Program Official

Principal Investigator

Awardee Organization

Baylor College Of Medicine
United States

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

Risk Stratification for and Early Detection of Liver Cancer

The Translational Research Center (TRC) includes a multidisciplinary team of clinical and translational researchers that has a strong track record of collaborative work, with the collective mission of reducing the burden of HCC. At the center of the proposed TRC lie two unique active prospective (in-HCC surveillance) cohorts of patients with cirrhosis. One of the cohorts comes from a Cancer Prevention and Research Institute of Texas (CPRIT) funded ongoing prospective multicenter study (Texas HCC Consortium) that is on target to recruit > 3000 patients with cirrhosis (>12,000 surveillance episodes and 200 expected HCC cases) from diverse etiologies (including cured HCV and non-alcoholic fatty liver disease). These patients are under routine bi-annual surveillance at 5 medical centers in Texas. The second is a cohort of >700 patients (>1,300 visits surveillance episodes and 33 incident HCC cases as of September 2017) recruited from and prospectively followed at the Houston VA, most with cured HCV. The TRC will leverage, extend follow up, and harmonize data and samples from both cohorts, collectively resulting in a > 23,000 episodes of HCC surveillance (and > 300 expected HCC) with bio-banked specimens, clinical and radiological data for each episode, rendering it an invaluable resource for the proposed research and other trans-consortium projects. Using data from these cohorts, we will develop and test novel personalized risk stratification indices for predicting the future ‐ development to HCC in patients with cirrhosis across diverse etiologies (Aim 1). We will also develop and evaluate an early detection algorithm that combines existing HCC blood based biomarkers (e.g., AFP, AFP L3, DCP), their longitudinal changes over time and select host features (age, etiology) in a phase 3 study. We will also examine the performance of this algorithm in patients at different HCC risk strata (Aim 2). Our work will set the framework for incorporating other patient and liver disease related factors into (new) biomarker profiles, an area that is likely to remain highly relevant irrespective of the type of biomarker. We will evaluate highly promising methylated DNA markers (MDMs, liquid biopsy) as an independent test for HCC risk prediction in Aim 3. These markers have been identified in tissue case control phase 1 studies, reliable assays have been developed and they have excellent performance for HCC detection in phase 2 studies. We will validate individual markers in the study cohort and train an algorithm that combines the MDM to achieve maximum performance. In a phase 3 biomarker study, we will validate the algorithm in the test sample overall and in key subgroups based on HCC risk strata. Our approach (optimizing available markers while simultaneously maintaining a strong forward outlook) will have both an immediate and long-lasting impact on HCC related morbidity and mortality. The TRC will build on established and strong infra-structure and relationships to complete the proposed research. It also represents a new and exciting avenue for collaboration with other investigators within the U01 consortium.


  • Benhammou JN, Rich NE, Cholankeril G, Zhang P, Zeng W, Rao S, Tayob N, National Cancer Institute’s Translational Liver Consortium Early-Career Working Group, Li W, Wu X, Feng S, Fujiwara N, Meng X, Zhu S, Zaidi S. DETECT: Development of Technologies for Early HCC Detection. Gastroenterology. 2022 Jul;163(1):21-27. Epub 2022 Mar 23. PMID: 35339460
  • Natarajan Y, Kramer JR, Yu X, Li L, Thrift AP, El-Serag HB, Kanwal F. Risk of Cirrhosis and Hepatocellular Cancer in Patients With NAFLD and Normal Liver Enzymes. Hepatology (Baltimore, Md.). 2020 Oct;72(4):1242-1252. PMID: 32022277
  • Keeling SS, McDonald MF, Anand A, Handing GE, Prather LL, Christmann CR, Jalal PK, Kanwal F, Cholankeril G, Goss JA, Rana A. Significant improvements, but consistent disparities in survival for African Americans after liver transplantation. Clinical transplantation. 2022 Jun;36(6):e14646. Epub 2022 Mar 25. PMID: 35304775
  • Kanwal F, Shubrook JH, Adams LA, Pfotenhauer K, Wai-Sun Wong V, Wright E, Abdelmalek MF, Harrison SA, Loomba R, Mantzoros CS, Bugianesi E, Eckel RH, Kaplan LM, El-Serag HB, Cusi K. Clinical Care Pathway for the Risk Stratification and Management of Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology. 2021 Nov;161(5):1657-1669. Epub 2021 Sep 20. PMID: 34602251
  • Kim HS, Xiao X, Byun J, Jun G, DeSantis SM, Chen H, Thrift AP, El-Serag HB, Kanwal F, Amos CI. Synergistic Associations of PNPLA3 I148M Variant, Alcohol Intake, and Obesity With Risk of Cirrhosis, Hepatocellular Carcinoma, and Mortality. JAMA network open. 2022 Oct 3;5(10):e2234221. PMID: 36190732
  • Kramer JR, Cao Y, Li L, Smith D, Chhatwal J, El-Serag HB, Kanwal F. Longitudinal Associations of Risk Factors and Hepatocellular Carcinoma in Patients With Cured Hepatitis C Virus Infection. The American journal of gastroenterology. 2022 Nov 1;117(11):1834-1844. Epub 2022 Aug 23. PMID: 36327437
  • Kramer JR, Natarajan Y, Dai J, Yu X, Li L, El-Serag HB, Kanwal F. Effect of diabetes medications and glycemic control on risk of hepatocellular cancer in patients with nonalcoholic fatty liver disease. Hepatology (Baltimore, Md.). 2022 Jun;75(6):1420-1428. Epub 2021 Dec 19. PMID: 34779535
  • Zhang J, Ning J, Huang X, Li R. On the time-varying predictive performance of longitudinal biomarkers: Measure and estimation. Statistics in medicine. 2021 Oct 15;40(23):5065-5077. Epub 2021 Jun 22. PMID: 34159633
  • Kanwal F, Khaderi S, Singal AG, Marrero JA, Loo N, Asrani SK, Amos CI, Thrift AP, Gu X, Luster M, Al-Sarraj A, Ning J, El-Serag HB. Risk factors for HCC in contemporary cohorts of patients with cirrhosis. Hepatology (Baltimore, Md.). 2023 Mar 1;77(3):997-1005. Epub 2023 Feb 17. PMID: 35229329
  • Singal AG, El-Serag HB. Rational HCC screening approaches for patients with NAFLD. Journal of hepatology. 2022 Jan;76(1):195-201. Epub 2021 Sep 9. PMID: 34508791
  • Kanwal F, Singal AG. Surveillance for Hepatocellular Carcinoma: Current Best Practice and Future Direction. Gastroenterology. 2019 Jul;157(1):54-64. Epub 2019 Apr 12. PMID: 30986389
  • Wai-Sun Wong V, Kanwal F. On the Proposed Definition of Metabolic-Associated Fatty Liver Disease. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2021 May;19(5):865-870. Epub 2021 Jan 13. PMID: 33453398
  • Jacob JS, Shaikh A, Goli K, Rich NE, Benhammou JN, Ahmed A, Kim D, Rana A, Goss JA, Naggie S, Lee TH, Kanwal F, Cholankeril G. Improved Survival After Liver Transplantation for Patients With Human Immunodeficiency Virus (HIV) and HIV/Hepatitis C Virus Coinfection in the Integrase Strand Transfer Inhibitor and Direct-Acting Antiviral Eras. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2023 Feb 18;76(4):592-599. PMID: 36221143
  • Lymberopoulos P, Shaikh A, Rich NE, Benhammou JN, Kanwal F, Cholankeril G. Comparable Survival for Hepatitis C-Related Hepatocellular Carcinoma After Liver Transplantation Irrespective of Viremic Status. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2023 May;21(5):1362-1364.e1. Epub 2022 Mar 26. PMID: 35346850
  • El-Serag HB, Kanwal F, Feng Z, Marrero JA, Khaderi S, Singal AG, Texas Hepatocellular Carcinoma Consortium. Risk Factors for Cirrhosis in Contemporary Hepatology Practices-Findings From the Texas Hepatocellular Carcinoma Consortium Cohort. Gastroenterology. 2020 Jul;159(1):376-377. Epub 2020 Mar 29. PMID: 32234536
  • Cholankeril G, Kanwal F. NAFLD and HCC: Time to Bridge the Gap. Hepatology (Baltimore, Md.). 2021 Nov;74(5):2336-2338. Epub 2021 Aug 30. PMID: 34164841
  • Tayob N, Kanwal F, Alsarraj A, Hernaez R, El-Serag HB. The Performance of AFP, AFP-3, DCP as Biomarkers for Detection of Hepatocellular Carcinoma (HCC): A Phase 3 Biomarker Study in the United States. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2023 Feb;21(2):415-423.e4. Epub 2022 Feb 3. PMID: 35124267
  • Chen Q, Ayer T, Adee MG, Wang X, Kanwal F, Chhatwal J. Assessment of Incidence of and Surveillance Burden for Hepatocellular Carcinoma Among Patients With Hepatitis C in the Era of Direct-Acting Antiviral Agents. JAMA network open. 2020 Nov 2;3(11):e2021173. PMID: 33206188
  • Shaikh A, Goli K, Rich NE, Benhammou JN, Khaderi S, Hernaez R, Agopian VG, Vierling JM, Kim D, Ahmed A, Goss JA, Rana A, Kanwal F, Cholankeril G. Early Impact of MMaT-3 Policy on Liver Transplant Waitlist Outcomes for Hepatocellular Carcinoma. Transplantation direct. 2022 Apr 12;8(5):e1313. doi: 10.1097/TXD.0000000000001313. eCollection 2022 May. PMID: 35434283
  • Lymberopoulos P, Prakash S, Shaikh A, Bhatnagar A, Allam AK, Goli K, Goss JA, Kanwal F, Rana A, Kowdley KV, Jalal P, George Cholankeril. Long-term outcomes and trends in liver transplantation for hereditary hemochromatosis in the United States. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2023 Jan 1;29(1):15-25. Epub 2022 Jul 21. PMID: 35770428
  • Parikh ND, Tayob N, Al-Jarrah T, Kramer J, Melcher J, Smith D, Marquardt P, Liu PH, Tang R, Kanwal F, Singal AG. Barriers to Surveillance for Hepatocellular Carcinoma in a Multicenter Cohort. JAMA network open. 2022 Jul 1;5(7):e2223504. PMID: 35867057
  • Goff C, Shaikh A, Goli K, El-Serag HB, Kanwal F, Cholankeril G, Collaborators from Liver Cancer Investigator Working Group, Rana A, Aloor FZ, Cholankeril R, Rich NE, Benhammou JN, Kim D, Ahmed A, Goss J. Contemporary Changes in Etiology for Hepatocellular Carcinoma in Liver Transplantation. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2022 Jul 20. Epub 2022 Jul 20. PMID: 35870770
  • Chu J, Cholankeril G, Yu X, Rana A, Natarajan Y, El-Serag HB, Kramer J, Kanwal F. Clinical Course and Outcomes of Patients with Nonalcoholic Fatty Liver Disease-Related Hepatocellular Cancer (NAFLD-HCC). Digestive diseases and sciences. 2023 Mar;68(3):1060-1070. Epub 2022 Jun 27. PMID: 35759159
  • Kanneganti M, Marrero JA, Parikh ND, Kanwal F, Yokoo T, Mendiratta-Lala M, Rich NE, Gopal P, Singal AG. Clinical outcomes of patients with Liver Imaging Reporting and Data System 3 or Liver Imaging Reporting and Data System 4 observations in patients with cirrhosis: A systematic review. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. 2022 Dec;28(12):1865-1875. Epub 2022 Sep 5. PMID: 35980600
  • Kim HS, Yu X, Kramer J, Thrift AP, Richardson P, Hsu YC, Flores A, El-Serag HB, Kanwal F. Comparative performance of risk prediction models for hepatitis B-related hepatocellular carcinoma in the United States. Journal of hepatology. 2022 Feb;76(2):294-301. Epub 2021 Sep 23. PMID: 34563579
  • Singal AG, Lok AS, Feng Z, Kanwal F, Parikh ND. Conceptual Model for the Hepatocellular Carcinoma Screening Continuum: Current Status and Research Agenda. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2022 Jan;20(1):9-18. Epub 2020 Sep 19. PMID: 32961340
  • Cholankeril G, Kramer JR, Chu J, Yu X, Balakrishnan M, Li L, El-Serag HB, Kanwal F. Longitudinal changes in fibrosis markers are associated with risk of cirrhosis and hepatocellular carcinoma in non-alcoholic fatty liver disease. Journal of hepatology. 2023 Mar;78(3):493-500. Epub 2022 Nov 17. PMID: 36402450
  • Cholankeril G, El-Serag HB. Current Challenges and Future Direction in Surveillance for Hepatocellular Carcinoma in Patients with Nonalcoholic Fatty Liver Disease. Seminars in liver disease. 2023 Feb;43(1):89-99. Epub 2022 Oct 10. PMID: 36216350
  • Thrift AP, Kanwal F, Liu Y, Khaderi S, Singal AG, Marrero JA, Loo N, Asrani SK, Luster M, Al-Sarraj A, Ning J, Tsavachidis S, Gu X, Amos CI, El-Serag HB. Risk stratification for hepatocellular cancer among patients with cirrhosis using a hepatic fat polygenic risk score. PloS one. 2023 Feb 28;18(2):e0282309. doi: 10.1371/journal.pone.0282309. eCollection 2023. PMID: 36854015