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Grant Details

Grant Number: 5R01CA244588-05 Interpret this number
Primary Investigator: Peters, Ulrike
Organization: Fred Hutchinson Cancer Center
Project Title: Advancing Equity in Colorectal Cancer Genetic Risk Prediction Through Expansion of Racial/Ethnic Minority Representation
Fiscal Year: 2023


Abstract

Project Summary / Abstract As colorectal cancer (CRC) remains one of the leading causes of cancer death new approaches are of vital importance to make critical inroads in reducing the burden of this lethal disease. Precision medicine holds enormous promise as advances in genomic research that were previously unimaginable now offer vast commercial potential and are rapidly being moved into clinical practice, even though critical questions remain to be addressed. Polygenic risk scores (PRS) that aggregate common genetic risk variants into a single score to predict disease are a key example. Broad accessibility, plummeting genotyping costs, and the need to account for the patient's individual risk profile to improve screening have provided transformative opportunities in personalized prevention. However, wide-scale clinical adoption of PRS raises key ethical and scientific challenges. Arguably one of the most critical challenge is the fact that current PRS are substantially more effective in predicting risk in individuals of European ancestry compared with other populations due to the Euro- centric bias in genetic research. Accordingly, we need to develop an unbiased PRS that predicts CRC risk in all major racial/ethnic groups. However, this is only the first step towards implementation, which also requires the evaluation of the optimal risk-stratified screening approach and development of risk communication tool among others. To address these needs, we will develop and validate an unbiased PRS for CRC across ethnic/racial minority groups to inform risk-stratified CRC screening (Aim 1a). We will augment the PRS with an environmental/ lifestyle risk score (ERS) to account for other risk factors (Aim 1b) and examine differential effects by age of onset (Aim 1c), given the alarming increase of early onset CRC. In Aim 2a we will determine the optimal CRC screening strategy given an individual's risk defined in Aim 1 using our microsimulation modeling by incorporating differences in CRC incidence and mortality rates by age, sex and race/ethnicity, and in risk factor distributions across racial/ethnic groups. In Aim 2b we will evaluate the cost-effectiveness of risk stratified screening compared with current screening guidelines. Finally, we will develop a risk communication tool (Aim 3a) and investigate potential dissemination issues of risk-stratified CRC screening across ethnic/racial minority groups (Aim 3b). Our trans-disciplinary research team, which includes a community advisory board, is uniquely set up to address these critical questions as we 1) have brought together all known racially/ethnically diverse CRC studies totaling to over 120,000 CRC cases and controls, 2) have strong expertise in developing comprehensive genetic and environmental risk scores in racially/ethnically diverse populations, 3) lead one of the most comprehensive decision models for cost-effectiveness analysis which has consistently been used to inform US screening guidelines and 4) have expertise in implementation science for genetic research in minorities. Addressing all aims is critical to avoid a sequential science in this rapidly moving field of precision medicine.



Publications

Risk-Stratified Screening for Colorectal Cancer Using Genetic and Environmental Risk Factors: A Cost-Effectiveness Analysis Based on Real-World Data.
Authors: van den Puttelaar R. , Meester R.G.S. , Peterse E.F.P. , Zauber A.G. , Zheng J. , Hayes R.B. , Su Y.R. , Lee J.K. , Thomas M. , Sakoda L.C. , et al. .
Source: Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association, 2023 Dec; 21(13), p. 3415-3423.e29.
EPub date: 2023-03-09.
PMID: 36906080
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Elucidating the Risk of Colorectal Cancer for Variants in Hereditary Colorectal Cancer Genes.
Authors: Mahmood K. , Thomas M. , Qu C. , Gecco-Ccfr Consortium , Hsu L. , Buchanan D.D. , Peters U. .
Source: Gastroenterology, 2023 Oct; 165(4), p. 1070-1076.e3.
EPub date: 2023-07-14.
PMID: 37453563
Related Citations

Validation of a Genetic-Enhanced Risk Prediction Model for Colorectal Cancer in a Large Community-Based Cohort.
Authors: Su Y.R. , Sakoda L.C. , Jeon J. , Thomas M. , Lin Y. , Schneider J.L. , Udaltsova N. , Lee J.K. , Lansdorp-Vogelaar I. , Peterse E.F.P. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2023-03-06; 32(3), p. 353-362.
PMID: 36622766
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Separating the effects of early and later life adiposity on colorectal cancer risk: a Mendelian randomization study.
Authors: Papadimitriou N. , Bull C.J. , Jenab M. , Hughes D.J. , Bell J.A. , Sanderson E. , Timpson N.J. , Smith G.D. , Albanes D. , Campbell P.T. , et al. .
Source: BMC medicine, 2023-01-04; 21(1), p. 5.
EPub date: 2023-01-04.
PMID: 36600297
Related Citations

Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries.
Authors: Fernandez-Rozadilla C. , Timofeeva M. , Chen Z. , Law P. , Thomas M. , Schmit S. , Díez-Obrero V. , Hsu L. , Fernandez-Tajes J. , Palles C. , et al. .
Source: Nature genetics, 2023 Jan; 55(1), p. 89-99.
EPub date: 2022-12-20.
PMID: 36539618
Related Citations

Associations Between Glycemic Traits and Colorectal Cancer: A Mendelian Randomization Analysis.
Authors: Murphy N. , Song M. , Papadimitriou N. , Carreras-Torres R. , Langenberg C. , Martin R.M. , Tsilidis K.K. , Barroso I. , Chen J. , Frayling T.M. , et al. .
Source: Journal of the National Cancer Institute, 2022-05-09; 114(5), p. 740-752.
PMID: 35048991
Related Citations

Genetically proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers: A mendelian randomization analysis.
Authors: Yarmolinsky J. , Díez-Obrero V. , Richardson T.G. , Pigeyre M. , Sjaarda J. , Paré G. , Walker V.M. , Vincent E.E. , Tan V.Y. , Obón-Santacana M. , et al. .
Source: PLoS medicine, 2022 Feb; 19(2), p. e1003897.
EPub date: 2022-02-03.
PMID: 35113855
Related Citations

Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals.
Authors: Chen H. , Majumdar A. , Wang L. , Kar S. , Brown K.M. , Feng H. , Turman C. , Dennis J. , Easton D. , Michailidou K. , et al. .
Source: HGG advances, 2021-07-08; 2(3), p. 100041.
EPub date: 2021-06-12.
PMID: 34355204
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Genetically Predicted Circulating C-Reactive Protein Concentration and Colorectal Cancer Survival: A Mendelian Randomization Consortium Study.
Authors: Hua X. , Dai J.Y. , Lindström S. , Harrison T.A. , Lin Y. , Alberts S.R. , Alwers E. , Berndt S.I. , Brenner H. , Buchanan D.D. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2021 Jul; 30(7), p. 1349-1358.
EPub date: 2021-05-10.
PMID: 33972368
Related Citations

Circulating Levels of Testosterone, Sex Hormone Binding Globulin and Colorectal Cancer Risk: Observational and Mendelian Randomization Analyses.
Authors: Dimou N. , Mori N. , Harlid S. , Harbs J. , Martin R.M. , Smith-Byrne K. , Papadimitriou N. , Bishop D.T. , Casey G. , Colorado-Yohar S.M. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2021 Jul; 30(7), p. 1336-1348.
EPub date: 2021-04-20.
PMID: 33879453
Related Citations

Nongenetic Determinants of Risk for Early-Onset Colorectal Cancer.
Authors: Archambault A.N. , Lin Y. , Jeon J. , Harrison T.A. , Bishop D.T. , Brenner H. , Casey G. , Chan A.T. , Chang-Claude J. , Figueiredo J.C. , et al. .
Source: JNCI cancer spectrum, 2021 Jun; 5(3), .
EPub date: 2021-05-20.
PMID: 34041438
Related Citations

Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: a Mendelian randomization study.
Authors: Tsilidis K.K. , Papadimitriou N. , Dimou N. , Gill D. , Lewis S.J. , Martin R.M. , Murphy N. , Markozannes G. , Zuber V. , Cross A.J. , et al. .
Source: The American journal of clinical nutrition, 2021-06-01; 113(6), p. 1490-1502.
PMID: 33740060
Related Citations

Causal Effects of Lifetime Smoking on Breast and Colorectal Cancer Risk: Mendelian Randomization Study.
Authors: Dimou N. , Yarmolinsky J. , Bouras E. , Tsilidis K.K. , Martin R.M. , Lewis S.J. , Gram I.T. , Bakker M.F. , Brenner H. , Figueiredo J.C. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2021 May; 30(5), p. 953-964.
EPub date: 2021-03-02.
PMID: 33653810
Related Citations

Assessment of a Polygenic Risk Score for Colorectal Cancer to Predict Risk of Lynch Syndrome Colorectal Cancer.
Authors: Jenkins M.A. , Buchanan D.D. , Lai J. , Makalic E. , Dite G.S. , Win A.K. , Clendenning M. , Winship I.M. , Hayes R.B. , Huyghe J.R. , et al. .
Source: JNCI cancer spectrum, 2021 Apr; 5(2), .
EPub date: 2021-03-08.
PMID: 33928216
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