Related Experiment Video
Updated: May 7, 2026
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Comprehensive molecular characterization identifies therapeutic vulnerabilities in ovarian clear cell carcinoma
Yong Wu1,2, Xinyi Guo1,2, Tiantian Wang3,4,5
1Department 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.
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.
Insights
This study reveals key molecular drivers in ovarian clear cell carcinoma (OCCC), including epigenetic regulator mutations and ERBB2 amplification. Targeted therapies like HER2-ADCs show promise for advanced OCCC, offering new precision oncology strategies.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Ovarian clear cell carcinoma (OCCC) is an aggressive, chemo-resistant cancer subtype.
- Limited understanding of OCCC molecular features restricts targeted therapy development.
Purpose of the Study:
- To comprehensively characterize OCCC molecular landscape using multi-omics.
- To identify novel therapeutic vulnerabilities and targets for OCCC.
Main Methods:
- Integrative multi-omics study (WES, bulk RNA-seq, scRNA-seq) on 82 OCCC cases.
- Analysis of mutations, copy number alterations, and chromosomal translocations.
- Functional validation and patient-derived xenograft (PDX) models.
Main Results:
- Recurrent mutations in epigenetic regulators (ARID1A, EP300, SETD2B) identified.
- FOXA2 mutations enriched in advanced OCCC; ERBB2 amplification linked to poor survival.
- HER2-targeted antibody-drug conjugates (HER2-ADCs) demonstrated efficacy in preclinical models.
Conclusions:
- Established a molecular atlas and therapeutic subtyping framework for OCCC.
- Revealed OCCC-specific therapeutic vulnerabilities, including ERBB2 pathway.
- Provides insights for advancing precision oncology in OCCC management.
More Related Videos
09:40Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer
Published on: August 2, 2024
09:08Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
Published on: January 12, 2020
