TY - JOUR
T1 - Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
AU - Bolton, Kelly L.
AU - Chen, Denise
AU - de la Fuente, Rosario Corona
AU - Fu, Zhuxuan
AU - Murali, Rajmohan
AU - Köbel, Martin
AU - Tazi, Yanis
AU - Cunningham, Julie M.
AU - Chan, Irenaeus C.C.
AU - Wiley, Brian J.
AU - Moukarzel, Lea A.
AU - Winham, Stacey J.
AU - Armasu, Sebastian M.
AU - Lester, Jenny
AU - Elishaev, Esther
AU - Laslavic, Angela
AU - Kennedy, Catherine J.
AU - Piskorz, Anna
AU - Sekowska, Magdalena
AU - Brand, Alison H.
AU - Chiew, Yoke Eng
AU - Pharoah, Paul
AU - Elias, Kevin M.
AU - Drapkin, Ronny
AU - Churchman, Michael
AU - Gourley, Charlie
AU - DeFazio, Anna
AU - Karlan, Beth
AU - Brenton, James D.
AU - Weigelt, Britta
AU - Anglesio, Michael S.
AU - Huntsman, David
AU - Gayther, Simon
AU - Konner, Jason
AU - Modugno, Francesmary
AU - Lawrenson, Kate
AU - Goode, Ellen L.
AU - Papaemmanuil, Elli
N1 - Publisher Copyright:
©2022 The Authors; Published by the American Association for Cancer Research.
PY - 2022/11/15
Y1 - 2022/11/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85141113422&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-21-3817
DO - 10.1158/1078-0432.CCR-21-3817
M3 - Article
C2 - 35816189
AN - SCOPUS:85141113422
SN - 1078-0432
VL - 28
SP - 4947
EP - 4956
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 22
ER -