Gene Expression in Fixed Tissues and Outcome in Hepatocellular Carcinoma

Gene Expression in Fixed Tissues and Outcome in Hepatocellular Carcinoma
Yujin Hoshida, M.D., Ph.D., Augusto Villanueva, M.D., Masahiro Kobayashi, M.D., Judit Peix, A.S., Derek Y. Chiang, Ph.D., Amy Camargo, B.A., Supriya Gupta, B.S., Jamie Moore, M.A., B.S., Matthew J. Wrobel, M.S., Jim Lerner, B.S., Michael Reich, B.S., Jennifer A. Chan, M.D., Jonathan N. Glickman, M.D., Ph.D., Kenji Ikeda, M.D., Masaji Hashimoto, M.D., Goro Watanabe, M.D., Maria G. Daidone, Ph.D., Sasan Roayaie, M.D., Myron Schwartz, M.D., Swan Thung, M.D., Helga B. Salvesen, M.D., Ph.D., Stacey Gabriel, Ph.D., Vincenzo Mazzaferro, M.D., Jordi Bruix, M.D., Scott L. Friedman, M.D., Hiromitsu Kumada, M.D., Josep M. Llovet, M.D., and Todd R. Golub, M.D.



Published at www.nejm.org October 15, 2008 (10.1056/NEJMoa0804525)

ABSTRACT

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tissue was highly effective: samples from 90% of the patients yielded data of high quality, including samples that had been archived for more than 24 years.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.


Source Information

From the Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA (Y.H., D.Y.C., A.C., S.G., J.M., M.J.W., J.L., M.R., J.A.C., S.G., T.R.G.); Howard Hughes Medical Institute (T.R.G.), Dana–Farber Cancer Institute (Y.H., D.Y.C., T.R.G.), and Brigham and Women's Hospital (J.N.G.), Harvard Medical School, Boston; Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine, New York (A.V., J.P., S.R., M.S., S.T., S.L.F., J.M.L.); Toranomon Hospital, Tokyo (M.K., K.I., M.H., G.W., H.K.); National Cancer Institute, Milan (M.G.D., V.M.); Haukeland University Hospital, University of Bergen, Bergen, Norway (H.B.S.); and Barcelona Clinic Liver Cancer Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer Centro de Investigaciónes en Red de Enfermedades Hepáticas y Digestivas Hosptial Clínic Barcelona (J.B., J.M.L.) and Institució Catalana de Recerca i Estudis Avançats (J.M.L.) — both in Barcelona.

This article (10.1056/NEJMoa0804525) was published at www.nejm.org on October 15, 2008. It will appear in the November 6 issue of the Journal.

Address reprint requests to Dr. Golub at the Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard University, 7 Cambridge Center, Cambridge, MA 02142, or at golub@broad.mit.edu, or to Dr. Llovet at the Division of Liver Diseases, Box 1123, Mount Sinai School of Medicine, 1425 Madison Ave., New York, NY 10029, or at josep.llovet@mssm.edu.

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