Grant Number:	4R00CA230205-03 Interpret this number
Primary Investigator:	Shu, Xiang
Organization:	Sloan-Kettering Inst Can Research
Project Title:	Uncovering Roles of Metabolites in Colorectal Cancer Etiology
Fiscal Year:	2020

PROJECT SUMMARY Metabolic perturbation or reprogramming is considered one of the hallmarks of cancer. Several common metabolic disorders, such as obesity, type 2 diabetes, and dyslipidemia, have been linked to colorectal cancer (CRC) risk. With the advances in the techniques of metabolomics, hundreds to thousands of metabolites can be systematically measured in an agnostic manner. For a well-designed prospective metabolomic study of cancer, the identification of novel risk-associated biomarkers will shed new lights on the cancer etiology and related biological pathways. Conventional studies evaluating metabolites are costly and may suffer from biases commonly encountered in the observational studies. It has been increasingly recognized that genetic factors play a significant role in determining the levels of many metabolites. Herein, I propose a cost-efficient approach to systematically evaluate the associations between plasma levels of metabolites and CRC risk. I also incorporate didactic training on molecular/genetic epidemiology, causal inference, cancer biology and metabolism, and population genetics in this application to accomplish my research and career goals described below. The proposed research is composed of four aims. In aim 1, I will build models to predict metabolite levels using existing metabolomics and high-density genotyping data from a public database and possible data generated at Vanderbilt. In aim 2, metabolites with satisfactory prediction accuracy and meeting other criteria will be evaluated in three large-scale CRC consortia with a combined sample size of ~80,900 cases and 115,000 controls to assess the associations of genetically predicted metabolite levels with CRC risk. In collaboration with other investigators during the R00 phase of this award, I will then conduct a nested case- control study to confirm up to ten metabolites identified from in silico analysis by direct measurement of these metabolites using pre-diagnosis plasma collected in three large cohort studies (aim 3). Finally, I will evaluate the potential mediation effects of metabolites for the associations between lifestyle factors including obesity (body mass index and waist-hip-ratio), physical activity, red meat intakes, vegetable intakes, healthy eating index and CRC risk (aim 4). This innovative study will, for the first time, systematically search for novel metabolite biomarkers for CRC risk using genetic instruments and validate the identified associations by direct measurement. In addition, this study will expand the understanding of underlying mechanisms causing CRC. The proposed career development award will help me building advanced knowledge of genetic and molecular epidemiology, cancer metabolism, and CRC etiology and risk assessment to transition to a successful independent investigator.




Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants that Confer Risk for Breast Cancer.
Authors: Sun X. , Verma S.P. , Jia G. , Wang X. , Ping J. , Guo X. , Shu X.O. , Chen J. , Derkach A. , Cai Q. , et al. .
Source: Cancer Research, 2024-06-04 00:00:00.0; , .
EPub date: 2024-06-04 00:00:00.0.
PMID: 38832928
Related Citations

Drug-target Mendelian randomization revealed a significant association of genetically proxied metformin effects with increased prostate cancer risk.
Authors: Sun X. , Ping J. , Guo X. , Long J. , Cai Q. , Shu X.O. , Shu X. .
Source: Molecular Carcinogenesis, 2024 May; 63(5), p. 849-858.
EPub date: 2024-03-22 00:00:00.0.
PMID: 38517045
Related Citations

A genome-wide association study of contralateral breast cancer in the Women's Environmental Cancer and Radiation Epidemiology Study.
Authors: Sun X. , Reiner A.S. , Tran A.P. , Watt G.P. , Oh J.H. , Mellemkjær L. , Lynch C.F. , Knight J.A. , John E.M. , Malone K.E. , et al. .
Source: Breast Cancer Research : Bcr, 2024-01-23 00:00:00.0; 26(1), p. 16.
EPub date: 2024-01-23 00:00:00.0.
PMID: 38263039
Related Citations

Genome- and transcriptome-wide association studies of 386,000 Asian and European-ancestry women provide new insights into breast cancer genetics.
Authors: Jia G. , Ping J. , Shu X. , Yang Y. , Cai Q. , Kweon S.S. , Choi J.Y. , Kubo M. , Park S.K. , Bolla M.K. , et al. .
Source: American Journal Of Human Genetics, 2022-11-03 00:00:00.0; , .
EPub date: 2022-11-03 00:00:00.0.
PMID: 36356581
Related Citations

Associations between circulating proteins and risk of breast cancer by intrinsic subtypes: a Mendelian randomisation analysis.
Authors: Shu X. , Zhou Q. , Sun X. , Flesaker M. , Guo X. , Long J. , Robson M.E. , Shu X.O. , Zheng W. , Bernstein J.L. .
Source: British Journal Of Cancer, 2022-07-26 00:00:00.0; , .
EPub date: 2022-07-26 00:00:00.0.
PMID: 35882941
Related Citations

Prospective Proteomic Study Identifies Potential Circulating Protein Biomarkers for Colorectal Cancer Risk.
Authors: Sun X. , Shu X.O. , Lan Q. , Laszkowska M. , Cai Q. , Rothman N. , Wen W. , Zheng W. , Shu X. .
Source: Cancers, 2022-07-03 00:00:00.0; 14(13), .
EPub date: 2022-07-03 00:00:00.0.
PMID: 35805033
Related Citations

Mendelian randomization analyses of 23 known and suspected risk factors and biomarkers for breast cancer overall and by molecular subtypes.
Authors: Chen F. , Wen W. , Long J. , Shu X. , Yang Y. , Shu X.O. , Zheng W. .
Source: International Journal Of Cancer, 2022-04-11 00:00:00.0; , .
EPub date: 2022-04-11 00:00:00.0.
PMID: 35403707
Related Citations

Large-scale integrated analysis of genetics and metabolomic data reveals potential links between lipids and colorectal cancer risk.
Authors: Shu X. , Chen Z. , Long J. , Guo X. , Yang Y. , Qu C. , Ahn Y.O. , Cai Q. , Casey G. , Gruber S.B. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2022-03-10 00:00:00.0; , .
EPub date: 2022-03-10 00:00:00.0.
PMID: 35266989
Related Citations

Polygenic risk scores for prediction of breast cancer risk in Asian populations.
Authors: Ho W.K. , Tai M.C. , Dennis J. , Shu X. , Li J. , Ho P.J. , Millwood I.Y. , Lin K. , Jee Y.H. , Lee S.H. , et al. .
Source: Genetics In Medicine : Official Journal Of The American College Of Medical Genetics, 2022 Mar; 24(3), p. 586-600.
EPub date: 2021-12-15 00:00:00.0.
PMID: 34906514
Related Citations

TBX1 functions as a putative oncogene of breast cancer through promoting cell cycle progression.
Authors: Huang S. , Shu X. , Ping J. , Wu J. , Wang J. , Shidal C. , Guo X. , Bauer J.A. , Long J. , Shu X.O. , et al. .
Source: Carcinogenesis, 2022-02-11 00:00:00.0; 43(1), p. 12-20.
PMID: 34919666
Related Citations

Prospective study of oral microbiome and gastric cancer risk among Asian, African American and European American populations.
Authors: Yang Y. , Long J. , Wang C. , Blot W.J. , Pei Z. , Shu X. , Wu F. , Rothman N. , Wu J. , Lan Q. , et al. .
Source: International Journal Of Cancer, 2021-10-18 00:00:00.0; , .
EPub date: 2021-10-18 00:00:00.0.
PMID: 34664266
Related Citations

A Prospective Investigation of Circulating Metabolome Identifies Potential Biomarkers for Gastric Cancer Risk.
Authors: Shu X. , Cai H. , Lan Q. , Cai Q. , Ji B.T. , Zheng W. , Shu X.O. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2021 Sep; 30(9), p. 1634-1642.
EPub date: 2021-04-01 00:00:00.0.
PMID: 33795214
Related Citations

Functional Genomic Analyses of the 21q22.3 Locus Identifying Functional Variants and Candidate Gene YBEY for Breast Cancer Risk.
Authors: Shidal C. , Shu X. , Wu J. , Wang J. , Huang S. , Long J. , Bauer J.A. , Ping J. , Guo X. , Zheng W. , et al. .
Source: Cancers, 2021-04-23 00:00:00.0; 13(9), .
EPub date: 2021-04-23 00:00:00.0.
PMID: 33922500
Related Citations

Genetically predicted circulating protein biomarkers and ovarian cancer risk.
Authors: Considine D.P.C. , Jia G. , Shu X. , Schildkraut J.M. , Pharoah P.D.P. , Zheng W. , Kar S.P. , Ovarian Cancer Association Consortium .
Source: Gynecologic Oncology, 2020-11-24 00:00:00.0; , .
EPub date: 2020-11-24 00:00:00.0.
PMID: 33246661
Related Citations

Investigating the associations of glycemic load and glycemic index with lung cancer risk in the Southern Community Cohort Study.
Authors: Shu X. , Yu D. , Shu X.O. , Munro H.M. , Zheng W. , Blot W.J. .
Source: Cancer Causes & Control : Ccc, 2020-09-11 00:00:00.0; , .
EPub date: 2020-09-11 00:00:00.0.
PMID: 32915323
Related Citations

Re-evaluating genetic variants identified in candidate gene studies of breast cancer risk using data from nearly 280,000 women of Asian and European ancestry.
Authors: Yang Y. , Shu X. , Shu X.O. , Bolla M.K. , Kweon S.S. , Cai Q. , Michailidou K. , Wang Q. , Dennis J. , Park B. , et al. .
Source: Ebiomedicine, 2019 Oct; 48, p. 203-211.
EPub date: 2019-10-16 00:00:00.0.
PMID: 31629678
Related Citations

Evaluation of associations between genetically predicted circulating protein biomarkers and breast cancer risk.
Authors: Shu X. , Bao J. , Wu L. , Long J. , Shu X.O. , Guo X. , Yang Y. , Michailidou K. , Bolla M.K. , Wang Q. , et al. .
Source: International Journal Of Cancer, 2019-07-02 00:00:00.0; , .
EPub date: 2019-07-02 00:00:00.0.
PMID: 31265136
Related Citations