Risk stratification and molecular heterogeneity of endometrial cancer and expression profile of TIM-3: A retrospective cohort study

Yubo Zhang; Ruiye Yang; Chunyu Xu; Yanqin Zhang; Mengqi Deng; Di Wu; Fan Tang; Xinyu Liu; Yiding Han; Yang Zhan; Jinwei Miao

doi:10.1016/j.ygyno.2023.01.024

Risk stratification and molecular heterogeneity of endometrial cancer and expression profile of TIM-3: A retrospective cohort study

Gynecol Oncol. 2023 Mar:170:210-220. doi: 10.1016/j.ygyno.2023.01.024. Epub 2023 Jan 27.

Authors

Yubo Zhang¹, Ruiye Yang¹, Chunyu Xu¹, Yanqin Zhang¹, Mengqi Deng¹, Di Wu¹, Fan Tang¹, Xinyu Liu¹, Yiding Han², Yang Zhan², Jinwei Miao³

Affiliations

¹ Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital, Beijing, China.
² Department of Pathology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital, Beijing, China.
³ Department of Gynecologic Oncology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Beijing Maternal and Child Health Care Hospital, Beijing, China. Electronic address: jinweimiao@ccmu.edu.cn.

PMID: 36709662
DOI: 10.1016/j.ygyno.2023.01.024

Abstract

Objective: The present study aimed to implement ProMisE classification and risk grouping on a retrospective cohort of 628 patients with endometrial cancer (EC) and determine the molecular heterogeneity across subtypes and subgroups, as well as to investigate the potential beneficiary for TIM-3 checkpoint inhibition in ECs.

Methods: Protein expressions of p53, MMR, TIM-3 and CD8 were measured by immunohistochemistry, and massively parallel sequencing was conducted for 128 cancer-related genes. Patients were categorized into four ProMisE subtypes: MMR-deficient (MMRd), POLE-ultramutated (POLEmut), p53-wild type (p53wt), and p53-abnormal (p53abn), and were subjected to risk classification.

Results: 43 (6.9%) patients belonged to POLEmut, 118 (18.8%) to MMRd, 69 (11%) to p53abn, and 398 (63.3%) to p53wt. Compared to the 2016 stratification system, the 2021 ESGO/ESTRO/ESP risk stratification integrated with molecular classification revealed that 11 patients (11/628, 1.8%) were upgraded due to the p53abn signature, whereas 23 patients (23/628, 3.7%) were downgraded due to the POLEmut signature. JAK1 and RAD50 mutations showed higher frequencies in patients with aggressive phenotypes. RAD51B mutation was significantly related to poor RFS of the p53wt subtype but not of the other three molecular subgroups. TIM-3 expression was detected in 30.9% immune cells (ICs) and 29.0% tumor cells (TCs) in ECs, respectively. It was frequently expressed in POLEmut and MMRd ECs as compared to that in the other two molecular subtypes in TCs and ICs.

Conclusions: Our study revealed the molecular heterogeneity across subtypes and subgroups. The new risk stratification system changed the risk grouping of some patients due to the integration of molecular features. RAD51B mutation can further stratify the recurrence risk in the p53wt subtype. Patients with MMRd or POLEmut may benefit most from immunotherapy against TIM-3.

Keywords: Endometrial cancer; Gene mutations; Molecular subtypes; Risk groups; TIM-3.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Endometrial Neoplasms* / pathology
Female
Hepatitis A Virus Cellular Receptor 2
Humans
Retrospective Studies
Risk Assessment
Tumor Suppressor Protein p53* / genetics

Substances

Tumor Suppressor Protein p53
Hepatitis A Virus Cellular Receptor 2