Predicting risk of liver disease progression toward development of lethal complications: sorely needed unmet need
Hepatocellular carcinoma (HCC) is the primary histological type of liver cancer, the fastest rising cause of cancer-related deaths in the United States. HCC develops almost exclusively in livers affected with advanced fibrosis or cirrhosis caused by viral (e.g., hepatitis B virus [HBV] and hepatitis C virus [HCV]) and metabolic (e.g., alcohol-related liver disease [ARLD] and non-alcoholic fatty liver disease [NAFLD]) etiologies. Given the distinctively high HCC incidence (1%-7% per year) in individuals with the chronic liver diseases compared to general population, it is rational to focus on these patients for early tumor detection and preventive intervention. However, the vast size of patient population precludes applying these theoretically most impactful strategies to improve the dismal liver cancer prognosis (5-year survival rate is less than 15%-20%).
Prognostic Liver Signature (PLS)
To overcome the challenge and address the urgent unmet need, we identified a transcriptomic signature in fibrotic liver tissue, Prognostic Liver Signature (PLS), that predicts long-term risk of fibrotic liver disease progression toward development of HCC, liver failure, and death based on up to two decades of clinical follow-up in global liver disease patient populations. PLS is prognostic in the major liver disease etiologies namely HBV, HCV (even after viral cure), ALRD, and NAFLD. In addition, PLS monitors activation HCC-risk-driving molecular pathway that can be antagonized by pharmacological preventive intervention. For example, epidermal growth factor receptor (EGFR) signaling is a molecular hallmark encoded in PLS. A small molecule EGFR inhibitor, erlotinib, is now being tested as an HCC chemoprevention agent in a clinical trial as PLS as companion biomarker (NCT02273362).
Clinical PLS assay
To make the tool available to assist clinical decision making and support conduct of HCC prevention clinical trials, we have implemented PLS in an FDA-approved clinical diagnostic platform (NanoString) and established assay and analysis service. We accept request of assay and analysis from medical professionals and researchers. Please contact us to discuss your plan and samples.
Hepatocellular carcinoma (HCC) is the primary histological type of liver cancer, the fastest rising cause of cancer-related deaths in the United States. HCC develops almost exclusively in livers affected with advanced fibrosis or cirrhosis caused by viral (e.g., hepatitis B virus [HBV] and hepatitis C virus [HCV]) and metabolic (e.g., alcohol-related liver disease [ARLD] and non-alcoholic fatty liver disease [NAFLD]) etiologies. Given the distinctively high HCC incidence (1%-7% per year) in individuals with the chronic liver diseases compared to general population, it is rational to focus on these patients for early tumor detection and preventive intervention. However, the vast size of patient population precludes applying these theoretically most impactful strategies to improve the dismal liver cancer prognosis (5-year survival rate is less than 15%-20%).
Prognostic Liver Signature (PLS)
To overcome the challenge and address the urgent unmet need, we identified a transcriptomic signature in fibrotic liver tissue, Prognostic Liver Signature (PLS), that predicts long-term risk of fibrotic liver disease progression toward development of HCC, liver failure, and death based on up to two decades of clinical follow-up in global liver disease patient populations. PLS is prognostic in the major liver disease etiologies namely HBV, HCV (even after viral cure), ALRD, and NAFLD. In addition, PLS monitors activation HCC-risk-driving molecular pathway that can be antagonized by pharmacological preventive intervention. For example, epidermal growth factor receptor (EGFR) signaling is a molecular hallmark encoded in PLS. A small molecule EGFR inhibitor, erlotinib, is now being tested as an HCC chemoprevention agent in a clinical trial as PLS as companion biomarker (NCT02273362).
Clinical PLS assay
To make the tool available to assist clinical decision making and support conduct of HCC prevention clinical trials, we have implemented PLS in an FDA-approved clinical diagnostic platform (NanoString) and established assay and analysis service. We accept request of assay and analysis from medical professionals and researchers. Please contact us to discuss your plan and samples.
References
1. Lee YT, Fujiwara N, Yang JD, Hoshida Y. Risk stratification and early detection biomarkers for precision hepatocellular carcinoma screening. Hepatology. 2022.
2. Fujiwara N, Kubota N, Crouchet E, et al. Molecular signatures of long-term hepatocellular carcinoma risk in nonalcoholic fatty liver disease. Sci Transl Med. 2022 Jun 22;14(650):eabo4474
3. Fujiwara N, Friedman SL, Goossens N, Hoshida Y. Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. J Hepatol. 2018;68(3):526-549.
4. Qian T, Fujiwara N, Koneru B, et al. Molecular signature predictive of long-term liver fibrosis progression to inform anti-fibrotic drug development. Gastroenterology. 2022.
5. Hoshida Y, Villanueva A, Kobayashi M, et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med. 2008;359(19):1995-2004.
6. Hoshida Y, Villanueva A, Sangiovanni A, et al. Prognostic gene expression signature for patients with hepatitis C-related early-stage cirrhosis. Gastroenterology. 2013;144(5):1024-1030.
7. King LY, Canasto-Chibuque C, Johnson KB, et al. A genomic and clinical prognostic index for hepatitis C-related early-stage cirrhosis that predicts clinical deterioration. Gut. 2015;64(8):1296-1302.
8. Nakagawa S, Wei L, Song WM, et al. Molecular Liver Cancer Prevention in Cirrhosis by Organ Transcriptome Analysis and Lysophosphatidic Acid Pathway Inhibition. Cancer Cell. 2016;30(6):879-890.
9. Ono A, Goossens N, Finn RS, et al. Persisting risk of hepatocellular carcinoma after hepatitis C virus cure monitored by a liver transcriptome signature. Hepatology. 2017;66(4):1344-1346.
Past and current grants
NIH/NCI U01 CA283935, Singal, Hoshida (MPI)
NIH/NCI U01 CA288375, Hoshida, Chung, Moylan, Diehl (MPI)
NIH/NCI R01 CA233794S1, Hoshida (PI)
NIH/NCI R01 CA233794, Hoshida (PI)
CPRIT, RR180016, Hoshida (PI)
CPRIT, RP200554, Singal (PI), Hoshida (co-PI)
NIH/NCI R01 CA212008, Singal (PI)
NIH/NCI U01 CA230694, Singal (PI)
Irma T. Hirschl/Monique Weill-Caulier Scholar Award, Hoshida (PI)
U.S. Department of Defense, W81XWH-16-1-0363, Hoshida (PI)
NIH/NIDDK R01 DK099558, Hoshida (PI)
1. Lee YT, Fujiwara N, Yang JD, Hoshida Y. Risk stratification and early detection biomarkers for precision hepatocellular carcinoma screening. Hepatology. 2022.
2. Fujiwara N, Kubota N, Crouchet E, et al. Molecular signatures of long-term hepatocellular carcinoma risk in nonalcoholic fatty liver disease. Sci Transl Med. 2022 Jun 22;14(650):eabo4474
3. Fujiwara N, Friedman SL, Goossens N, Hoshida Y. Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. J Hepatol. 2018;68(3):526-549.
4. Qian T, Fujiwara N, Koneru B, et al. Molecular signature predictive of long-term liver fibrosis progression to inform anti-fibrotic drug development. Gastroenterology. 2022.
5. Hoshida Y, Villanueva A, Kobayashi M, et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med. 2008;359(19):1995-2004.
6. Hoshida Y, Villanueva A, Sangiovanni A, et al. Prognostic gene expression signature for patients with hepatitis C-related early-stage cirrhosis. Gastroenterology. 2013;144(5):1024-1030.
7. King LY, Canasto-Chibuque C, Johnson KB, et al. A genomic and clinical prognostic index for hepatitis C-related early-stage cirrhosis that predicts clinical deterioration. Gut. 2015;64(8):1296-1302.
8. Nakagawa S, Wei L, Song WM, et al. Molecular Liver Cancer Prevention in Cirrhosis by Organ Transcriptome Analysis and Lysophosphatidic Acid Pathway Inhibition. Cancer Cell. 2016;30(6):879-890.
9. Ono A, Goossens N, Finn RS, et al. Persisting risk of hepatocellular carcinoma after hepatitis C virus cure monitored by a liver transcriptome signature. Hepatology. 2017;66(4):1344-1346.
Past and current grants
NIH/NCI U01 CA283935, Singal, Hoshida (MPI)
NIH/NCI U01 CA288375, Hoshida, Chung, Moylan, Diehl (MPI)
NIH/NCI R01 CA233794S1, Hoshida (PI)
NIH/NCI R01 CA233794, Hoshida (PI)
CPRIT, RR180016, Hoshida (PI)
CPRIT, RP200554, Singal (PI), Hoshida (co-PI)
NIH/NCI R01 CA212008, Singal (PI)
NIH/NCI U01 CA230694, Singal (PI)
Irma T. Hirschl/Monique Weill-Caulier Scholar Award, Hoshida (PI)
U.S. Department of Defense, W81XWH-16-1-0363, Hoshida (PI)
NIH/NIDDK R01 DK099558, Hoshida (PI)