DNA Methylation Profiles of Ovarian Clear Cell Carcinoma
Ovarian clear cell carcinoma (OCCC) is a rare ovarian cancer histotype that tends to be resistant to standard platinum-based chemotherapeutics. We sought to better understand the role of DNA methylation in clinical and biological subclassification of OCCC. We interrogated genome-wide methylation usi...
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| Published in | Cancer epidemiology, biomarkers & prevention Vol. 31; no. 1; pp. 132 - 141 |
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| Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
01.01.2022
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| Subjects | |
| Online Access | Get full text |
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| Abstract | Ovarian clear cell carcinoma (OCCC) is a rare ovarian cancer histotype that tends to be resistant to standard platinum-based chemotherapeutics. We sought to better understand the role of DNA methylation in clinical and biological subclassification of OCCC.
We interrogated genome-wide methylation using DNA from fresh frozen tumors from 271 cases, applied nonsmooth nonnegative matrix factorization (nsNMF) clustering, and evaluated clinical associations and biological pathways.
Two approximately equally sized clusters that associated with several clinical features were identified. Compared with Cluster 2 (
= 137), Cluster 1 cases (
= 134) presented at a more advanced stage, were less likely to be of Asian ancestry, and tended to have poorer outcomes including macroscopic residual disease following primary debulking surgery (
< 0.10). Subset analyses of targeted tumor sequencing and IHC data revealed that Cluster 1 tumors showed
mutation and abnormal p53 expression, and Cluster 2 tumors showed aneuploidy and
mutation (
< 0.05). Cluster-defining CpGs included 1,388 CpGs residing within 200 bp of the transcription start sites of 977 genes; 38% of these genes (
= 369 genes) were differentially expressed across cluster in transcriptomic subset analysis (
< 10
). Differentially expressed genes were enriched for six immune-related pathways, including IFNα and IFNγ responses (
< 10
).
DNA methylation clusters in OCCC correlate with disease features and gene expression patterns among immune pathways.
This work serves as a foundation for integrative analyses that better understand the complex biology of OCCC in an effort to improve potential for development of targeted therapeutics. |
|---|---|
| AbstractList | Ovarian clear cell carcinoma (OCCC) is a rare ovarian cancer histotype that tends to be resistant to standard platinum-based chemotherapeutics. We sought to better understand the role of DNA methylation in clinical and biological subclassification of OCCC.
We interrogated genome-wide methylation using DNA from fresh frozen tumors from 271 cases, applied nonsmooth nonnegative matrix factorization (nsNMF) clustering, and evaluated clinical associations and biological pathways.
Two approximately equally sized clusters that associated with several clinical features were identified. Compared with Cluster 2 (
= 137), Cluster 1 cases (
= 134) presented at a more advanced stage, were less likely to be of Asian ancestry, and tended to have poorer outcomes including macroscopic residual disease following primary debulking surgery (
< 0.10). Subset analyses of targeted tumor sequencing and IHC data revealed that Cluster 1 tumors showed
mutation and abnormal p53 expression, and Cluster 2 tumors showed aneuploidy and
mutation (
< 0.05). Cluster-defining CpGs included 1,388 CpGs residing within 200 bp of the transcription start sites of 977 genes; 38% of these genes (
= 369 genes) were differentially expressed across cluster in transcriptomic subset analysis (
< 10
). Differentially expressed genes were enriched for six immune-related pathways, including IFNα and IFNγ responses (
< 10
).
DNA methylation clusters in OCCC correlate with disease features and gene expression patterns among immune pathways.
This work serves as a foundation for integrative analyses that better understand the complex biology of OCCC in an effort to improve potential for development of targeted therapeutics. BACKGROUNDOvarian clear cell carcinoma (OCCC) is a rare ovarian cancer histotype that tends to be resistant to standard platinum-based chemotherapeutics. We sought to better understand the role of DNA methylation in clinical and biological subclassification of OCCC.METHODSWe interrogated genome-wide methylation using DNA from fresh frozen tumors from 271 cases, applied nonsmooth nonnegative matrix factorization (nsNMF) clustering, and evaluated clinical associations and biological pathways.RESULTSTwo approximately equally sized clusters that associated with several clinical features were identified. Compared with Cluster 2 (N = 137), Cluster 1 cases (N = 134) presented at a more advanced stage, were less likely to be of Asian ancestry, and tended to have poorer outcomes including macroscopic residual disease following primary debulking surgery (P < 0.10). Subset analyses of targeted tumor sequencing and IHC data revealed that Cluster 1 tumors showed TP53 mutation and abnormal p53 expression, and Cluster 2 tumors showed aneuploidy and ARID1A/PIK3CA mutation (P < 0.05). Cluster-defining CpGs included 1,388 CpGs residing within 200 bp of the transcription start sites of 977 genes; 38% of these genes (N = 369 genes) were differentially expressed across cluster in transcriptomic subset analysis (P < 10-4). Differentially expressed genes were enriched for six immune-related pathways, including IFNα and IFNγ responses (P < 10-6).CONCLUSIONSDNA methylation clusters in OCCC correlate with disease features and gene expression patterns among immune pathways.IMPACTThis work serves as a foundation for integrative analyses that better understand the complex biology of OCCC in an effort to improve potential for development of targeted therapeutics. Abstract Background: Ovarian clear cell carcinoma (OCCC) is a rare ovarian cancer histotype that tends to be resistant to standard platinum-based chemotherapeutics. We sought to better understand the role of DNA methylation in clinical and biological subclassification of OCCC. Methods: We interrogated genome-wide methylation using DNA from fresh frozen tumors from 271 cases, applied nonsmooth nonnegative matrix factorization (nsNMF) clustering, and evaluated clinical associations and biological pathways. Results: Two approximately equally sized clusters that associated with several clinical features were identified. Compared with Cluster 2 (N = 137), Cluster 1 cases (N = 134) presented at a more advanced stage, were less likely to be of Asian ancestry, and tended to have poorer outcomes including macroscopic residual disease following primary debulking surgery (P < 0.10). Subset analyses of targeted tumor sequencing and IHC data revealed that Cluster 1 tumors showed TP53 mutation and abnormal p53 expression, and Cluster 2 tumors showed aneuploidy and ARID1A/PIK3CA mutation (P < 0.05). Cluster-defining CpGs included 1,388 CpGs residing within 200 bp of the transcription start sites of 977 genes; 38% of these genes (N = 369 genes) were differentially expressed across cluster in transcriptomic subset analysis (P < 10−4). Differentially expressed genes were enriched for six immune-related pathways, including IFNα and IFNγ responses (P < 10−6). Conclusions: DNA methylation clusters in OCCC correlate with disease features and gene expression patterns among immune pathways. Impact: This work serves as a foundation for integrative analyses that better understand the complex biology of OCCC in an effort to improve potential for development of targeted therapeutics. |
| Author | Brand, Alison H Köbel, Martin Chiew, Yoke-Eng Piskorz, Anna McCauley, Bryan M Elias, Kevin M Weiglt, Britta Sekowska, Magdalena Fu, Zhuxuan DeFazio, Anna Laslavic, Angela Drapkin, Ronny Churchman, Michael Konner, Jason Armasu, Sebastian M Papaemmanuil, Elli Elishaev, Esther Bolton, Kelly L Goode, Ellen L Karlan, Beth Y Kennedy, Catherine J Modugno, Francesmary Lester, Jenny Lawrenson, Kate Huntsman, David G Brenton, James D Cunningham, Julie M Wang, Chen Gourley, Charlie Winham, Stacey J |
| AuthorAffiliation | 12. David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, USA 17. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada 24. Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA 21. Weill Cornell Medical College of Cornell University, New York, NY, USA 7. Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia 18. Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada 5. Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia 11. Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA 20. Department of Laboratory and Pathology Medicine, University of Calgary, Calgary, AB, Canada 6. University of Sydney, |
| AuthorAffiliation_xml | – name: 2. Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA – name: 11. Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA – name: 16. British Columbia’s Ovarian Cancer Research (OVCARE) Program, BC Cancer, Vancouver General Hospital, and University of British Columbia, Vancouver, BC, Canada – name: 3. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA – name: 20. Department of Laboratory and Pathology Medicine, University of Calgary, Calgary, AB, Canada – name: 9. Nicola Murray Centre for Ovarian Cancer Research, Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK – name: 12. David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, USA – name: 19. Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC, Canada – name: 10. Womens Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, PA, USA – name: 24. Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA – name: 14. Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA – name: 23. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Women’s Cancer Program at the Samuel Oschin Cancer Institute Cedars-Sinai Medical Center, Los Angeles, CA, USA – name: 21. Weill Cornell Medical College of Cornell University, New York, NY, USA – name: 1. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA – name: 7. Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia – name: 8. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA – name: 13. Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK – name: 17. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada – name: 18. Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada – name: 22. Washington University, Department of Medicine, St Louis, USA – name: 15. Brigham and Women’s Hospital, Boston, MA, USA – name: 4. Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA – name: 5. Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia – name: 6. University of Sydney, Sydney, New South Wales, Australia |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/34697060$$D View this record in MEDLINE/PubMed |
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| Snippet | Ovarian clear cell carcinoma (OCCC) is a rare ovarian cancer histotype that tends to be resistant to standard platinum-based chemotherapeutics. We sought to... Abstract Background: Ovarian clear cell carcinoma (OCCC) is a rare ovarian cancer histotype that tends to be resistant to standard platinum-based... BACKGROUNDOvarian clear cell carcinoma (OCCC) is a rare ovarian cancer histotype that tends to be resistant to standard platinum-based chemotherapeutics. We... |
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| SubjectTerms | Adenocarcinoma, Clear Cell - ethnology Adenocarcinoma, Clear Cell - genetics Adenocarcinoma, Clear Cell - pathology Adult Aged Aged, 80 and over Aneuploidy Class I Phosphatidylinositol 3-Kinases - genetics CpG Islands - genetics Disease Progression DNA Methylation DNA-Binding Proteins - genetics Female Gene Expression Profiling Gene Expression Regulation, Neoplastic Humans Middle Aged Mutation Neoplasm Staging Ovarian Neoplasms - ethnology Ovarian Neoplasms - genetics Ovarian Neoplasms - pathology Prognosis Transcription Factors - genetics Tumor Suppressor Protein p53 - genetics |
| Title | DNA Methylation Profiles of Ovarian Clear Cell Carcinoma |
| URI | https://www.ncbi.nlm.nih.gov/pubmed/34697060 https://search.proquest.com/docview/2586450673 https://pubmed.ncbi.nlm.nih.gov/PMC8755592 |
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