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[Preprint]. 2025 Jun 16:2025.06.13.25329599.

doi: 10.1101/2025.06.13.25329599.

Red meat intake interacts with a TGF-β-pathway-based polygenic risk score to impact colorectal cancer risk: Application of a novel approach for polygenic risk score construction

Joel Sanchez Mendez¹, Bryan Queme², Yubo Fu², John Morrison², Juan P Lewinger², Eric Kawaguchi², Huaiyu Mi², Mireia Obón-Santacana^{3

4

5}, Ferran Moratalla-Navarro^{3

4

5

6}, Vicente Martín^{5

7

8}, Victor Moreno^{3

4

5

6}, Yi Lin⁹, Stephanie A Bien⁹, Conghui Qu⁹, Yu-Ru Su⁹, Emily White^{9

10}, Tabitha A Harrison⁹, Jeroen R Huyghe⁹, Catherine M Tangen⁹, Polly A Newcomb^{9

10}, Amanda I Phipps^{9

10}, Claire E Thomas⁹, David V Conti², Jun Wang², Elizabeth A Platz¹¹, Temitope O Keku¹², Christina C Newton¹³, Caroline Y Um¹³, Anshul Kundaje^{14

15}, Anna Shcherbina^{14

15}, Neil Murphy¹⁶, Marc J Gunter^{16

17}, Niki Dimou¹⁶, Nikos Papadimitriou¹⁶, Stéphane Bézieau¹⁸, Franzel Jb van Duijnhoven¹⁹, Satu Männistö²⁰, Gad Rennert^{21

22

23}, Alicja Wolk²⁴, Michael Hoffmeister²⁵, Hermann Brenner^{25

26

27}, Jenny Chang-Claude^{28

29}, Yu Tian^{28

30}, Loïc Le Marchand³¹, Michelle Cotterchio³², Konstantinos K Tsilidis¹⁷, D Timothy Bishop³³, Yohannes Adama Melaku^{34

35}, Brigid M Lynch^{35

36}, Daniel D Buchanan^{37

38

39}, Cornelia M Ulrich^{40

41}, Jennifer Ose^{40

41}, Anita R Peoples^{40

41}, Andrew J Pellatt⁴², Li Li⁴³, Matthew Am Devall⁴³, Peter T Campbell⁴⁴, Demetrius Albanes⁴⁵, Stephanie J Weinstein⁴⁵, Sonja I Berndt⁴⁵, Stephen B Gruber⁴⁶, Edward Ruiz-Narvaez⁴⁷, Mingyang Song^{48

49}, Amit D Joshi^{48

49}, David A Drew⁴⁹, Jessica L Petrick⁵⁰, Andrew T Chan^{48

49

51

52

53

54}, Marios Giannakis^{53

55}, Li Hsu^{9

56}, Ulrike Peters^{9

10}, W James Gauderman², Mariana C Stern¹

Affiliations

¹ Department of Population and Public Health Sciences & USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
² Division of Biostatistics, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, California, USA.
³ Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, 08908 Barcelona, Spain.
⁴ ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona Spain.
⁵ Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain.
⁶ Department of Clinical Sciences, Faculty of Medicine and health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), University of Barcelona (UB), L'Hospitalet de Llobregat, 08908 Barcelona, Spain.
⁷ The Research Group in Gene - Environment and Health Interactions (GIIGAS) / Institut of Biomedicine (IBIOMED), Universidad de León, 24071 León, Spain.
⁸ Faculty of Health Sciences, Department of Biomedical Sciences, Area of Preventive Medicine and Public Health, Universidad de León, 24071 León, Spain.
⁹ Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
¹⁰ Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA.
¹¹ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
¹² Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina, USA.
¹³ Department of Population Science, American Cancer Society, Atlanta, Georgia.
¹⁴ Department of Genetics, Stanford University, Stanford, California, USA.
¹⁵ Department of Computer Science, Stanford University, Stanford, California, USA.
¹⁶ Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.
¹⁷ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
¹⁸ Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.
¹⁹ Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands.
²⁰ Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland.
²¹ Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
²² Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
²³ Clalit National Cancer Control Center, Haifa, Israel.
²⁴ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
²⁵ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁶ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
²⁷ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁸ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁹ University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany.
³⁰ School of Public Health, Capital Medical University, Beijing, China.
³¹ University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
³² Prevention and Cancer Control, Cancer Care Ontario, Toronto, ON, Canada.
³³ Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
³⁴ Flinders Health and Medical Research Institute, Adelaide Institute for Sleep Health, Flinders University, Adelaide, South Australia, Australia.
³⁵ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
³⁶ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia.
³⁷ Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010 Australia.
³⁸ University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010 Australia.
³⁹ Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
⁴⁰ Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
⁴¹ Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA.
⁴² Department of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁴³ Department of Family Medicine, University of Virginia, Charlottesville, Virginia, USA.
⁴⁴ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
⁴⁵ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
⁴⁶ Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte CA, USA.
⁴⁷ Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
⁴⁸ Departments of Epidemiology and Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.
⁴⁹ Clinical and Translational Epidemiology Unit and Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁵⁰ Slone Epidemiology Center at, Boston University, Boston, Massachusetts, USA.
⁵¹ Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁵² Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁵³ Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
⁵⁴ Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.
⁵⁵ Dana-Farber Cancer Institute, Harvard Medical School, Harvard University, Boston, Massachusetts, USA.
⁵⁶ Department of Biostatistics, University of Washington, Seattle, Washington, USA.

PMID: 40568668
PMCID: PMC12191096
DOI: 10.1101/2025.06.13.25329599

Red meat intake interacts with a TGF-β-pathway-based polygenic risk score to impact colorectal cancer risk: Application of a novel approach for polygenic risk score construction

Joel Sanchez Mendez et al. medRxiv. 2025.

[Preprint]. 2025 Jun 16:2025.06.13.25329599.

doi: 10.1101/2025.06.13.25329599.

Authors

Affiliations

¹ Department of Population and Public Health Sciences & USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
² Division of Biostatistics, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, California, USA.
³ Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, 08908 Barcelona, Spain.
⁴ ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona Spain.
⁵ Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain.
⁶ Department of Clinical Sciences, Faculty of Medicine and health Sciences and Universitat de Barcelona Institute of Complex Systems (UBICS), University of Barcelona (UB), L'Hospitalet de Llobregat, 08908 Barcelona, Spain.
⁷ The Research Group in Gene - Environment and Health Interactions (GIIGAS) / Institut of Biomedicine (IBIOMED), Universidad de León, 24071 León, Spain.
⁸ Faculty of Health Sciences, Department of Biomedical Sciences, Area of Preventive Medicine and Public Health, Universidad de León, 24071 León, Spain.
⁹ Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
¹⁰ Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA.
¹¹ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
¹² Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina, USA.
¹³ Department of Population Science, American Cancer Society, Atlanta, Georgia.
¹⁴ Department of Genetics, Stanford University, Stanford, California, USA.
¹⁵ Department of Computer Science, Stanford University, Stanford, California, USA.
¹⁶ Nutrition and Metabolism Branch, International Agency for Research on Cancer, Lyon, France.
¹⁷ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
¹⁸ Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.
¹⁹ Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, The Netherlands.
²⁰ Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland.
²¹ Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
²² Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
²³ Clalit National Cancer Control Center, Haifa, Israel.
²⁴ Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
²⁵ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁶ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
²⁷ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁸ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁹ University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany.
³⁰ School of Public Health, Capital Medical University, Beijing, China.
³¹ University of Hawaii Cancer Center, Honolulu, Hawaii, USA.
³² Prevention and Cancer Control, Cancer Care Ontario, Toronto, ON, Canada.
³³ Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.
³⁴ Flinders Health and Medical Research Institute, Adelaide Institute for Sleep Health, Flinders University, Adelaide, South Australia, Australia.
³⁵ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
³⁶ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia.
³⁷ Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010 Australia.
³⁸ University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010 Australia.
³⁹ Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
⁴⁰ Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.
⁴¹ Department of Population Health Sciences, University of Utah, Salt Lake City, Utah, USA.
⁴² Department of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
⁴³ Department of Family Medicine, University of Virginia, Charlottesville, Virginia, USA.
⁴⁴ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
⁴⁵ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
⁴⁶ Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte CA, USA.
⁴⁷ Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan, USA.
⁴⁸ Departments of Epidemiology and Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.
⁴⁹ Clinical and Translational Epidemiology Unit and Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁵⁰ Slone Epidemiology Center at, Boston University, Boston, Massachusetts, USA.
⁵¹ Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁵² Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁵³ Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
⁵⁴ Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.
⁵⁵ Dana-Farber Cancer Institute, Harvard Medical School, Harvard University, Boston, Massachusetts, USA.
⁵⁶ Department of Biostatistics, University of Washington, Seattle, Washington, USA.

PMID: 40568668
PMCID: PMC12191096
DOI: 10.1101/2025.06.13.25329599

Abstract

Background: High intake of red and/or processed meat are established colorectal cancer (CRC) risk factors. Genome-wide association studies (GWAS) have reported 204 variants (G) associated with CRC risk. We used functional annotation data to identify subsets of variants within known pathways and constructed pathway-based Polygenic Risk Scores (pPRS) to model pPRS x environment (E) interactions.

Methods: A pooled sample of 30,812 cases and 40,504 CRC controls of European ancestry from 27 studies were analyzed. Quantiles for red and processed meat intake were constructed. The 204 GWAS variants were annotated to genes with AnnoQ and assessed for overrepresentation in PANTHER-reported pathways. pPRS's were constructed from significantly overrepresented pathways. Covariate-adjusted logistic regression models evaluated pPRSxE interactions with red or processed meat intake in relation to CRC risk.

Results: A total of 30 variants were overrepresented in four pathways: Alzheimer disease-presenilin, Cadherin/WNT-signaling, Gonadotropin-releasing hormone receptor, and TGF-β signaling. We found a significant interaction between TGF-β-pPRS and red meat intake (p = 0.003). When variants in the TGF-β pathway were assessed, significant interactions with red meat for rs2337113 (intron SMAD7 gene, Chr18), and rs2208603 (intergenic region BMP5, Chr6) (p = 0.013 & 0.011, respectively) were observed. We did not find evidence of pPRS x red meat interactions for other pathways or with processed meat.

Conclusions: This pathway-based interaction analysis revealed a significant interaction between variants in the TGF-β pathway and red meat consumption that impacts CRC risk.

Impact: These findings shed light into the possible mechanistic link between CRC risk and red meat consumption.

PubMed Disclaimer

Conflict of interest statement

C.M.U. has as cancer center director oversight over research funded by several pharmaceutical companies but has not received funding directly herself.

Figures

**Figure 1.**
Pathways overrepresented in CRC, showing the number of variants associated with each pathway and the extent of overlap among annotated variants. CRC; colorectal cancer. Note: Set size and intersection size correspond to the number of single nucleotide polymorphisms contained in each pathway-based Polygenic Risk Score (pPRS) and exhibiting overlap, respectively.

**Figure 2.**
Correlogram for pathway-based polygenic risk scores (pPRS). The numbers correspond to Pearson’s correlation coefficients. Overall PRS contains 204 SNPs that have been previously associated with CRC risk. CRC; colorectal cancer

**Figure 3.**
Odds Ratios and 95% CI for pathway-based Polygenic Risk Score interactions (pPRSxE) with **(A)** red meat, and **(B)** processed meat intake in association with colorectal cancer (CRC) risk. OR; Odds Ratio, CI; Confidence Interval NOTE: The No Pathway PRS contains variants that have previously shown a genome-wide significant association with colorectal cancer but were not overrepresented in biological pathways. For variants that are exclusively overrepresented in a single pathway, a second subset is generated (i.e., “Uniques”) and the appropriate pPRS computed. P-value corresponds to a 1-degree-of-freedom test of pPRSxE. All models were adjusted for study, age, sex, and the first three principal components.

See this image and copyright information in PMC

References

1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021. May;71(3):209–49. - PubMed
1. Morgan E, Arnold M, Gini A, Lorenzoni V, Cabasag CJ, Laversanne M, et al. Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN. Gut. 2023. Feb;72(2):338–44. - PubMed
1. Petimar J, Smith-Warner SA, Rosner B, Chan AT, Giovannucci EL, Tabung FK. Adherence to The World Cancer Research Fund/American Institute for Cancer Research 2018 Recommendations for Cancer Prevention and Risk of Colorectal Cancer. Cancer Epidemiol Biomark Prev Publ Am Assoc Cancer Res Cosponsored Am Soc Prev Oncol. 2019. Sep;28(9):1469–79. - PMC - PubMed
1. Clinton SK, Giovannucci EL, Hursting SD. The World Cancer Research Fund/American Institute for Cancer Research Third Expert Report on Diet, Nutrition, Physical Activity, and Cancer: Impact and Future Directions. J Nutr. 2020. Apr 1;150(4):663–71. - PMC - PubMed
1. Key TJ. Fruit and vegetables and cancer risk. Br J Cancer. 2011. Jan 4;104(1):6–11. - PMC - PubMed

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This is a preprint.

Red meat intake interacts with a TGF-β-pathway-based polygenic risk score to impact colorectal cancer risk: Application of a novel approach for polygenic risk score construction

Affiliations

Red meat intake interacts with a TGF-β-pathway-based polygenic risk score to impact colorectal cancer risk: Application of a novel approach for polygenic risk score construction

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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