Gene Expression in Hepatocellular Carcinoma: Pilot Study of Potential Transarterial Chemoembolization Response Biomarkers

doi:10.1016/j.jvir.2014.12.610

Journal of Vascular and Interventional Radiology

Volume 26, Issue 5, May 2015, Pages 723-732

https://doi.org/10.1016/j.jvir.2014.12.610 Get rights and content

Abstract

Purpose

To perform a feasibility study to explore the relationship between hepatocellular carcinoma genetics and transarterial chemoembolization treatment response to identify potential biomarkers associated with enhanced treatment efficacy.

Materials and Methods

In this single-institution study, pretreatment hepatocellular carcinoma biopsy specimens for tumors in 19 patients (14 men, five women; mean age, 59 y) treated with chemoembolization between 2007 and 2013 were analyzed for a panel of 60 chemotherapy-sensitivity, hypoxia, mitosis, and inflammatory genes with the QuantiGene Plex 2.0 mRNA detection assay. Demographic, disease, and procedure data and tumor response outcomes were collected. Quantitative mRNA levels were compared based on radiologic response between tumors exhibiting complete response (CR) versus partial response (PR).

Results

The study sample included 19 biopsy specimens from tumors (mean size, 3.0 cm; grade 1, n = 6; grade 2, n = 9; grade 3, n = 4) in patients treated with a mean of two conventional chemoembolization sessions. Thirteen and six tumors exhibited CR and PR, respectively, at a mean of 116 days after treatment. Tumors with CR showed a significant increase in (P < .05) or trend toward (P < .1) greater (range, 1.49–3.50 fold) pretreatment chemotherapy-sensitivity and mitosis (ATF4, BAX, CCNE1, KIF11, NFX1, PPP3CA, SNX1, TOP2A, and TOP2B) gene mRNA expression compared with tumors with PR, in addition to lower CXCL10 levels (0.48-fold), and had significantly (P < .05) higher (1.65-fold) baseline VEGFA levels.

Conclusions

Genetic signatures may allow prechemoembolization stratification of tumor response probability, and gene analysis may therefore offer an opportunity to personalize locoregional therapy by enhancing treatment modality allocation. Further corroboration of identified markers and exploration of their respective predictive capacity thresholds is necessary.

Section snippets

Materials and Methods

Institutional review board approval was granted for this study. Patients provided written informed consent for HCC biopsy procedures.

Tumor Pathologic Characteristics, Chemoembolization Procedures, and Tumor Response Outcomes

The 38 tumors included in the genetic analysis included grades 1 (n = 9; 24%), 2 (n = 19; 50%), and 3 (n = 10; 26%). The 19 cases assessed for outcomes correlation included tumor grades 1 (n = 6; 32%), 2 (n = 9; 47%), and 3 (n = 4; 21%).

There were no chemoembolization procedure–related complications, although four of 36 patients (11%) required hospital readmission for management of postembolization syndrome. Eighteen of 19 patients (95%) in the outcomes correlation subset complied with the

Discussion

The present investigation characterized an HCC genetic panel and assessed the potential utility of its members as markers of chemoembolization response. In comparing the relative expression of 60 genes stratified by imaging response, 11 elements that showed a statistically evident differential manifestation in tumors that showed a CR versus a PR were identified. These hereditary units spanned genes related to DNA transcription (ATF4, NFX1, TOP2A, TOP2B), cell mitosis (CCNE1, KIF11), apoptosis (

Acknowledgments

This study was funded by the University of Illinois at Chicago Cancer Center in the form of a Junior Investigator Pilot Research Grant.

The authors thank Dr. Stefan J. Green and Vaiva Liakaite of the University of Illinois at Chicago Research Resources Center DNA Services Facility for their academic and technical expertise and assistance in planning and conducting genetic analyses for this investigation.

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Laboratory InvestigationGene Expression in Hepatocellular Carcinoma: Pilot Study of Potential Transarterial Chemoembolization Response Biomarkers

Abstract

Purpose

Materials and Methods

Results

Conclusions

Section snippets

Materials and Methods

Tumor Pathologic Characteristics, Chemoembolization Procedures, and Tumor Response Outcomes

Discussion

Acknowledgments

American Association for the Study of Liver Disease. Management of hepatocellular carcinoma: an update

Hepatology

Transarterial therapy for hepatocellular carcinoma: which technique is more effective? A systematic review of cohort and randomized studies

Cardiovasc Intervent Radiol

Radiologic-pathologic correlation of hepatocellular carcinoma treated with chemoembolization

Cardiovasc Intervent Radiol

Efficacy and nontarget effects of transarterial chemoembolization in bridging of hepatocellular carcinoma patients to liver transplantation: a histopathologic study

J Vasc Interv Radiol

Hypoxia and hepatocellular carcinoma: The therapeutic target for hepatocellular carcinoma

J Gastroenterol Hepatol

Screening of anticancer drugs for chemoembolization of hepatocellular carcinoma

Anticancer Drugs

Comparison of hypoxia-inducible factor-1alpha expression before and after transcatheter arterial embolization in rabbit VX2 liver tumors

J Vasc Interv Radiol

Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1

Mol Cell Biol

Increased expression of vascular endothelial growth factor and angiogenesis in the early stage of multistep hepatocarcinogenesis

Arch Pathol Lab Med

Tumor microvessel density as a predictor of recurrence after resection of hepatocellular carcinoma: a prospective study

J Clin Oncol

The changing face of percutaneous image-guided biopsy: molecular profiling and genomic analysis in current practice

J Vasc Interv Radiol

Gene expression in fixed tissues and outcome in hepatocellular carcinoma

N Engl J Med

Relevance network between chemosensitivity and transcriptome in human hepatoma cells

Mol Cancer Ther

Hypoxia-specific gene expression for ischemic disease gene therapy

Adv Drug Deliv Rev

Chemoembolization of hepatocellular carcinoma with cisplatin, doxorubicin, mitomycin-C, Ethiodol, and polyvinyl alcohol: prospective evaluation of response and survival in a U.S. population

J Vasc Interv Radiol

Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver

J Hepatol

EASL and mRECIST responses are independent prognostic factors for survival in hepatocellular cancer patients treated with transarterial embolization

J Hepatol

Molecular pathways: hepatitis C virus, CXCL10, and the inflammatory road to liver cancer

Clin Cancer Res

Prognostic molecular markers in hepatocellular carcinoma: a systematic review

Eur J Cancer

Chemoembolization of hepatocellular carcinoma

J Vasc Interv Radiol

Application of QuantiGene nucleic acid quantification technology for high throughput screening

J Biomol Screen

GAPDH as a housekeeping gene: analysis of GAPDH mRNA expression in a panel of 72 human tissues

Physiol Genomics

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Cancer Res

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Laboratory Investigation
Gene Expression in Hepatocellular Carcinoma: Pilot Study of Potential Transarterial Chemoembolization Response Biomarkers