Summary of Study ST002773

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001730. The data can be accessed directly via it's Project DOI: 10.21228/M8371M This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST002773
Study TitleA nested case-control study of untargeted plasma metabolomics and lung cancer risk among never-smoking women in Shanghai Women’s Health Study
Study SummaryBackground: The etiology of lung cancer among never smokers has not been fully elucidated despite 15% of cases in men and 53% in women worldwide are not smoking-related. Metabolomics provides a snapshot of dynamic biochemical activities, including those found to be driving tumor formation and progression. This study used untargeted metabolomics with network analysis to agnostically identify network modules and independent metabolites in pre-diagnostic blood samples among never-smokers to further understand the pathogenesis of lung cancer. Methods and Findings: Within the prospective Shanghai Women’s Health Study, we conducted a nested case-control study of 395 never-smoking incident lung cancer cases and 395 never-smoking controls matched on age. We performed liquid chromatography high-resolution mass spectrometry to quantify 20,348 metabolic features in plasma. We agnostically constructed 28 network modules using a weighted correlation network analysis approach and assessed associations for network modules and individual metabolites with lung cancer using conditional logistic regression models, adjusting for covariates. We accounted for multiple testing using a false discovery rate (FDR) < 0.20. We identified a network module of 122 metabolic features enriched in lysophosphatidylethanolamines that was associated with all lung cancer combined (p = 0.001, FDR = 0.028) and lung adenocarcinoma (p = 0.002, FDR = 0.056) and another network module of 440 metabolic features that was associated with lung adenocarcinoma (p = 0.014, FDR = 0.196). Metabolic features were enriched in pathways associated with cell growth and proliferation, including oxidative stress, bile acid biosynthesis, and metabolism of nucleic acids, carbohydrates, and amino acids, including 1-carbon compounds. Conclusions: Our prospective study suggests that untargeted plasma metabolomics in pre-diagnostic samples could provide new insights into the etiology of lung cancer in never-smokers. Replication and further characterization of these associations are warranted.
Institute
Emory University
DepartmentGangarosa Department of Environmental Health
LaboratoryComprehensive Laboratory for Untargeted Exposome Science
Last NameWalker
First NameDouglas
Address1518 Clifton Rd, CNR 7025, Atlanta, GA 30322
Emaildouglas.walker@emory.edu
Phone(404) 727-6123
Submit Date2023-06-19
Num Groups2
Total Subjects790
Num Females790
Study CommentsSamples were collected from participants enrolled in the Shanghai Women's Health Study
Raw Data AvailableYes
Raw Data File Type(s)raw(Thermo)
Analysis Type DetailLC-MS
Release Date2024-02-28
Release Version1
Douglas Walker Douglas Walker
https://dx.doi.org/10.21228/M8371M
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:

Project:

Project ID:PR001730
Project DOI:doi: 10.21228/M8371M
Project Title:A nested case-control study of untargeted plasma metabolomics and lung cancer risk among never-smoking women in Shanghai Women’s Health Study
Project Summary:Background: The etiology of lung cancer among never smokers has not been fully elucidated despite 15% of cases in men and 53% in women worldwide are not smoking-related. Metabolomics provides a snapshot of dynamic biochemical activities, including those found to be driving tumor formation and progression. This study used untargeted metabolomics with network analysis to agnostically identify network modules and independent metabolites in pre-diagnostic blood samples among never-smokers to further understand the pathogenesis of lung cancer. Methods and Findings: Within the prospective Shanghai Women’s Health Study, we conducted a nested case-control study of 395 never-smoking incident lung cancer cases and 395 never-smoking controls matched on age. We performed liquid chromatography high-resolution mass spectrometry to quantify 20,348 metabolic features in plasma. We agnostically constructed 28 network modules using a weighted correlation network analysis approach and assessed associations for network modules and individual metabolites with lung cancer using conditional logistic regression models, adjusting for covariates. We accounted for multiple testing using a false discovery rate (FDR) < 0.20. We identified a network module of 122 metabolic features enriched in lysophosphatidylethanolamines that was associated with all lung cancer combined (p = 0.001, FDR = 0.028) and lung adenocarcinoma (p = 0.002, FDR = 0.056) and another network module of 440 metabolic features that was associated with lung adenocarcinoma (p = 0.014, FDR = 0.196). Metabolic features were enriched in pathways associated with cell growth and proliferation, including oxidative stress, bile acid biosynthesis, and metabolism of nucleic acids, carbohydrates, and amino acids, including 1-carbon compounds. Conclusions: Our prospective study suggests that untargeted plasma metabolomics in pre-diagnostic samples could provide new insights into the etiology of lung cancer in never-smokers. Replication and further characterization of these associations are warranted.
Institute:Emory University
Department:Gangarosa Department of Environmental Health
Laboratory:Comprehensive Laboratory for Untargeted Exposome Science
Last Name:Walker
First Name:Douglas
Address:1518 Clifton Rd, CNR 7025, Atlanta, GA 30322
Email:Douglas.walker@emory.edu
Phone:(404) 727-6123
Funding Source:This work is partly supported by National Natural Science Foundation of China (NSFC 91643203) and the National Institutes of Health/National Cancer Institute (HHSN261201500229P).
Publications:A nested case-control study of untargeted plasma metabolomics and lung cancer risk among never-smoking women in Shanghai Women’s Health Study. In review
Contributors:Mohammad L Rahman, Xiao-Ou Shu, Douglas Walker, Dean P Jones, Wei Hu, Bu-tian Ji, Batel Blechter, Jason YY Wong, Qiuyin Cai, Gong Yang, Yu-Tang Gao, Wei Zheng, Nathaniel Rothman, Qing Lan

Subject:

Subject ID:SU002880
Subject Type:Human
Subject Species:Homo sapiens
Taxonomy ID:9606
Gender:Female
Species Group:Mammals

Factors:

Subject type: Human; Subject species: Homo sapiens (Factor headings shown in green)

mb_sample_id local_sample_id Subject_ID LungCancer
SA294464nist1NIST_1950 NA
SA294465nist2NIST_1950 NA
SA294466q3June2014_11aPooledQAQC NA
SA294467q3June2014_10fPooledQAQC NA
SA294468q3June2014_11bPooledQAQC NA
SA294469q3June2014_11dPooledQAQC NA
SA294470q3June2014_11fPooledQAQC NA
SA294471q3June2014_11ePooledQAQC NA
SA294472q3June2014_10ePooledQAQC NA
SA294473q3June2014_11cPooledQAQC NA
SA294474q3June2014_10dPooledQAQC NA
SA294475q3June2014_9ePooledQAQC NA
SA294476q3June2014_9dPooledQAQC NA
SA294477q3June2014_9fPooledQAQC NA
SA294478q3June2014_10aPooledQAQC NA
SA294479q3June2014_10cPooledQAQC NA
SA294480q3June2014_10bPooledQAQC NA
SA294481q3June2014_12aPooledQAQC NA
SA294482q3June2014_12cPooledQAQC NA
SA294483q3June2014_14aPooledQAQC NA
SA294484q3June2014_13fPooledQAQC NA
SA294485q3June2014_14bPooledQAQC NA
SA294486q3June2014_14cPooledQAQC NA
SA294487q3June2014_14ePooledQAQC NA
SA294488q3June2014_14dPooledQAQC NA
SA294489q3June2014_13ePooledQAQC NA
SA294490q3June2014_13cPooledQAQC NA
SA294491q3June2014_12dPooledQAQC NA
SA294492q3June2014_9cPooledQAQC NA
SA294493q3June2014_12ePooledQAQC NA
SA294494q3June2014_12fPooledQAQC NA
SA294495q3June2014_13bPooledQAQC NA
SA294496q3June2014_13aPooledQAQC NA
SA294497q3June2014_12bPooledQAQC NA
SA294498q3June2014_9aPooledQAQC NA
SA294499q3June2014_5dPooledQAQC NA
SA294500q3June2014_5cPooledQAQC NA
SA294501q3June2014_5bPooledQAQC NA
SA294502q3June2014_5ePooledQAQC NA
SA294503q3June2014_5fPooledQAQC NA
SA294504q3June2014_6bPooledQAQC NA
SA294505q3June2014_6aPooledQAQC NA
SA294506q3June2014_5aPooledQAQC NA
SA294507q3June2014_4fPooledQAQC NA
SA294508q3June2014_4aPooledQAQC NA
SA294509q3June2014_3fPooledQAQC NA
SA294510q3June2014_4bPooledQAQC NA
SA294511q3June2014_4cPooledQAQC NA
SA294512q3June2014_4ePooledQAQC NA
SA294513q3June2014_4dPooledQAQC NA
SA294514q3June2014_6cPooledQAQC NA
SA294515q3June2014_6dPooledQAQC NA
SA294516q3June2014_8cPooledQAQC NA
SA294517q3June2014_8bPooledQAQC NA
SA294518q3June2014_8aPooledQAQC NA
SA294519q3June2014_8dPooledQAQC NA
SA294520q3June2014_8ePooledQAQC NA
SA294521q3June2014_14fPooledQAQC NA
SA294522q3June2014_8fPooledQAQC NA
SA294523q3June2014_7fPooledQAQC NA
SA294524q3June2014_7ePooledQAQC NA
SA294525q3June2014_6fPooledQAQC NA
SA294526q3June2014_6ePooledQAQC NA
SA294527q3June2014_7aPooledQAQC NA
SA294528q3June2014_7bPooledQAQC NA
SA294529q3June2014_7dPooledQAQC NA
SA294530q3June2014_7cPooledQAQC NA
SA294531q3June2014_9bPooledQAQC NA
SA294532q3June2014_15bPooledQAQC NA
SA294533q3June2014_22cPooledQAQC NA
SA294534q3June2014_22bPooledQAQC NA
SA294535q3June2014_22aPooledQAQC NA
SA294536q3June2014_22dPooledQAQC NA
SA294537q3June2014_22ePooledQAQC NA
SA294538q3June2014_23aPooledQAQC NA
SA294539q3June2014_22fPooledQAQC NA
SA294540q3June2014_21fPooledQAQC NA
SA294541q3June2014_21ePooledQAQC NA
SA294542q3June2014_20fPooledQAQC NA
SA294543q3June2014_20ePooledQAQC NA
SA294544q3June2014_21aPooledQAQC NA
SA294545q3June2014_21bPooledQAQC NA
SA294546q3June2014_21dPooledQAQC NA
SA294547q3June2014_21cPooledQAQC NA
SA294548q3June2014_23bPooledQAQC NA
SA294549q3June2014_23cPooledQAQC NA
SA294550q3June2014_25bPooledQAQC NA
SA294551q3June2014_25aPooledQAQC NA
SA294552q3June2014_24fPooledQAQC NA
SA294553q3June2014_25cPooledQAQC NA
SA294554q3June2014_25dPooledQAQC NA
SA294555q3June2014_25fPooledQAQC NA
SA294556q3June2014_25ePooledQAQC NA
SA294557q3June2014_24ePooledQAQC NA
SA294558q3June2014_24dPooledQAQC NA
SA294559q3June2014_23ePooledQAQC NA
SA294560q3June2014_23dPooledQAQC NA
SA294561q3June2014_23fPooledQAQC NA
SA294562q3June2014_24aPooledQAQC NA
SA294563q3June2014_24cPooledQAQC NA
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Collection:

Collection ID:CO002873
Collection Summary:This case-control study was nested in a prospective Shanghai Women’s Health Study (December 28, 1996 - May 23, 2000), which has been previously described [17, 18]. Briefly, the SWHS is a population-based prospective cohort study in Shanghai, China where 74,942 women aged 40-70 years were recruited by a trained interviewer and a community health worker. The women were followed through multiple in-person interviews and self-administered questionnaires to obtain information on demographics, occupational and environmental exposures, lifestyle, dietary, and other factors, including environmental tobacco smoke (ETS) and body mass index (BMI). The participation rate was 92.7%. Cohort members are followed for cancer diagnosis through in-person follow-up surveys administered every 2–3 years and annual record linkage with the Shanghai Cancer Registry and Vital Statistics Unit. All incident lung cancer cases were eligible for the current study. All study participants provided written informed consent before being interviewed, and the study protocols were approved by the institutional review boards of all participating institutions.
Sample Type:Blood (plasma)

Treatment:

Treatment ID:TR002889
Treatment Summary:Lung cancer cases were defined based on the International Classification of Diseases for Oncology, Second Edition (ICD-O-2), and included all primary malignant cancers that were coded as 80003, 80413, 80703, 81403, 82403, 82603, 84803, 85503, and 85603. Lung cancer was diagnosed between 2000-2014 (average follow-up: 7.0 years; range: 0 – 13 years). For each case of lung cancer, a never-smoking control matched on age (± 2 years) were selected. A total of 790 (395 cases-control pairs) lifetime never-smokers based on the standard definition used by the U.S. Centers for Disease Control (CDC) of adults who has never smoked, or who has smoked less than 100 cigarettes in their lifetime were included in the analysis.

Sample Preparation:

Sampleprep ID:SP002886
Sampleprep Summary:Samples are prepared for metabolomics analysis using established methods (Johnson et al. (2010). Analyst; Go et al. (2015). Tox Sci). Prior to analysis, plasma aliquots were removed from storage at -80°C and thawed on ice. Each cryotube is then vortexed briefly to ensure homogeneity, and 50 μL transferred to a clean microfuge tube. Immediately after, the plasma is treated with 100 μL of ice-cold LC-MS grade acetonitrile (Sigma Aldrich) containing 2.5 μL of internal standard solution with eight stable isotopic chemicals selected to cover a range of chemical properties. Following addition of acetonitrile, plasma is then equilibrated for 30 min on ice, upon which precipitated proteins are removed by centrifuge (16.1 ×g at 4°C for 10 min). The resulting supernatant (100 μL) is removed, added to a low volume autosampler vial and maintained at 4°C until analysis (<22 h).
Sampleprep Protocol ID:EmoryUniversity_HRM_SP_082016_01.pdf
Sampleprep Protocol Filename:EmoryUniversity_HRM_SP_082016_01.pdf
Processing Method:Protein Precipitation with Acetonitrile
Processing Storage Conditions:On ice

Combined analysis:

Analysis ID AN004513 AN004514
Analysis type MS MS
Chromatography type HILIC Reversed phase
Chromatography system Thermo Dionex Ultimate 3000 RS Thermo Dionex Ultimate 3000 RS
Column Higgins Analytical TARGA C18 (50 x 2.1mm,5um) Waters XBridge BEH Amide (50 x 2.1mm,2.5um)
MS Type ESI ESI
MS instrument type Orbitrap Orbitrap
MS instrument name Thermo Q Exactive HF hybrid Orbitrap Thermo Q Exactive HF hybrid Orbitrap
Ion Mode POSITIVE NEGATIVE
Units Peak Intensity Peak Intensity

Chromatography:

Chromatography ID:CH003390
Chromatography Summary:The HILIC column is operated parallel to reverse phase column for simultaneous analytical separation and column flushing through the use of a dual head HPLC pump equipped with 10-port and 6-port switching valves. During operation of HILIC separation method, the MS is operated in positive ion mode and 10 μL of sample is injected onto the HILIC column while the reverse phase column is flushing with wash solution. Flow rate is maintained at 0.35 mL/min until 1.5 min, increased to 0.4 mL/min at 4 min and held for 1 min. Solvent A is 100% LC-MS grade water, solvent B is 100% LC-MS grade acetonitrile and solvent C is 2% formic acid (v/v) in LC-MS grade water. Initial mobile phase conditions are 22.5% A, 75% B, 2.5% C hold for 1.5 min, with linear gradient to 77.5% A, 20% B, 2.5% C at 4 min, hold for 1 min, resulting in a total analytical run time of 5 min. During the flushing phase (reverse phase analytical separation), the HILIC column is equilibrated with a wash solution of 77.5% A, 20% B, 2.5% C.
Methods ID:EmoryUniversity_HRM_DC5min_082016_01.pdf
Instrument Name:Thermo Dionex Ultimate 3000 RS
Column Name:Higgins Analytical TARGA C18 (50 x 2.1mm,5um)
Column Temperature:40
Flow Gradient:Initial mobile phase conditions are 22.5% A, 75% B, 2.5% C hold for 1.5 min, with linear gradient to 77.5% A, 20% B, 2.5% C at 4 min, hold for 1 min, resulting in a total analytical run time of 5 min. During the flushing phase (reverse phase analytical separation), the HILIC column is equilibrated with a wash solution of 77.5% A, 20% B, 2.5% C.
Flow Rate:0.35-0.4 mL/min
Solvent A:100% water
Solvent B:100% acetonitrile
Chromatography Type:HILIC
Solvent C:100% water; 2% formic acid
  
Chromatography ID:CH003391
Chromatography Summary:The C18 column is operated parallel to the HILIC column for simultaneous analytical separation and column flushing through the use of a dual head HPLC pump equipped with 10-port and 6-port switching valves. During operation of the C18 method, the MS is operated in negative ion mode and 10 μL of sample is injected onto the C18 column while the HILIC column is flushing with wash solution. Flow rate is maintained at 0.4 mL/min until 1.5 min, increased to 0.5 mL/min at 2 min and held for 3 min. Solvent A is 100% LC-MS grade water, solvent B is 100% LC-MS grade acetonitrile and solvent C is 10mM ammonium acetate in LC-MS grade water. Initial mobile phase conditions are 60% A, 35% B, 5% C hold for 0.5 min, with linear gradient to 0% A, 95% B, 5% C at 1.5 min, hold for 3.5 min, resulting in a total analytical run time of 5 min. During the flushing phase (HILIC analytical separation), the C18 column is equilibrated with a wash solution of 0% A, 95% B, 5% C until 2.5 min, followed by an equilibration solution of 60% A, 35% B, 5% C for 2.5 min.
Methods ID:EmoryUniversity_HRM_DC5min_082016_01.pdf
Instrument Name:Thermo Dionex Ultimate 3000 RS
Column Name:Waters XBridge BEH Amide (50 x 2.1mm,2.5um)
Column Temperature:40
Flow Gradient:Initial mobile phase conditions are 60% A, 35% B, 5% C hold for 0.5 min, with linear gradient to 0% A, 95% B, 5% C at 1.5 min, hold for 3.5 min, resulting in a total analytical run time of 5 min. During the flushing phase (HILIC analytical separation), the C18 column is equilibrated with a wash solution of 0% A, 95% B, 5% C until 2.5 min, followed by an equilibration solution of 60% A, 35% B, 5% C for 2.5 min.
Flow Rate:0.4-0.5 mL/min
Solvent A:100% water
Solvent B:100% acetonitrile
Chromatography Type:Reversed phase
Solvent C:100% water; 10 mM ammonium acetate

MS:

MS ID:MS004260
Analysis ID:AN004513
Instrument Name:Thermo Q Exactive HF hybrid Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:Data were acquired using full-scan mode in batches of 40 samples. Following analysis of all samples, peaks were extracted and aligned using 5 different parameters setting in apLCMS. The resulting 5 feature tables were merged using xMSanalyzer, triplicates were averaged, and batch corrected using COMBAT.
Ion Mode:POSITIVE
Capillary Temperature:300
Ion Source Temperature:250
Spray Voltage:+3500
Analysis Protocol File:EmoryUniversity_HRM_FusionMS_082016_01.pdf
  
MS ID:MS004261
Analysis ID:AN004514
Instrument Name:Thermo Q Exactive HF hybrid Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:Data were acquired using full-scan mode in batches of 40 samples. Following analysis of all samples, peaks were extracted and aligned using 5 different parameters setting in apLCMS. The resulting 5 feature tables were merged using xMSanalyzer, triplicates were averaged, and batch corrected using COMBAT.
Ion Mode:NEGATIVE
Capillary Temperature:300
Ion Source Temperature:250
Spray Voltage:-4000
Analysis Protocol File:EmoryUniversity_HRM_FusionMS_082016_01.pdf
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