The genetic landscape of endometrial clear cell carcinomas

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

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.

Related collections

Most cited references 31

Record: found
Abstract: found
Article: found

Is Open Access

A clinically applicable molecular-based classification for endometrial cancers

A Talhouk, M K McConechy, Richard S Leung … (2015)

Background: Classification of endometrial carcinomas (ECs) by morphologic features is inconsistent, and yields limited prognostic and predictive information. A new system for classification based on the molecular categories identified in The Cancer Genome Atlas is proposed. Methods: Genomic data from the Cancer Genome Atlas (TCGA) support classification of endometrial carcinomas into four prognostically significant subgroups; we used the TCGA data set to develop surrogate assays that could replicate the TCGA classification, but without the need for the labor-intensive and cost-prohibitive genomic methodology. Combinations of the most relevant assays were carried forward and tested on a new independent cohort of 152 endometrial carcinoma cases, and molecular vs clinical risk group stratification was compared. Results: Replication of TCGA survival curves was achieved with statistical significance using multiple different molecular classification models (16 total tested). Internal validation supported carrying forward a classifier based on the following components: mismatch repair protein immunohistochemistry, POLE mutational analysis and p53 immunohistochemistry as a surrogate for ‘copy-number' status. The proposed molecular classifier was associated with clinical outcomes, as was stage, grade, lymph-vascular space invasion, nodal involvement and adjuvant treatment. In multivariable analysis both molecular classification and clinical risk groups were associated with outcomes, but differed greatly in composition of cases within each category, with half of POLE and mismatch repair loss subgroups residing within the clinically defined ‘high-risk' group. Combining the molecular classifier with clinicopathologic features or risk groups provided the highest C-index for discrimination of outcome survival curves. Conclusions: Molecular classification of ECs can be achieved using clinically applicable methods on formalin-fixed paraffin-embedded samples, and provides independent prognostic information beyond established risk factors. This pragmatic molecular classification tool has potential to be used routinely in guiding treatment for individuals with endometrial carcinoma and in stratifying cases in future clinical trials.

0 comments Cited 267 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Classification of endometrial carcinoma: more than two types.

Rajmohan Murali, Robert A. Soslow, Britta Weigelt (2014)

Endometrial cancer is the most common gynaecological malignancy in Europe and North America. Traditional classification of endometrial carcinoma is based either on clinical and endocrine features (eg, types I and II) or on histopathological characteristics (eg, endometrioid, serous, or clear-cell adenocarcinoma). Subtypes defined by the different classification systems correlate to some extent, but there is substantial heterogeneity in biological, pathological, and molecular features within tumour types from both classification systems. In this Review we provide an overview of traditional and newer genomic classifications of endometrial cancer. We discuss how a classification system that incorporates genomic and histopathological features to define biologically and clinically relevant subsets of the disease would be useful. Such integrated classification might facilitate development of treatments tailored to specific disease subgroups and could potentially enable delivery of precision medicine to patients with endometrial cancer. Copyright © 2014 Elsevier Ltd. All rights reserved.