Molecular subtypes of clear cell carcinoma of the endometrium: Opportunities for prognostic and predictive stratification

Kim, Soyoun Rachel; Cloutier, Basile Tessier; Leung, Samuel; Cochrane, Dawn R.; Britton, Heidi; Pina, Annick; Storness-Bliss, Claudine; Farnell, David; Huang, Leo; Shum, Kathryn; Lum, Amy; Senz, Janine; Lee, Cheng‐Han; Gilks, C. Blake; Hoang, Lien; McAlpine, Jessica N.

doi:10.1016/j.ygyno.2020.04.043

Cited by 94 publications

(93 citation statements)

References 36 publications

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“…For example, it does not include all different subtypes of EC, such as clear cell carcinomas, which constitute 2–3% of EC diagnoses, and is more frequently diagnosed than carcinosarcoma [ 233 ]. The pathogenesis of clear cell carcinomas is not well described and identifying dysregulated genes within this subtype may further our understanding [ 234 ]. Furthermore, the TCGA-UCEC dataset does not contain survival data for all patients included in this study, thus limits our survival analysis, and it is not completely representative of the carcinosarcoma patients included in the differential expression analysis.…”

Section: Discussionmentioning

confidence: 99%

Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer

Bradfield

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Hill

et al. 2020

MPs

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Endometrial cancer (EC) is the commonest gynaecological malignancy. Current prognostic markers are inadequate to accurately predict patient survival, necessitating novel prognostic markers, to improve treatment strategies. Telomerase has a unique role within the endometrium, whilst aberrant telomerase activity is a hallmark of many cancers. The aim of the current in silico study is to investigate the role of telomere and telomerase associated genes and proteins (TTAGPs) in EC to identify potential prognostic markers and therapeutic targets. Analysis of RNA-seq data from The Cancer Genome Atlas identified differentially expressed genes (DEGs) in EC (568 TTAGPs out of 3467) and ascertained DEGs associated with histological subtypes, higher grade endometrioid tumours and late stage EC. Functional analysis demonstrated that DEGs were predominantly involved in cell cycle regulation, while the survival analysis identified 69 DEGs associated with prognosis. The protein-protein interaction network constructed facilitated the identification of hub genes, enriched transcription factor binding sites and drugs that may target the network. Thus, our in silico methods distinguished many critical genes associated with telomere maintenance that were previously unknown to contribute to EC carcinogenesis and prognosis, including NOP56, WFS1, ANAPC4 and TUBB4A. Probing the prognostic and therapeutic utility of these novel TTAGP markers will form an exciting basis for future research.

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Section: Discussionmentioning

confidence: 99%

Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer

Bradfield

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Hill

et al. 2020

MPs

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“…The relationships between TCGA‐based molecular subtypes and histotypes are shown in Figure 1 and Table 1 [10,13,15,16,19,22–34], and the four molecular subtypes are described below. It should be noted that there may be publication bias in the cases included in Table 1, such that they may not be representative of a population‐based case series.…”

Section: Figurementioning

confidence: 99%

“…The PORTEC‐3 clinical trial results suggest that patients with p53abn ECs have superior outcomes when treated with chemotherapy in addition to radiation, compared with radiotherapy alone [12]. It has become clear that EC is too heterogeneous a disease to be classified using a simple binary system, as more than 30% of ECs are of MMRd or POLE mut molecular subtypes, which do not correspond exclusively to either type I or type II [25,26,53].…”

Section: Figurementioning

confidence: 99%

“…POLE mut clear cell carcinomas have the most favorable prognosis, while p53abn clear cell carcinomas are associated with aggressive behavior, i.e. the behavior of clear cell carcinoma is similar to that of non‐clear cell EC of these molecular subtypes [26,77,78]. NSMP clear cell ECs, however, differ from NSMP endometrioid carcinomas, as they are associated with a worse prognosis [26].…”

Section: Rare Endometrial Carcinoma Histotypes: Molecular Subtypes Anmentioning

confidence: 99%

“…the behavior of clear cell carcinoma is similar to that of non‐clear cell EC of these molecular subtypes [26,77,78]. NSMP clear cell ECs, however, differ from NSMP endometrioid carcinomas, as they are associated with a worse prognosis [26]. Tumors that show mixed clear cell and endometrioid components are MMRd in most cases,[35] whereas MMRd pure clear cell carcinomas are uncommon [26,32].…”

Section: Rare Endometrial Carcinoma Histotypes: Molecular Subtypes Anmentioning

confidence: 99%

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Endometrial carcinoma: molecular subtypes, precursors and the role of pathology in early diagnosis

Huvila

Pors

Thompson

et al. 2021

The Journal of Pathology

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Endometrial carcinoma (EC) is classified into a wide range of morphological variants; this list has expanded over the past decade with the inclusion of mesonephric‐like and dedifferentiated carcinoma as EC variants in the fifth edition of the WHO Classification of Female Genital Tumours, and recognition that carcinosarcoma is a biphasic carcinoma rather than a sarcoma. Each EC variant has distinct molecular abnormalities, including TCGA‐based molecular subtypes, allowing further subclassification and adding complexity. In contrast to this rapid progress in understanding EC, there are only two recognized EC precursor lesions: endometrial atypical hyperplasia/endometrioid intraepithelial neoplasia (EAH/EIN) and serous intraepithelial carcinoma, a situation that has not changed for many years. Diagnosis of EC precursors is a cornerstone of surgical pathology practice, with early diagnosis contributing to the relatively favorable prognosis of EC. In this review we relate the precursor lesions to each of the EC morphological variants and molecular subtypes, discuss how successful early diagnosis is for each variant/molecular subtype and how it might be improved, and identify knowledge gaps where there is insufficient understanding of EC histogenesis. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Pure and mixed clear cell carcinoma of the endometrium: A molecular and immunohistochemical analysis study

et al. 2023

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Background: Uterine clear cell carcinoma (CCC) consists of either pure clear cell histology but can also display other histological components (mixed uterine CCCs). In this study, the molecular and immunohistochemical background of pure and mixed uterine CCC was compared. Secondly, it was evaluated whether histological classification and molecular background affected clinical outcome. Methods: A retrospective multicenter study was performed comparing pure uterine CCCs (n = 22) and mixed uterine CCCs (n = 21). Targeted next-generation sequencing using a 12-gene targeted panel classified cases as polymerase-ε (POLE) mutated, microsatellite instable (MSI), TP53 wildtype or TP53 mutated. Immunohistochemistry was performed for estrogen receptor, progesterone receptor, L1 cell adhesion molecule, MSH6, and PMS2. Results:The following molecular subgroups were identified for pure and mixed uterine CCCs, respectively: POLE mutated 0% (0/18) and 6% (1/18); MSI in 6%(1/18) and 50% (9/18); TP53 wildtype in 56% (10/18) and 22% (4/18); TP53 mutated in 39% (7/18) and 22% (4/18) (p = 0.013). Patients with mixed CCCs had improved outcome compared to patients with pure CCCs. Frequent TP53 mutations were found in pure CCCs and frequent MSI in mixed CCCs, associated with clinical outcome. Conclusion:Pure and mixed uterine CCCs are two entities with different clinical outcomes, which could be explained by different molecular backgrounds. These results underline the relevance of both morphological and molecular evaluation, and may assist in tailoring treatment.

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Molecular subtypes of clear cell carcinoma of the endometrium: Opportunities for prognostic and predictive stratification

Cited by 94 publications

References 36 publications

Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer

Investigating the Role of Telomere and Telomerase Associated Genes and Proteins in Endometrial Cancer

Endometrial carcinoma: molecular subtypes, precursors and the role of pathology in early diagnosis

Pure and mixed clear cell carcinoma of the endometrium: A molecular and immunohistochemical analysis study

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