Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer

David A Drew^{1

2}, Andre E Kim³, Yi Lin⁴, Conghui Qu⁴, John Morrison³, Juan Pablo Lewinger³, Eric Kawaguchi³, Jun Wang⁵, Yubo Fu³, Natalia Zemlianskaia³, Virginia Díez-Obrero^{6

7

8}, Stephanie A Bien⁴, Niki Dimou⁹, Demetrius Albanes¹⁰, James W Baurley^{11

12}, Anna H Wu⁵, Daniel D Buchanan^{13

14

15}, John D Potter^{4

16}, Ross L Prentice⁴, Sophia Harlid¹⁷, Volker Arndt¹⁸, Elizabeth L Barry¹⁹, Sonja I Berndt¹⁰, Emmanouil Bouras²⁰, Hermann Brenner^{18

21

22}, Arif Budiarto¹¹, Andrea Burnett-Hartman²³, Peter T Campbell²⁴, Robert Carreras-Torres^{6

25}, Graham Casey²⁶, Jenny Chang-Claude^{27

28}, David V Conti³, Matthew A M Devall²⁹, Jane C Figueiredo^{3

30}, Stephen B Gruber^{31

32}, Andrea Gsur³³, Marc J Gunter^{9

34}, Tabitha A Harrison⁴, Akihisa Hidaka⁴, Michael Hoffmeister¹⁸, Jeroen R Huyghe⁴, Mark A Jenkins³⁵, Kristina M Jordahl^{4

36}, Anshul Kundaje^{37

38}, Loic Le Marchand³⁹, Li Li^{29

40}, Brigid M Lynch^{35

41}, Neil Murphy⁹, Rami Nassir⁴², Polly A Newcomb^{4

43}, Christina C Newton⁴⁴, Mireia Obón-Santacana^{6

45

46}, Shuji Ogino^{47

48

49

50}, Jennifer Ose^{51

52}, Rish K Pai⁵³, Julie R Palmer⁵⁴, Nikos Papadimitriou⁹, Bens Pardamean¹¹, Andrew J Pellatt⁵⁵, Anita R Peoples^{51

52}, Elizabeth A Platz⁵⁶, Gad Rennert^{57

58

59}, Edward Ruiz-Narvaez⁶⁰, Lori C Sakoda^{4

61}, Peter C Scacheri⁶², Stephanie L Schmit^{63

64}, Robert E Schoen⁶⁵, Mariana C Stern⁵, Yu-Ru Su⁶⁶, Duncan C Thomas³, Yu Tian^{27

67}, Konstantinos K Tsilidis^{34

68}, Cornelia M Ulrich^{51

52}, Caroline Y Um⁴⁴, Fränzel J B van Duijnhoven⁶⁹, Bethany Van Guelpen^{17

70}, Emily White^{4

36}, Li Hsu^{4

71}, Victor Moreno^{6

45

46

72}, Ulrike Peters^{4

36}, Andrew T Chan^{1

2}, W James Gauderman³

Affiliations

¹ Clinical & Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
² Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
³ Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁴ Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
⁵ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
⁶ Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
⁷ Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
⁸ Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
⁹ Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France.
¹⁰ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
¹¹ Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia.
¹² BioRealm LLC, Walnut, CA, USA.
¹³ Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010 Australia.
¹⁴ University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010 Australia.
¹⁵ Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
¹⁶ Research Centre for Hauora and Health, Massey University, Wellington, New Zealand.
¹⁷ Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
¹⁸ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁹ Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
²⁰ Laboratory of Hygiene, Social & Preventive Medicine and Medical Statistics, Department of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.
²¹ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
²² German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
²³ Institute for Health Research, Kaiser Permanente Colorado, Denver, CO, USA.
²⁴ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
²⁵ Digestive Diseases and Microbiota Group, Girona Biomedical Research Institute (IDIBGI), Salt, 17190 Girona, Spain.
²⁶ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
²⁷ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁸ University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany.
²⁹ Department of Family Medicine, University of Virginia, Charlottesville, VA, USA.
³⁰ Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³¹ Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA.
³² Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, USA.
³³ Center for Cancer Research, Medical University Vienna, Vienna, Austria.
³⁴ Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, UK.
³⁵ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
³⁶ Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
³⁷ Department of Genetics, Stanford University, Stanford, CA, USA.
³⁸ Department of Computer Science, Stanford University, Stanford, CA, USA.
³⁹ University of Hawaii Cancer Center, Honolulu, HI, USA.
⁴⁰ UVA Comprehensive Cancer Center, Charlottesville, VA, USA.
⁴¹ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
⁴² Department of Pathology, School of Medicine, Umm Al-Qura University, Mecca, Saudi Arabia.
⁴³ School of Public Health, University of Washington, Seattle, WA, USA.
⁴⁴ Department of Population Science, American Cancer Society, Atlanta, GA, USA.
⁴⁵ Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, 08908 Barcelona, Spain.
⁴⁶ Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain.
⁴⁷ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
⁴⁸ Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
⁴⁹ Harvard Medical School, Boston, MA, USA.
⁵⁰ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵¹ Huntsman Cancer Institute, Salt Lake City, UT, USA.
⁵² Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
⁵³ Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, AZ, USA.
⁵⁴ Slone Epidemiology Center at Boston University, Boston, MA, USA.
⁵⁵ Department of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁵⁶ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁵⁷ Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
⁵⁸ Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
⁵⁹ Clalit National Cancer Control Center, Haifa, Israel.
⁶⁰ Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁶¹ Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
⁶² Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
⁶³ Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
⁶⁴ Population and Cancer Prevention Program, Case Comprehensive Cancer Center, Cleveland, OH, USA.
⁶⁵ Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
⁶⁶ Biostatistics Division, Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
⁶⁷ School of Public Health, Capital Medical University, Beijing, China.
⁶⁸ Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
⁶⁹ Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, Netherlands.
⁷⁰ Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
⁷¹ Department of Biostatistics, University of Washington, Seattle, WA, USA.
⁷² 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.

PMID: 38809988
PMCID: PMC11135391
DOI: 10.1126/sciadv.adk3121

Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer

David A Drew et al. Sci Adv. 2024.

. 2024 May 31;10(22):eadk3121.

doi: 10.1126/sciadv.adk3121. Epub 2024 May 29.

Authors

Affiliations

¹ Clinical & Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
² Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
³ Division of Biostatistics, Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁴ Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA.
⁵ Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
⁶ Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
⁷ Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Madrid, Spain.
⁸ Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain.
⁹ Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France.
¹⁰ Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
¹¹ Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia.
¹² BioRealm LLC, Walnut, CA, USA.
¹³ Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010 Australia.
¹⁴ University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010 Australia.
¹⁵ Genomic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia.
¹⁶ Research Centre for Hauora and Health, Massey University, Wellington, New Zealand.
¹⁷ Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
¹⁸ Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁹ Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
²⁰ Laboratory of Hygiene, Social & Preventive Medicine and Medical Statistics, Department of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.
²¹ Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
²² German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
²³ Institute for Health Research, Kaiser Permanente Colorado, Denver, CO, USA.
²⁴ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
²⁵ Digestive Diseases and Microbiota Group, Girona Biomedical Research Institute (IDIBGI), Salt, 17190 Girona, Spain.
²⁶ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
²⁷ Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
²⁸ University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany.
²⁹ Department of Family Medicine, University of Virginia, Charlottesville, VA, USA.
³⁰ Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
³¹ Department of Medical Oncology & Therapeutics Research, City of Hope National Medical Center, Duarte, CA, USA.
³² Center for Precision Medicine, City of Hope National Medical Center, Duarte, CA, USA.
³³ Center for Cancer Research, Medical University Vienna, Vienna, Austria.
³⁴ Department of Epidemiology and Biostatistics, Imperial College London, School of Public Health, London, UK.
³⁵ Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
³⁶ Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA.
³⁷ Department of Genetics, Stanford University, Stanford, CA, USA.
³⁸ Department of Computer Science, Stanford University, Stanford, CA, USA.
³⁹ University of Hawaii Cancer Center, Honolulu, HI, USA.
⁴⁰ UVA Comprehensive Cancer Center, Charlottesville, VA, USA.
⁴¹ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
⁴² Department of Pathology, School of Medicine, Umm Al-Qura University, Mecca, Saudi Arabia.
⁴³ School of Public Health, University of Washington, Seattle, WA, USA.
⁴⁴ Department of Population Science, American Cancer Society, Atlanta, GA, USA.
⁴⁵ Unit of Biomarkers and Susceptibility (UBS), Oncology Data Analytics Program (ODAP), Catalan Institute of Oncology (ICO), L'Hospitalet del Llobregat, 08908 Barcelona, Spain.
⁴⁶ Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), 28029 Madrid, Spain.
⁴⁷ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
⁴⁸ Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
⁴⁹ Harvard Medical School, Boston, MA, USA.
⁵⁰ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵¹ Huntsman Cancer Institute, Salt Lake City, UT, USA.
⁵² Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
⁵³ Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, AZ, USA.
⁵⁴ Slone Epidemiology Center at Boston University, Boston, MA, USA.
⁵⁵ Department of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁵⁶ Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
⁵⁷ Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
⁵⁸ Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
⁵⁹ Clalit National Cancer Control Center, Haifa, Israel.
⁶⁰ Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA.
⁶¹ Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
⁶² Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
⁶³ Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
⁶⁴ Population and Cancer Prevention Program, Case Comprehensive Cancer Center, Cleveland, OH, USA.
⁶⁵ Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
⁶⁶ Biostatistics Division, Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
⁶⁷ School of Public Health, Capital Medical University, Beijing, China.
⁶⁸ Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
⁶⁹ Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, Netherlands.
⁷⁰ Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden.
⁷¹ Department of Biostatistics, University of Washington, Seattle, WA, USA.
⁷² 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.

PMID: 38809988
PMCID: PMC11135391
DOI: 10.1126/sciadv.adk3121

Abstract

Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.

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Figures

**Fig. 1.. Association of regular aspirin/NSAID use with CRC according to sex and tumor location.**
Results from meta-analysis of association between regular use of (A) aspirin/NSAID or (B) aspirin-only and colorectal cancer, overall and stratified by sex and tumor site. Models adjusted for age and sex. Heterogeneity measures include Cochran’s Q statistic p-value (P_het) and Higgin’s statistic (I²), which describes the proportion of observed variance due to heterogeneity and not attributed to sampling error.

**Fig. 2.. Manhattan plots of genome-wide interaction scans.**
(A) traditional logistic regression interaction test (1-df) for aspirin/NSAID (B) traditional logistic regression interaction test (1-df) for aspirin-only, (C) 3-df joint test for aspirin/NSAID, and (D) 3-df joint test for aspirin-only. Red line represents a genome-wide significance threshold of 5 × 10⁻⁸/2.5 after adjustment for multiple testing.

**Fig. 3.. Forest plots of GxE interactions for identified SNPs and aspirin/NSAID and risk of CRC stratified by tumor molecular subtypes.**
ORs (dots) and 95% CIs (error bars) are plotted for each case stratified by the presence (*BRAF* mutant; CIMP-high; MSI-high; *KRA*S mutant) or absence (*BRAF* wild type; CIMP-low/negative; Non-MSI-high; *KRAS* wild type) of the marker in cases versus controls (referent) for each identified SNP: (A) *rs72833769* and (B) *rs350047*. The P value for heterogeneity (P_het) between estimates for cases with the molecular marker present versus absent and the overall association of the interaction for cases with molecular marker data versus controls is also provided.

See this image and copyright information in PMC

References

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Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer

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Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer

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