Proteogenomic insights into early-onset endometrioid endometrial carcinoma: predictors for fertility-sparing therapy response

Nat Genet. 2024 Apr;56(4):637-651. doi: 10.1038/s41588-024-01703-z.

Zhe Hu ^# ¹ ², Zimeng Wu ^# ¹ ², Wei Liu ^# ³, Yan Ning ^# ⁴, Jingbo Liu ^# ¹ ², Wencheng Ding ^# ², Junpeng Fan ¹ ², Shuyan Cai ³, Qinlan Li ¹ ², Wenting Li ¹ ², Xiaohang Yang ¹ ², Yingyu Dou ¹ ², Wei Wang ¹ ², Wenju Peng ¹ ², Funian Lu ¹ ², Xucui Zhuang ¹ ², Tianyu Qin ¹ ², Xiaoyan Kang ¹ ², Chenzhao Feng ¹ ², Zhiying Xu ³, Qiaoying Lv ³, Qian Wang ³, Chao Wang ³, Xinyu Wang ⁵, Zhiqi Wang ⁶, Jianliu Wang ⁶, Jie Jiang ⁷, Beibei Wang ¹ ², Gordon B Mills ⁸, Ding Ma ¹ ², Qinglei Gao ^# ⁹ ¹⁰, Kezhen Li ^# ¹¹ ¹², Gang Chen ^# ¹³ ¹⁴, Xiaojun Chen ^# ¹⁵, Chaoyang Sun ^# ¹⁶ ¹⁷

Affiliations

1 Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China.
2 National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China.
3 Obstetrics and Gynecology Hospital of Fudan University, Shanghai, P. R. China.
4 Department of Pathology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, P. R. China.
5 The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P. R. China.
6 Department of Obstetrics and Gynecology, Peking University People's Hospital; Peking University People's Hospital, Xicheng District, Beijing, P. R. China.
7 Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University, Jinan, P. R. China.
8 OHSU Knight Cancer Institute, Portland, OR, USA.
9 Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China. [email protected].
10 National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China. [email protected].
11 Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China. [email protected].
12 National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China. [email protected].
13 Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China. [email protected].
14 National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China. [email protected].
15 Obstetrics and Gynecology Hospital of Fudan University, Shanghai, P. R. China. [email protected].
16 Department of Gynecological Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China. [email protected].
17 National Clinical Research Center for Obstetrics and Gynecology, Cancer Biology Research Center (Key Laboratory of the Ministry of Education), Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China. [email protected].
# Contributed equally.

PMID: 38565644 DOI: 10.1038/s41588-024-01703-z

Abstract

Endometrial carcinoma remains a public health concern with a growing incidence, particularly in younger women. Preserving fertility is a crucial consideration in the management of early-onset endometrioid endometrial carcinoma (EEEC), particularly in patients under 40 who maintain both reproductive desire and capacity. To illuminate the molecular characteristics of EEEC, we undertook a large-scale multi-omics study of 215 patients with endometrial carcinoma, including 81 with EEEC. We reveal an unexpected association between exposome-related mutational signature and EEEC, characterized by specific CTNNB1 and SIGLEC10 hotspot mutations and disruption of downstream pathways. Interestingly, SIGLEC10^Q144K mutation in EEECs resulted in aberrant Siglec-10 protein expression and promoted progestin resistance by interacting with Estrogen Receptor alpha. We also identified potential protein biomarkers for progestin response in fertility-sparing treatment for EEEC. Collectively, our study establishes a proteogenomic resource of EEECs, uncovering the interactions between exposome and genomic susceptibilities that contribute to the development of primary prevention and early detection strategies for EEECs.

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