TY - JOUR
T1 - The oxford classic links epithelial-to-mesenchymal transition to immunosuppression in poor prognosis ovarian cancers
AU - Hu, Zhiyuan
AU - Cunnea, Paula
AU - Zhong, Zhe
AU - Lu, Haonan
AU - Osagie, Oloruntoba I.
AU - Campo, Leticia
AU - Artibani, Mara
AU - Nixon, Katherine
AU - Ploski, Jennifer
AU - Gonzalez, Laura Santana
AU - Alsaadi, Abdulkhaliq
AU - Wietek, Nina
AU - Damato, Stephen
AU - Dhar, Sunanda
AU - Blagden, Sarah P.
AU - Yau, Christopher
AU - Hester, Joanna
AU - Albukhari, Ashwag
AU - Aboagye, Eric O.
AU - Fotopoulou, Christina
AU - Ahmed, Ahmed
N1 - Funding Information: Z. Hu reports a patent for biomarkers in ovarian cancer pending. H. Lu reports grants from Qingzhen Biotech outside the submitted work. C. Yau reports a patent for biomarkers in ovarian cancer pending to A. Ahmed. J. Hester reports grants from Celgene-BMS outside the submitted work. E.O. Aboagye reports other from GE Healthcare outside the submitted work. C. Fotopoulou reports other from Roche, Sequana, Ethicon, and GlaxoSmithKline outside the submitted work. A. Ahmed reports personal fees and other from Singula Bio Ltd outside the submitted work, as well as has a patent for ovarian cancer biomarkers pending. No disclosures were reported by the other authors. Funding Information: The research was supported by Ovarian Cancer Action (to A. Ahmed), the Cancer Research UK Oxford Centre (to A. Ahmed), Oxford Biomedical Research Centre (BRC), National Institute for Health Research (to A. Ahmed), and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London. C. Fotopoulou and P. Cunnea were supported by the Myrovlytis Trust and Imperial Health Charity (to P. Cunnea). We acknowledge Ms. Nona Rama for help with tumor collection and Katherine Costello for clinical data collection. We acknowledge Dr. Mariolina Salio for her suggestions on macrophages. We acknowledge Professor Douglas A. Levine for his advice on BRCA data availability. Tissue samples were provided by the Imperial College Healthcare NHS Trust Tissue Bank. Other investigators may have received samples from these same tissues. Publisher Copyright: © 2021 American Association for Cancer Research. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/3/1
Y1 - 2021/3/1
N2 - Purpose: Using RNA sequencing, we recently developed the 52-gene-based Oxford classifier of carcinoma of the ovary (Oxford Classic, OxC) for molecular stratification of serous ovarian cancers (SOCs) based on the molecular profiles of their cell of origin in the fallopian tube epithelium. Here, we developed a 52-gene NanoString panel for the OxC to test the robustness of the classifier. Experimental Design: We measured the expression of the 52 genes in an independent cohort of prospectively collected SOC samples (n ¼ 150) from a homogenous cohort who were treated with maximal debulking surgery and chemotherapy. We performed data mining of published expression profiles of SOCs and validated the classifier results on tissue arrays comprising 137 SOCs. Results: We found evidence of profound nongenetic heterogeneity in SOCs. Approximately 20% of SOCs were classified as epithelial-to-mesenchymal transition-high (EMT-high) tumors, which were associated with poor survival. This was independent of established prognostic factors, such as tumor stage, tumor grade, and residual disease after surgery (HR, 3.3; P ¼ 0.02). Mining expression data of 593 patients revealed a significant association between the EMT scores of tumors and the estimated fraction of alternatively activated macrophages (M2; P < 0.0001), suggesting a mechanistic link between immunosuppression and poor prognosis in EMT-high tumors. Conclusions: The OxC-defined EMT-high SOCs carry particularly poor prognosis independent of established clinical parameters. These tumors are associated with high frequency of immunosuppressive macrophages, suggesting a potential therapeutic target to improve clinical outcome.
AB - Purpose: Using RNA sequencing, we recently developed the 52-gene-based Oxford classifier of carcinoma of the ovary (Oxford Classic, OxC) for molecular stratification of serous ovarian cancers (SOCs) based on the molecular profiles of their cell of origin in the fallopian tube epithelium. Here, we developed a 52-gene NanoString panel for the OxC to test the robustness of the classifier. Experimental Design: We measured the expression of the 52 genes in an independent cohort of prospectively collected SOC samples (n ¼ 150) from a homogenous cohort who were treated with maximal debulking surgery and chemotherapy. We performed data mining of published expression profiles of SOCs and validated the classifier results on tissue arrays comprising 137 SOCs. Results: We found evidence of profound nongenetic heterogeneity in SOCs. Approximately 20% of SOCs were classified as epithelial-to-mesenchymal transition-high (EMT-high) tumors, which were associated with poor survival. This was independent of established prognostic factors, such as tumor stage, tumor grade, and residual disease after surgery (HR, 3.3; P ¼ 0.02). Mining expression data of 593 patients revealed a significant association between the EMT scores of tumors and the estimated fraction of alternatively activated macrophages (M2; P < 0.0001), suggesting a mechanistic link between immunosuppression and poor prognosis in EMT-high tumors. Conclusions: The OxC-defined EMT-high SOCs carry particularly poor prognosis independent of established clinical parameters. These tumors are associated with high frequency of immunosuppressive macrophages, suggesting a potential therapeutic target to improve clinical outcome.
UR - http://www.scopus.com/inward/record.url?scp=85102318668&partnerID=8YFLogxK
U2 - https://doi.org/10.1158/1078-0432.CCR-20-2782
DO - https://doi.org/10.1158/1078-0432.CCR-20-2782
M3 - Article
C2 - 33446563
SN - 1078-0432
VL - 27
SP - 1570
EP - 1579
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 5
ER -