Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes

Kelly L. Bolton, Denise Chen, Rosario Corona de la Fuente, Zhuxuan Fu, Rajmohan Murali, Martin Köbel, Yanis Tazi, Julie M. Cunningham, Irenaeus C.C. Chan, Brian J. Wiley, Lea A. Moukarzel, Stacey J. Winham, Sebastian M. Armasu, Jenny Lester, Esther Elishaev, Angela Laslavic, Catherine J. Kennedy, Anna Piskorz, Magdalena Sekowska, Alison H. BrandYoke Eng Chiew, Paul Pharoah, Kevin M. Elias, Ronny Drapkin, Michael Churchman, Charlie Gourley, Anna DeFazio, Beth Karlan, James D. Brenton, Britta Weigelt, Michael S. Anglesio, David Huntsman, Simon Gayther, Jason Konner, Francesmary Modugno, Kate Lawrenson, Ellen L. Goode, Elli Papaemmanuil

Research output: Contribution to journalArticlepeer-review


Purpose: To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes. Experimental Design: We profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival. Results: We detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including ARID1A (in 49% of tumors), PIK3CA (49%), TERT (20%), and TP53 (16%). Clustering of cancer driver mutations and RNA expression converged upon two distinct subclasses of CCOC. The first was dominated by ARID1A-mutated tumors with enriched expression of canonical CCOC genes and markers of platinum resistance; the second was largely comprised of tumors with TP53 mutations and enriched for the expression of genes involved in extracellular matrix organization and mesenchymal differentiation. Compared with the ARID1A-mutated group, women with TP53-mutated tumors were more likely to have advanced-stage disease, no antecedent history of endometriosis, and poorer survival, driven by their advanced stage at presentation. In women with ARID1A-mutated tumors, there was a trend toward a lower rate of response to first-line platinum-based therapy. Conclusions: Our study suggests that CCOC consists of two distinct molecular subclasses with distinct clinical presentation and outcomes, with potential relevance to both traditional and experimental therapy responsiveness.

Original languageEnglish (US)
Pages (from-to)4947-4956
Number of pages10
JournalClinical Cancer Research
Issue number22
StatePublished - Nov 15 2022

ASJC Scopus subject areas

  • Medicine(all)


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