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Association of Copy Number Variation Signature and Survival in Patients With Serous Ovarian Cancer

IMPORTANCE: Tailoring therapeutic regimens to individual patients with ovarian cancer is informed by severity of disease using a variety of clinicopathologic indicators. Although DNA repair variations are increasingly used for therapy selection in ovarian cancer, molecular features are not widely us...

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Autores principales: Graf, Ryon P., Eskander, Ramez, Brueggeman, Leo, Stupack, Dwayne G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Medical Association 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239953/
https://www.ncbi.nlm.nih.gov/pubmed/34181012
http://dx.doi.org/10.1001/jamanetworkopen.2021.14162
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author Graf, Ryon P.
Eskander, Ramez
Brueggeman, Leo
Stupack, Dwayne G.
author_facet Graf, Ryon P.
Eskander, Ramez
Brueggeman, Leo
Stupack, Dwayne G.
author_sort Graf, Ryon P.
collection PubMed
description IMPORTANCE: Tailoring therapeutic regimens to individual patients with ovarian cancer is informed by severity of disease using a variety of clinicopathologic indicators. Although DNA repair variations are increasingly used for therapy selection in ovarian cancer, molecular features are not widely used for general assessment of patient prognosis and disease severity. OBJECTIVE: To distill a highly dynamic characteristic, signature of copy number variations (CNV), into a risk score that could be easily validated analytically or repurposed for use given existing US Food and Drug Administration (FDA)–approved multigene assays. DESIGN, SETTING, AND PARTICIPANTS: This genetic association study used the Cancer Genome Atlas Ovarian Cancer database to assess for genome-wide survival associations agnostic to gene function. Regions enriched for significant associations were compared to associations from scrambled data. CNV associations were condensed into a risk score, which was internally validated using bootstrapping. The participants were patients with serous ovarian cancer (stages I-IV) diagnosed from 1992 to 2013. Statistical analysis was performed from April to July 2020. MAIN OUTCOMES AND MEASURES: Overall survival (OS). RESULTS: Among 564 patients with serous ovarian cancer, the mean (SD) age was 59.7 (11.5) years; 34 (6%) identified as Black or African American. A total of 13 genome regions, comprising 14 alterations, were identified as significantly risk associated. Composite risk score was independent of total CNV burden, total mutational burden, BRCA status, and open-source genome-wide DNA repair deficiency signatures. Binned terciles yielded high-, standard-, and low-risk groups with respective median OS estimates of 2.9 (95% CI, 2.3-3.2) years, 4.1 (95% CI, 3.7-4.8) years, and 5.7 (95% CI, 4.7-7.4) years, respectively (P < .001). Associated 5-year survival estimates in each tercile were 15% (95% CI, 10%-22%), 36% (95% CI, 29%-46%), and 53% (95% CI, 45%-62%). The risk score had more discriminatory ability to prognosticate OS than age, clinical stage, grade, and race combined, and was strongly additive to significant clinical features (P < .001). Simulated adaptation of FDA-approved assays showed similar performance. Gene ontology analyses of identified regions showed an enrichment for regulatory miRNAs and protein kinase regulators. CONCLUSIONS AND RELEVANCE: This study found that a CNV-based risk score is independent to and stronger than current or near-future ovarian cancer genomic biomarkers to prognosticate OS. CNV regions identified were not strongly associated with canonical ovarian cancer biological pathways, identifying candidates for future mechanistic investigations. External validation of the CNV risk score, especially in concert with more extensive clinical features, could be pursued via existing FDA-approved assays.
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spelling pubmed-82399532021-07-13 Association of Copy Number Variation Signature and Survival in Patients With Serous Ovarian Cancer Graf, Ryon P. Eskander, Ramez Brueggeman, Leo Stupack, Dwayne G. JAMA Netw Open Original Investigation IMPORTANCE: Tailoring therapeutic regimens to individual patients with ovarian cancer is informed by severity of disease using a variety of clinicopathologic indicators. Although DNA repair variations are increasingly used for therapy selection in ovarian cancer, molecular features are not widely used for general assessment of patient prognosis and disease severity. OBJECTIVE: To distill a highly dynamic characteristic, signature of copy number variations (CNV), into a risk score that could be easily validated analytically or repurposed for use given existing US Food and Drug Administration (FDA)–approved multigene assays. DESIGN, SETTING, AND PARTICIPANTS: This genetic association study used the Cancer Genome Atlas Ovarian Cancer database to assess for genome-wide survival associations agnostic to gene function. Regions enriched for significant associations were compared to associations from scrambled data. CNV associations were condensed into a risk score, which was internally validated using bootstrapping. The participants were patients with serous ovarian cancer (stages I-IV) diagnosed from 1992 to 2013. Statistical analysis was performed from April to July 2020. MAIN OUTCOMES AND MEASURES: Overall survival (OS). RESULTS: Among 564 patients with serous ovarian cancer, the mean (SD) age was 59.7 (11.5) years; 34 (6%) identified as Black or African American. A total of 13 genome regions, comprising 14 alterations, were identified as significantly risk associated. Composite risk score was independent of total CNV burden, total mutational burden, BRCA status, and open-source genome-wide DNA repair deficiency signatures. Binned terciles yielded high-, standard-, and low-risk groups with respective median OS estimates of 2.9 (95% CI, 2.3-3.2) years, 4.1 (95% CI, 3.7-4.8) years, and 5.7 (95% CI, 4.7-7.4) years, respectively (P < .001). Associated 5-year survival estimates in each tercile were 15% (95% CI, 10%-22%), 36% (95% CI, 29%-46%), and 53% (95% CI, 45%-62%). The risk score had more discriminatory ability to prognosticate OS than age, clinical stage, grade, and race combined, and was strongly additive to significant clinical features (P < .001). Simulated adaptation of FDA-approved assays showed similar performance. Gene ontology analyses of identified regions showed an enrichment for regulatory miRNAs and protein kinase regulators. CONCLUSIONS AND RELEVANCE: This study found that a CNV-based risk score is independent to and stronger than current or near-future ovarian cancer genomic biomarkers to prognosticate OS. CNV regions identified were not strongly associated with canonical ovarian cancer biological pathways, identifying candidates for future mechanistic investigations. External validation of the CNV risk score, especially in concert with more extensive clinical features, could be pursued via existing FDA-approved assays. American Medical Association 2021-06-28 /pmc/articles/PMC8239953/ /pubmed/34181012 http://dx.doi.org/10.1001/jamanetworkopen.2021.14162 Text en Copyright 2021 Graf RP et al. JAMA Network Open. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the CC-BY License.
spellingShingle Original Investigation
Graf, Ryon P.
Eskander, Ramez
Brueggeman, Leo
Stupack, Dwayne G.
Association of Copy Number Variation Signature and Survival in Patients With Serous Ovarian Cancer
title Association of Copy Number Variation Signature and Survival in Patients With Serous Ovarian Cancer
title_full Association of Copy Number Variation Signature and Survival in Patients With Serous Ovarian Cancer
title_fullStr Association of Copy Number Variation Signature and Survival in Patients With Serous Ovarian Cancer
title_full_unstemmed Association of Copy Number Variation Signature and Survival in Patients With Serous Ovarian Cancer
title_short Association of Copy Number Variation Signature and Survival in Patients With Serous Ovarian Cancer
title_sort association of copy number variation signature and survival in patients with serous ovarian cancer
topic Original Investigation
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8239953/
https://www.ncbi.nlm.nih.gov/pubmed/34181012
http://dx.doi.org/10.1001/jamanetworkopen.2021.14162
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