinomas (TCGA), ECCs less frequently harbored TP53 mutations. Using a surrogate model for the molecular-based TCGA classification, all molecular subtypes previously identified in endometrial endometrioid and serous carcinomas were present in the ECCs studied, including POLE, MMR-deficient, copy-number high (serous-like)/p53 abnormal and copy-number low (endometrioid)/p53 wild-type, which were significantly associated with disease-free survival in univariate analysis. These findings demonstrate that ECCs are a histologically and genetically heterogeneous group of tumors with varying outcomes. Furthermore, our data suggest that the classification of ECCs as being generally “high-grade” or “type II” tumors may not be warranted.
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DOI：
10.1097/igc.0000000000000681
发表时间：
2016-06
期刊：
International journal of gynecological cancer : official journal of the International Gynecological Cancer Society
影响因子：
--
作者：
Billingsley CC;Cohn DE;Mutch DG;Hade EM;Goodfellow PJ
通讯作者：
Goodfellow PJ
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1038/nrc1299
发表时间：
2004-03
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
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使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
影响因子：
11.2
作者：
Carter H;Chen S;Isik L;Tyekucheva S;Velculescu VE;Kinzler KW;Vogelstein B;Karchin R
通讯作者：
Karchin R