Display options
Cite
Fujiwara N, Kobayashi M, Fobar AJ, et al. A blood-based prognostic liver secretome signature and long-term hepatocellular carcinoma risk in advanced liver fibrosis. Med (N Y). 2021;2(7):836-850.e10doi: 10.1016/j.medj.2021.03.017.
Fujiwara, N., Kobayashi, M., Fobar, A. J., Hoshida, A., Marquez, C. A., Koneru, B., Panda, G., Taguri, M., Qian, T., Raman, I., Li, Q. Z., Hoshida, H., Sezaki, H., Kumada, H., Tateishi, R., Yokoo, T., Yopp, A. C., Chung, R. T., Fuchs, B. C., Baumert, T. F., Marrero, J. A., Parikh, N. D., Zhu, S., Singal, A. G., & Hoshida, Y. (2021). A blood-based prognostic liver secretome signature and long-term hepatocellular carcinoma risk in advanced liver fibrosis. Med (New York, N.Y.), 2(7), 836-850.e10. https://doi.org/10.1016/j.medj.2021.03.017
Fujiwara, Naoto, et al. "A blood-based prognostic liver secretome signature and long-term hepatocellular carcinoma risk in advanced liver fibrosis." Med (New York, N.Y.) vol. 2,7 (2021): 836-850.e10. doi: https://doi.org/10.1016/j.medj.2021.03.017
Fujiwara N, Kobayashi M, Fobar AJ, Hoshida A, Marquez CA, Koneru B, Panda G, Taguri M, Qian T, Raman I, Li QZ, Hoshida H, Sezaki H, Kumada H, Tateishi R, Yokoo T, Yopp AC, Chung RT, Fuchs BC, Baumert TF, Marrero JA, Parikh ND, Zhu S, Singal AG, Hoshida Y. A blood-based prognostic liver secretome signature and long-term hepatocellular carcinoma risk in advanced liver fibrosis. Med (N Y). 2021 Jul 09;2(7):836-850.e10. doi: 10.1016/j.medj.2021.03.017. Epub 2021 Apr 21. PMID: 34318286; PMCID: PMC8312635.
Copy Download .nbib Format: NLM
Share it on

Med (N Y). 2021 Jul 09;2(7):836-850.e10. doi: 10.1016/j.medj.2021.03.017. Epub 2021 Apr 21.

A blood-based prognostic liver secretome signature and long-term hepatocellular carcinoma risk in advanced liver fibrosis.

Med (New York, N.Y.)

Naoto Fujiwara, Masahiro Kobayashi, Austin J Fobar, Ayaka Hoshida, Cesia A Marquez, Bhuvaneswari Koneru, Gayatri Panda, Masataka Taguri, Tongqi Qian, Indu Raman, Quan-Zhen Li, Hiroki Hoshida, Hitomi Sezaki, Hiromitsu Kumada, Ryosuke Tateishi, Takeshi Yokoo, Adam C Yopp, Raymond T Chung, Bryan C Fuchs, Thomas F Baumert, Jorge A Marrero, Neehar D Parikh, Shijia Zhu, Amit G Singal, Yujin Hoshida

Affiliations

  1. Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390, U.S.
  2. Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
  3. Department of Hepatology, Toranomon Hospital, Tokyo, 105-8470, Japan.
  4. Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, 48109, U.S.
  5. Department of Data Science, School of Data Science, Yokohama City University, Kanagawa, 236-0027, Japan.
  6. Microarray Core Facility, Department of Immunology, BioCenter, University of Texas Southwestern Medical Center, Dallas, TX, 75390, U.S.
  7. Department of Radiology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, U.S.
  8. Division of Surgical Oncology, Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX, 75390, U.S.
  9. Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, U.S.
  10. Division of Surgical Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, U.S.
  11. Ferring Pharmaceuticals, San Diego, CA, 92121, U.S.
  12. Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, University of Strasbourg and IHU, Pole Hépato-digestif, Strasbourg University Hospitals, Strasbourg, 67200, France.

PMID: 34318286 PMCID: PMC8312635 DOI: 10.1016/j.medj.2021.03.017

Abstract

BACKGROUND: Accurate non-invasive prediction of long-term hepatocellular carcinoma (HCC) risk in advanced liver fibrosis is urgently needed for cost-effective HCC screening; however, this currently remains an unmet need.

METHODS: A serum-protein-based prognostic liver secretome signature (PLSec) was bioinformatically derived from previously validated hepatic transcriptome signatures and optimized in 79 patients with advanced liver fibrosis. We independently validated PLSec for HCC risk in 331 cirrhosis patients with mixed etiologies (validation set 1 [V1]) and thereafter developed a score with clinical prognostic variables. The score was then validated in two independent cohorts: validation set 2 (V2): 164 patients with advanced liver fibrosis due to hepatitis C virus (HCV) infection cured after direct-acting antiviral therapy; validation set 3 (V3): 146 patients with advanced liver fibrosis with successfully-treated HCC and cured HCV infection.

FINDINGS: An 8-protein blood-based PLSec recapitulated transcriptome-based hepatic HCC risk status. In V1, PLSec was significantly associated with incident HCC risk (adjusted hazard ratio [aHR], 2.35; 95% confidence interval [CI], 1.30-4.23). A composite score with serum alpha-fetoprotein (PLSec-AFP) was defined in V1, and validated in V2 (adjusted odds ratio, 3.80 [95%CI, 1.66-8.66]) and V3 (aHR, 3.08 [95%CI, 1.78-5.31]; c-index, 0.74). PLSec-AFP outperformed AFP alone (Brier score, 0.165 vs. 0.186 in V2; 0.196 vs. 0.206 in V3, respectively).

CONCLUSIONS: The blood-based PLSec-AFP can accurately stratify patients with advanced liver fibrosis for long-term HCC risk and thereby guide risk-based tailored HCC screening.

Conflict of interest statement

DECLARATION OF INTERESTS Y.H. serves as an advisory board member for Helio Health and founding shareholder for Alentis Therapeutics, and received a research funding from Morphic Therapeutics. T.F.B. s

References

  1. Lancet. 2018 Nov 10;392(10159):1736-1788 - PubMed
  2. Gut. 2021 Feb;70(2):401-407 - PubMed
  3. Springerplus. 2013 May 14;2(1):222 - PubMed
  4. Hepatology. 2017 Oct;66(4):1344-1346 - PubMed
  5. Science. 2015 Jan 23;347(6220):1260419 - PubMed
  6. J Stat Softw. 2010;33(1):1-22 - PubMed
  7. Oncology. 2017;93(2):92-98 - PubMed
  8. Lancet. 2019 Apr 6;393(10179):1453-1464 - PubMed
  9. Liver Int. 2018 Apr;38(4):695-705 - PubMed
  10. Clin Transl Gastroenterol. 2017 Jun 22;8(6):e101 - PubMed
  11. Hepatology. 2018 Aug;68(2):723-750 - PubMed
  12. Ann Intern Med. 2019 Sep 3;171(5):318-327 - PubMed
  13. Proteomics. 2015 Sep;15(18):3163-8 - PubMed
  14. J Hepatol. 2016 Jun;64(6):1403-15 - PubMed
  15. Medicine (Baltimore). 2018 Oct;97(43):e12954 - PubMed
  16. Gastroenterology. 2013 May;144(5):1024-30 - PubMed
  17. Gastroenterology. 2019 Nov;157(5):1253-1263.e2 - PubMed
  18. Bioinformatics. 2018 May 15;34(10):1690-1696 - PubMed
  19. PLoS One. 2019 Oct 10;14(10):e0223514 - PubMed
  20. Alcohol Alcohol. 2016 Jul;51(4):465-73 - PubMed
  21. Acad Radiol. 2013 Jul;20(7):863-73 - PubMed
  22. Gut. 2015 Aug;64(8):1296-302 - PubMed
  23. Hum Immunol. 2006 Jan-Feb;67(1-2):27-32 - PubMed
  24. Gastroenterology. 2017 Oct;153(4):996-1005.e1 - PubMed
  25. J Gastroenterol Hepatol. 2015 Feb;30(2):379-88 - PubMed
  26. Nature. 2019 Nov;575(7783):512-518 - PubMed
  27. World Health Organ Tech Rep Ser. 1995;854:1-452 - PubMed
  28. Proc Natl Acad Sci U S A. 2019 Mar 26;116(13):6308-6312 - PubMed
  29. Stat Med. 1996 Feb 28;15(4):361-87 - PubMed
  30. Genomics. 2019 Dec;111(6):1839-1852 - PubMed
  31. J Hepatol. 2017 Nov;67(5):933-939 - PubMed
  32. J Natl Cancer Inst. 2010 Oct 6;102(19):1462-7 - PubMed
  33. Nucleic Acids Res. 2019 Jan 8;47(D1):D506-D515 - PubMed
  34. Ann Hepatol. 2013 Mar-Apr;12(2):236-47 - PubMed
  35. Gastroenterology. 2019 Jun;156(8):2313-2329.e7 - PubMed
  36. Clin Gastroenterol Hepatol. 2021 Jan;19(1):162-170.e4 - PubMed
  37. N Engl J Med. 2020 Mar 12;382(11):1018-1028 - PubMed
  38. Cell Syst. 2015 Dec 23;1(6):417-425 - PubMed
  39. Nat Biotechnol. 2019 Apr;37(4):420-423 - PubMed
  40. Gastroenterology. 2019 Nov;157(5):1264-1278.e4 - PubMed
  41. Clin Gastroenterol Hepatol. 2016 Nov;14(11):1619-1628 - PubMed
  42. Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50 - PubMed
  43. Hepatology. 2020 Nov;72(5):1654-1665 - PubMed
  44. Int J Cancer. 2017 Mar 1;140(5):1042-1049 - PubMed
  45. Nucleic Acids Res. 2014 Jan;42(Database issue):D959-65 - PubMed
  46. J Proteome Res. 2017 Dec 1;16(12):4299-4310 - PubMed
  47. BMC Med. 2017 Mar 14;15(1):52 - PubMed
  48. J Stat Softw. 2012 Sep;50(11):1-23 - PubMed
  49. N Engl J Med. 2008 Nov 6;359(19):1995-2004 - PubMed
  50. Stat Med. 1999 Sep 15-30;18(17-18):2529-45 - PubMed
  51. Hepatol Res. 2019 Oct;49(10):1109-1113 - PubMed
  52. Nat Immunol. 2015 Dec;16(12):1235-44 - PubMed
  53. Dig Dis Sci. 2017 Oct;62(10):2932-2942 - PubMed
  54. Clin Cancer Res. 2015 Nov 1;21(21):4960-9 - PubMed
  55. PLoS One. 2015 May 21;10(5):e0127518 - PubMed
  56. Asia Pac J Clin Nutr. 2008;17(3):370-4 - PubMed
  57. Cancer Cell. 2016 Dec 12;30(6):879-890 - PubMed
  58. Hepatology. 2021 Feb;73(2):713-725 - PubMed
  59. Liver Int. 2019 Dec;39(12):2214-2229 - PubMed
  60. Clin Gastroenterol Hepatol. 2020 Nov;18(12):2650-2666 - PubMed
  61. J Hepatol. 2018 Mar;68(3):526-549 - PubMed
  62. CA Cancer J Clin. 2018 Nov;68(6):394-424 - PubMed
  63. Hepatology. 2017 Apr;65(4):1196-1205 - PubMed
  64. Am J Gastroenterol. 2020 Oct;115(10):1642-1649 - PubMed
  65. Nucleic Acids Res. 2015 Jul 1;43(W1):W401-7 - PubMed
  66. Ann Hepatol. 2019 Nov - Dec;18(6):855-861 - PubMed

Publication Types

Grant support