Gene expression in fixed tissues and outcome in hepatocellular carcinoma
Open accessAbstract
BACKGROUND: It is a challenge to identify patients who, after undergoing potentially curative treatment for hepatocellular carcinoma, are at greatest risk for recurrence. Such high-risk patients could receive novel interventional measures. An obstacle to the development of genome-based predictors of outcome in patients with hepatocellular carcinoma has been the lack of a means to carry out genomewide expression profiling of fixed, as opposed to frozen, tissue. METHODS: We aimed to demonstrate the feasibility of gene-expression profiling of more than 6000 human genes in formalin-fixed, paraffin-embedded tissues. We applied the method to tissues from 307 patients with hepatocellular carcinoma, from four series of patients, to discover and validate a gene-expression signature associated with survival. RESULTS: The expression-profiling method for formalin-fixed, paraffin-embedded tissue was highly effective: samples from 90% of the patients yielded data of high quality, including samples that had been archived for more than 24 years. Gene-expression profiles of tumor tissue failed to yield a significant association with survival. In contrast, profiles of the surrounding nontumoral liver tissue were highly correlated with survival in a training set of tissue samples from 82 Japanese patients, and the signature was validated in tissues from an independent group of 225 patients from the United States and Europe (P=0.04). CONCLUSIONS: We have demonstrated the feasibility of genomewide expression profiling of formalin-fixed, paraffin-embedded tissues and have shown that a reproducible gene-expression signature correlated with survival is present in liver tissue adjacent to the tumor in patients with hepatocellular carcinoma.
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Hepatocytic markers, HCC signature genes, and cancer-associated gene families (oncogenes, transcription factors, and protein kinases) from GSEA were overrepresented in MP genes.
“Notably, hepatocytic markers28, HCC signature genes29, and cancer-associated gene families (oncogenes, transcription factors, and protein kinases) from GSEA30 were overrepresented in MP genes (Fig. 1g).”
From Alternative promoters in CpG depleted regions are prevalently associated with epigenetic misregulation of liver cancer transcriptomes (2023) · cites this paper as [29]
The signature also includes pathways frequently deregulated in other human cancers, such as pancreatic adenocarcinoma and bladder, small cell lung, prostate, and estrogen-dependent and hereditary breast cancers.
“and also includes pathways frequently deregulated in other human cancers, such as pancreatic adenocarcinoma and bladder, small cell lung, prostate, and estrogen-dependent and hereditary breast cancers (Table S4–5)”
From Circadian Homeostasis of Liver Metabolism Suppresses Hepatocarcinogenesis (2016) · cites this paper as Hoshida et al., 2008
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- Authors
- Hoshida, Y., Villanueva, A., Kobayashi, M., Peix, J., Chiang, D. Y., Camargo, A., Gupta, S., Moore, J., Wrobel, M. J., Lerner, J., Reich, M., Chan, J. A., Glickman, J. N., Ikeda, K., Hashimoto, M., Watanabe, G., Daidone, M. G., Roayaie, S., Schwartz, M., Thung, S., Salvesen, H. B., Gabriel, S., Mazzaferro, V., Bruix, J., Friedman, S. L., Kumada, H., Llovet, J. M., & Golub, T. R.
- Affiliations
- Broad Institute (US)
- Icahn School of Medicine at Mount Sinai (US)
- Toranomon Hospital (JP)
- Brigham and Women's Hospital (US)
- Haukeland University Hospital (NO)
- Hospital Clínic de Barcelona (ES)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- ORCID
- Hoshida, Yujin
- Villanueva, Augusto
- Kobayashi, Masahiro
- Peix, Judit
- Chiang, Derek Y.
- Gupta, Supriya
- Reich, Michael
- Chan, Jennifer A.
- Glickman, Jonathan N.
- Ikeda, Kenji
- Hashimoto, Masaji
- Daidone, Maria G.
- Roayaie, Sasan
- Schwartz, Myron
- Thung, Swan
- Gabriel, Stacey
- Mazzaferro, Vincenzo
- Bruix, Jordi
- Friedman, Scott L.
- Llovet, Josep M.
- Golub, Todd R.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2008-11-06
- Volume
- 359
- Issue
- 19
- Pages
- 1995-2004
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC2963075
- OpenAlex
- W2009671859
- Cited by
- 1,286
- References
- 22
- Citations by year
- 2026: 24 · 2025: 23 · 2024: 33 · 2023: 48 · 2022: 65 · 2021: 85 · 2020: 62 · 2019: 67 · 2018: 51 · 2017: 70 · 2016: 64 · 2015: 104 · 2014: 100 · 2013: 88 · 2012: 114
- FWCI
- 39.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- National Cancer Institute (U54CA112962)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK076986, DK37340, R01DK037340)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene expression and cancer classification
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Keywords
- hepatocellular carcinoma, gene expression profiling, formalin-fixed paraffin-embedded tissue, prognostic gene signature, survival prediction, tumor recurrence, archived tissue samples
- MeSH terms
- Aged, Feasibility Studies, Female, Carcinoma, Hepatocellular, Humans, Liver, Liver Neoplasms, Male, Middle Aged, Neoplasm Recurrence, Local, Prognosis, Gene Expression Regulation, Neoplastic, Multivariate Analysis, Survival Analysis, Polymerase Chain Reaction, Paraffin Embedding, Tissue Fixation, Oligonucleotide Array Sequence Analysis, Gene Expression Profiling, Genome-Wide Association Study
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