Comprehensive molecular characterization identifies therapeutic vulnerabilities in ovarian clear cell carcinoma

Yong Wu; Xinyi Guo; Tiantian Wang; Tianyi Zhao; Siyu Chen; Ying Su; Qin Li; Jun Zhu; Lingfang Xia; Xingzhu Ju; Xiaohua Wu; Shenglin Huang; Zhixiang Hu; Xiaojun Chen

doi:10.1186/s13073-026-01663-5

Comprehensive molecular characterization identifies therapeutic vulnerabilities in ovarian clear cell carcinoma

Genome Med. 2026 May 6. doi: 10.1186/s13073-026-01663-5. Online ahead of print.

Authors

Yong Wu^#^{1

2}, Xinyi Guo^#^{1

2}, Tiantian Wang^#^{3

4

5}, Tianyi Zhao^#⁶, Siyu Chen^{1

2}, Ying Su^{1

2}, Qin Li^{1

2}, Jun Zhu¹, Lingfang Xia¹, Xingzhu Ju¹, Xiaohua Wu^{7

8}, Shenglin Huang^{9

10}, Zhixiang Hu^{11

12}, Xiaojun Chen^{13

14}

Affiliations

¹ Department of Gynecologic Oncology, Shanghai Key Laboratory of Medical Epigenetics, International Co- laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University Shanghai Cancer Center, Fudan University, 305 Rm., 7# Bldg., 270 Dong An Rd, Shanghai, 200032, China.
² Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
³ Department of Biophysics, College of Basic Medical Sciences, Naval Medical University (Second Military Medical University), Shanghai, China.
⁴ Department of Biophysics, Team NMU-China of the International Genetically Engineered Machine Competition, Naval Medical University (Second Military Medical University), Shanghai, China.
⁵ Department of Urology, Changhai Hospital, Second Military Medical University (Naval Medical University), Shanghai, 200433, China.
⁶ Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
⁷ Department of Gynecologic Oncology, Shanghai Key Laboratory of Medical Epigenetics, International Co- laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University Shanghai Cancer Center, Fudan University, 305 Rm., 7# Bldg., 270 Dong An Rd, Shanghai, 200032, China. wu.xh@fudan.edu.cn.
⁸ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. wu.xh@fudan.edu.cn.
⁹ Department of Gynecologic Oncology, Shanghai Key Laboratory of Medical Epigenetics, International Co- laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University Shanghai Cancer Center, Fudan University, 305 Rm., 7# Bldg., 270 Dong An Rd, Shanghai, 200032, China. slhuang@fudan.edu.cn.
¹⁰ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. slhuang@fudan.edu.cn.
¹¹ Department of Gynecologic Oncology, Shanghai Key Laboratory of Medical Epigenetics, International Co- laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University Shanghai Cancer Center, Fudan University, 305 Rm., 7# Bldg., 270 Dong An Rd, Shanghai, 200032, China. zhixiang_hu@fudan.edu.cn.
¹² Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. zhixiang_hu@fudan.edu.cn.
¹³ Department of Gynecologic Oncology, Shanghai Key Laboratory of Medical Epigenetics, International Co- laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University Shanghai Cancer Center, Fudan University, 305 Rm., 7# Bldg., 270 Dong An Rd, Shanghai, 200032, China. doccxj2020@163.com.
¹⁴ Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. doccxj2020@163.com.

^# Contributed equally.

PMID: 42087217
DOI: 10.1186/s13073-026-01663-5

Abstract

Background: Ovarian clear cell carcinoma (OCCC) is a rare aggressive, and chemo-resistant subtype of epithelial ovarian cancer. Current limitations in precisely characterizing its molecular features have resulted in restricted availability of clinical targeted therapies and significant therapeutic challenges.

Methods: To address this unmet need, we conducted an integrative multi-omics study of 82 OCCC cases, incorporating whole-exome sequencing (WES), bulk RNA sequencing, and single-cell RNA sequencing (scRNA-seq).

Results: Our analysis uncovered recurrent mutations in multiple epigenetic regulators including ARID1A, EP300, and SETD2B, reinforcing chromatin remodeling as a hallmark of OCCC pathogenesis. Strikingly, FOXA2 mutations were absent in early-stage tumors but specifically enriched in advanced-stage cases (19% frequency), with functional validation demonstrating their role in driving malignant progression. Copy number alteration profiling revealed frequent amplifications in chromosomal arms such as 17q, which contains the ERBB2 oncogene that potentially regulates OCCC progression. Chromosomal translocations were detected in 35.59% of cases, including a novel FGFR2/RPAP3 fusion with therapeutic implications. Notably, scRNA-seq delineated immune-rich subsets characterized by abundant cytotoxic T-cell and B-cell infiltration, suggesting immunotherapeutic opportunities in a patient subset. Moreover, molecular subtyping identified ERBB2 amplification/overexpression as a high-risk feature strongly associated with poor survival. Patient-derived xenograft (PDX) models and a retrospective analysis of two clinical cases demonstrated that HER2-targeted antibody-drug conjugates (HER2-ADCs) significantly suppressed tumor growth and progression in OCCC patients with HER2 expression.

Conclusions: In summary, our study establishes the comprehensive molecular atlas and a targeted therapeutic subtyping framework, revealing therapeutic vulnerabilities and providing novel insights for advancing precision oncology in OCCC management.

Keywords: HER2-ADC; OCCC; target therapy; therapeutic vulnerabilities.

Abstract

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