Validation of ovarian cancer metabolomics risk factors and early detection markers
Principal Investigator
Name
Oana Zeleznik
Degrees
PhD
Institution
Brigham and Women's Hospital
Position Title
Associate Epidemiologist
Email
About this CDAS Project
Study
PLCO
(Learn more about this study)
Project ID
2019-0021
Initial CDAS Request Approval
Aug 2, 2019
Title
Validation of ovarian cancer metabolomics risk factors and early detection markers
Summary
Ovarian cancer has few known risk factors, hampering identification of high-risk women. Thus, we assessed the association of pre-diagnostic plasma metabolites (N=427) with risk of ovarian cancer in a matched case-control study (252 cases, 252 controls) nested within the Nurses’ Health Studies (manuscripts in review/preparation).
C16:0 sphingomyelins (SM), C18:0 SM, C16:0 ceramide and SM sum were significantly positively associated with ovarian cancer risk, with ORs ranging from 1.95-2.10, with stronger ORs for postmenopausal women (2.02-3.22). ORs were generally similar for serous/poorly differentiated and endometrioid/clear cell tumors, although most did not meet the Bonferroni-adjusted p-value for significance. C18:1 lysophosphatidylcholines (LPC) and the ratio of LPC to phosphatidylcholines (PC) were significantly inversely, while C18:0 SM was significantly positively, associated with risk of endometrioid/clear cell tumors.
In an agnostic analysis, pseudouridine was associated with risk of ovarian cancer, serous, and with non-serous disease (OR range: 2.57-7.61). No association remained significant after accounting for multiple comparisons using permutation tests. Eight data derived metabolite modules and 19 metabolite classes were associated with risk (overall: 4 modules, 9 classes; serous: 2 modules, 13 classes; non-serous: 6 modules, 13 classes). Triacylglycerols (TAGs) characterized 3 of 8 significant modules and were an overrepresented class. TAGs with lower acly carbon content and fewer double bonds were inversely, while TAGs with more acly carbon content and more double bonds were positively associated with total and serous ovarian cancer.
Elevated levels of circulating pseudouridine and SMs 3-23 years before diagnosis were associated with increased risk of ovarian cancer, regardless of histotype, with stronger associations among postmenopausal women, rapidly fatal tumors and cases with blood collection closer in time to diagnosis.
Additionally, we identified metabolites associated with ovarian cancer among cases diagnosed up to 3 years after blood collection. Ovarian cancer is often diagnosed at a late stage. We hypothesize that cases diagnosed up to three years after blood collection already had ovarian cancer at the time of the blood collection and can be used to identify early detection markers. The most significant early detection markers, after adjusting for ovarian cancer risk factors, were 3 ceramides, 1-methylnicotineamide, and methylimidazole acetic acid.
To the best of our knowledge, this represents the largest prospective study of metabolomics and ovarian cancer risk. However, our sample size was low and due to this, we propose to validate the metabolomics risk factors and early detection markers of ovarian cancer identified in the Nurses Health Studies in PLCO.
We propose to create a prospective 1:1 matched case-control study nested within PLCO including all cases with plasma samples collected before an ovarian cancer diagnosis. Before measuring all study samples we will conduct a reproducibility pilot study, similar to what we did in the Nurses’ Health Studies, to assess the feasibility of the metabolomics platform on the PLCO samples. The plasma metabolomics will be measured at the same laboratory that measured metabolomics in the Nurses’ samples, the Broad Institute of MIT and Harvard in Cambridge, MA.
C16:0 sphingomyelins (SM), C18:0 SM, C16:0 ceramide and SM sum were significantly positively associated with ovarian cancer risk, with ORs ranging from 1.95-2.10, with stronger ORs for postmenopausal women (2.02-3.22). ORs were generally similar for serous/poorly differentiated and endometrioid/clear cell tumors, although most did not meet the Bonferroni-adjusted p-value for significance. C18:1 lysophosphatidylcholines (LPC) and the ratio of LPC to phosphatidylcholines (PC) were significantly inversely, while C18:0 SM was significantly positively, associated with risk of endometrioid/clear cell tumors.
In an agnostic analysis, pseudouridine was associated with risk of ovarian cancer, serous, and with non-serous disease (OR range: 2.57-7.61). No association remained significant after accounting for multiple comparisons using permutation tests. Eight data derived metabolite modules and 19 metabolite classes were associated with risk (overall: 4 modules, 9 classes; serous: 2 modules, 13 classes; non-serous: 6 modules, 13 classes). Triacylglycerols (TAGs) characterized 3 of 8 significant modules and were an overrepresented class. TAGs with lower acly carbon content and fewer double bonds were inversely, while TAGs with more acly carbon content and more double bonds were positively associated with total and serous ovarian cancer.
Elevated levels of circulating pseudouridine and SMs 3-23 years before diagnosis were associated with increased risk of ovarian cancer, regardless of histotype, with stronger associations among postmenopausal women, rapidly fatal tumors and cases with blood collection closer in time to diagnosis.
Additionally, we identified metabolites associated with ovarian cancer among cases diagnosed up to 3 years after blood collection. Ovarian cancer is often diagnosed at a late stage. We hypothesize that cases diagnosed up to three years after blood collection already had ovarian cancer at the time of the blood collection and can be used to identify early detection markers. The most significant early detection markers, after adjusting for ovarian cancer risk factors, were 3 ceramides, 1-methylnicotineamide, and methylimidazole acetic acid.
To the best of our knowledge, this represents the largest prospective study of metabolomics and ovarian cancer risk. However, our sample size was low and due to this, we propose to validate the metabolomics risk factors and early detection markers of ovarian cancer identified in the Nurses Health Studies in PLCO.
We propose to create a prospective 1:1 matched case-control study nested within PLCO including all cases with plasma samples collected before an ovarian cancer diagnosis. Before measuring all study samples we will conduct a reproducibility pilot study, similar to what we did in the Nurses’ Health Studies, to assess the feasibility of the metabolomics platform on the PLCO samples. The plasma metabolomics will be measured at the same laboratory that measured metabolomics in the Nurses’ samples, the Broad Institute of MIT and Harvard in Cambridge, MA.
Aims
• Validate metabolomics risk factors of ovarian cancer identified in the Nurses’ Health Studies in an independent cohort, the PLCO.
• Validate early detection markers of ovarian cancer identified in the Nurses’ Health Studies in an independent cohort, the PLCO.
Collaborators
Shelley Tworoger (Oregon Health and Science University)
Oana Zeleznik (Harvard Medical Shool and Brigham and Women's Hospital)
Britton Trabert (National Institutes of Health)
Nicolas Wentzensen (National Institutes of Health)
Approved Addenda
This project has one or more approved addenda.
- Measuring blood proteomics to validate novel early detection biomarkers for ovarian cancer.
- Integration of TCR repertoire changes with omics data for early detection of epithelial ovarian cancer