Principal Investigator

Awardee Organization

University Of Chicago
United States

Fiscal Year
Activity Code
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Colonic responses to vitamin D and aspirin in African- and European-Americans

African Americans (AA) have the greatest burden of colorectal cancer (CRC) in the US, and biological reasons for this disparity remain incompletely understood. Interactions between host and environmental factors, including chemopreventive treatments, are known to modify CRC risk, and there is emerging evidence of differences in treatment effects between AA and European Americans (EA) for the two most promising chemopreventive agents, vitamin D and aspirin. Our broad objective is to model and understand how interethnic differences in treatment responses could contribute to CRC disparities. Our laboratory has optimized stem cell-derived human organoid cultures to study cellular responses between individuals that have not been feasible using traditional models. In this proposal, we use colonic organoids to test the central hypothesis that transcriptional, chromatin accessibility and cellular responses to vitamin D and/or aspirin differ between AA and EA, and that these inter-ethnic differences could impact CRC risk and clinical treatment response. We previously treated ex vivo primary colon tissue from AA and EA with active vitamin D (1,25D) and identified several genes with inter-ethnic response differences. The success of finding genes with inter-ethnic response differences provides rationale for extending our genome-wide approach to 1,25D, aspirin and combination treatments in a larger sample size of colonic organoids (80 AA & 80 EA) to achieve greater power to identify inter-ethnic differences in transcriptional networks as well as chromatin accessibility. We will replicate observed differences in an independent cohort of organoids as well as test for cancer-relevant cellular treatment phenotypes in a subset of treated organoids (50 AA & 50 EA) (Aim 1). Further, using RNA-seq data obtained in Aim 1, we will test for a genetic contribution to response differences between individuals and ethnicities using allele specific expression. The response genes and SNPs identified will be tested for enrichment among genes and SNPs from NIH-funded CRC GWAS and chemoprevention trials as well as tested mechanistically using functional assays (Aim 2). The outcomes of our innovative study will: i) elucidate underlying biology and genetic architecture of responses to vitamin D and aspirin in the colon and how they differ by ethnicity, ii) connect cellular response with CRC risk and response to chemoprevention, and iii) identify genes and SNPs for mechanistic studies as well as for possible development as novel biomarkers for personalized CRC prevention in order to, ultimately, reduce CRC disparities.


  • Muller C, Ihionkhan E, Stoffel EM, Kupfer SS. Disparities in Early-Onset Colorectal Cancer. Cells. 2021 Apr 26;10. (5). PMID: 33925893
  • Bhasin N, Alleyne D, Gray OA, Kupfer SS. Vitamin D Regulation of the Uridine Phosphorylase 1 Gene and Uridine-Induced DNA Damage in Colon in African Americans and European Americans. Gastroenterology. 2018 Oct;155(4):1192-1204.e9. Epub 2018 Jun 30. PMID: 29964038
  • Gupta N, Kupfer SS, Davis AM. Colorectal Cancer Screening. JAMA. 2019 May 28;321(20):2022-2023. PMID: 31021387
  • Dougherty U, Mustafi R, Zhu H, Zhu X, Deb D, Meredith SC, Ayaloglu-Butun F, Fletcher M, Sanchez A, Pekow J, Deng Z, Amini N, Konda VJ, Rao VL, Sakuraba A, Kwesi A, Kupfer SS, Fichera A, Joseph L, Hart J, He F, He TC, West-Szymanski D, Li YC, Bissonnette M. Upregulation of polycistronic microRNA-143 and microRNA-145 in colonocytes suppresses colitis and inflammation-associated colon cancer. Epigenetics. 2021 Dec;16(12):1317-1334. Epub 2020 Dec 28. PMID: 33356812
  • Gupta N, Drogan C, Kupfer SS. How many is too many? Polyposis syndromes and what to do next. Current opinion in gastroenterology. 2022 Jan 1;38(1):39-47. PMID: 34839308
  • Li J, Witonsky D, Sprague E, Alleyne D, Bielski MC, Lawrence KM, Kupfer SS. Genomic and epigenomic active vitamin D responses in human colonic organoids. Physiological genomics. 2021 Jun 1;53(6):235-248. Epub 2021 Apr 26. PMID: 33900108
  • Wick M, Gross CC, Tumani H, Wildemann B, Stangel M, On Behalf Of The German Society Of Csf Diagnostics And Clinical Neurochemistry Dgln E V. Automated Analysis of Cerebrospinal Fluid Cells Using Commercially Available Blood Cell Analysis Devices-A Critical Appraisal. Cells. 2021 May 18;10. (5). PMID: 34069775
  • Stoll J, Kupfer SS. Risk Assessment and Genetic Testing for Inherited Gastrointestinal Syndromes. Gastroenterology & hepatology. 2019 Sep;15(9):462-470. PMID: 31787853
  • Heald B, Hampel H, Church J, Dudley B, Hall MJ, Mork ME, Singh A, Stoffel E, Stoll J, You YN, Yurgelun MB, Kupfer SS, Collaborative Group of the Americas on Inherited Gastrointestinal Cancer. Collaborative Group of the Americas on Inherited Gastrointestinal Cancer Position statement on multigene panel testing for patients with colorectal cancer and/or polyposis. Familial cancer. 2020 Jul;19(3):223-239. PMID: 32172433
  • Muller C, Nielsen SM, Hatchell KE, Yang S, Michalski ST, Hamlington B, Nussbaum RL, Esplin ED, Kupfer SS. Underdiagnosis of Hereditary Colorectal Cancers Among Medicare Patients: Genetic Testing Criteria for Lynch Syndrome Miss the Mark. JCO precision oncology. 2021 Jul 1;5. doi: 10.1200/PO.21.00132. eCollection 2021. PMID: 34585040
  • Kupfer SS, Burke CA. Patients in Whom to Consider Genetic Evaluation and Testing for Hereditary Colorectal Cancer Syndromes. The American journal of gastroenterology. 2020 Jan;115(1):1-4. PMID: 31634263
  • Tjaden J, Muller C, Wideroff G, Ma K, Satiya J, Sussman D, Yen E, Kupfer SS, Melson J. Metachronous Advanced Neoplasia on Surveillance Colonoscopy in Patients With Young- vs Older-onset of Colorectal Cancer. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2021 Sep;19(9):1967-1969. Epub 2019 Jul 24. PMID: 31351134
  • Muller C, Yurgelun M, Kupfer SS. Precision Treatment and Prevention of Colorectal Cancer-Hope or Hype? Gastroenterology. 2020 Jan;158(2):441-446. Epub 2019 Oct 14. PMID: 31622623
  • Witonsky D, Bielski MC, Li J, Lawrence KM, Mendoza IN, Usman H, Kupfer SS. Genomic and epigenomic responses to aspirin in human colonic organoids. Physiological genomics. 2023 Mar 1;55(3):101-112. Epub 2023 Jan 16. PMID: 36645669
  • Kupfer SS, Gupta S, Weitzel JN, Samadder J. AGA Clinical Practice Update on Colorectal and Pancreatic Cancer Risk and Screening in BRCA1 and BRCA2 Carriers: Commentary. Gastroenterology. 2020 Aug;159(2):760-764. Epub 2020 Apr 23. PMID: 32335146
  • Faust N, Muller C, Prenner J, Lee SM, Kupfer SS. Low Rates of Genetic Counseling and Testing in Individuals at Risk for Lynch Syndrome Reported in the National Health Interview Survey. Gastroenterology. 2020 Mar;158(4):1159-1161. Epub 2019 Dec 6. PMID: 31816299
  • Xicola RM, Clark JR, Carroll T, Alvikas J, Marwaha P, Regan MR, Lopez-Giraldez F, Choi J, Emmadi R, Alagiozian-Angelova V, Kupfer SS, Ellis NA, Llor X. Implication of DNA repair genes in Lynch-like syndrome. Familial cancer. 2019 Jul;18(3):331-342. PMID: 30989425
  • Muller C, Matthews L, Kupfer SS, Weiss JM. Effective Identification of Lynch Syndrome in Gastroenterology Practice. Current treatment options in gastroenterology. 2019 Dec;17(4):666-680. PMID: 31677041
  • Farah F, Patel SG, Espinoza JM, Jensen N, Katona BW, Muller C, Kupfer SS, Weiss JM, Hinton A, Stanich PP. Yield of upper gastrointestinal screening in colonic adenomatous polyposis of unknown etiology: a multicenter study. Endoscopy international open. 2022 Apr 14;10(4):E528-E533. doi: 10.1055/a-1784-0166. eCollection 2022 Apr. PMID: 35433207
  • Kupfer SS. Block, Blood, or Both? Outcomes, Opportunities, and Barriers in Colorectal Cancer Universal Testing. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2022 Mar;20(3):e354-e356. Epub 2021 Jun 2. PMID: 34089853
  • Kastrinos F, Kupfer SS, Gupta S. Colorectal Cancer Risk Assessment and Precision Approaches to Screening: Brave New World or Worlds Apart? Gastroenterology. 2023 Apr;164(5):812-827. Epub 2023 Feb 24. PMID: 36841490