Association of patterns of class I histone deacetylase expression with patient prognosis in gastric cancer: a retrospective analysis

doi:10.1016/S1470-2045(08)70004-4

The Lancet Oncology

Volume 9, Issue 2, February 2008, Pages 139-148

https://doi.org/10.1016/S1470-2045(08)70004-4 Get rights and content

Summary

Background

Although histone deacetylases (HDACs) are known to have an important regulatory role in cancer cells, and HDAC inhibitors (HDIs) have entered late-phase clinical trials for the treatment of several cancers, little is known about the expression patterns of HDAC isoforms in tumours. We aimed to clarify these expression patterns and identify potential diagnostic and prognostic uses of selected class I HDAC isoforms in gastric cancer.

Methods

Tissue samples from a training cohort and a validation cohort of patients with gastric cancer from two German institutions were used for analyses. Tissue microarrays were generated from tumour tissue collected from patients in the training group, whereas tissue slides were used in the validation group. The tissues were scored for expression of class I HDAC isoforms 1, 2, and 3. Overall expression patterns (gHDAC) were grouped as being negative (all three isoforms negative), partially positive (one or two isoforms positive), or completely positive (all isoforms positive), and correlated with clinicopathological parameters and patient survival. The main endpoints were amount of expression of each of the three HDAC isoforms, patterns of expression of gHDAC, effect of metastasis on expression of HDAC and gHDAC, and overall survival according to HDAC expression patterns.

Findings

2617 tissue microarray spots from 143 patients in the training cohort and 606 tissue slides from 150 patients in the validation cohort were studied. 52 of the 143 (36%) gastric tumours in the training cohort and 32 of the 150 (21%) gastric tumours in the validation cohort showed nuclear expression of all three HDAC isoforms. 60 (42%) of tumours in the training cohort and 65 (43%) in the validation cohort expressed one or two isoforms in the nuclei, whereas 31 (22%) of tumours in the training cohort and 53 (35%) in the validation cohort were scored negative for all three proteins. gHDAC expression in both cohorts was higher when lymph-node metastases were present (p=0·0175 for the training group and p=0·0242 for the validation group). Survival data were available for 49 patients in the training group and 123 patients in the validation group. In the validation cohort, 3-year survival was 44% (95% CI 34–57) in the HDAC1-negative group, 50% (39–64) in the HDAC2-negative group, and 48% (34–67) in the gHDAC-negative group. 3-year survival decreased to 21% (11–37) when HDAC1 was positive, 16% (9–31) when HDAC2 was positive, and 5% (1–31) when gHDAC (all isoforms) were positive. Those patients highly expressing one or two isoforms (the gHDAC-intermediate group) had an estimated 3-year survival of 40% (29–56). In multivariate analyses, high gHDAC and HDAC2 expression were associated with shorter survival in the training cohort (gHDAC: hazard ratio [HR] 4·15 [1·23–13·99], p=0·0250; HDAC2: HR 3·58 [1·36–9·44], p=0·0100) and in the validation cohort (gHDAC: HR 2·18 [1·19–4·01], p=0·0433; HDAC2: HR 1·72 [1·08–2·73], p=0·0225), independent of standard clinical predictors.

Interpretation

High HDAC expression is significantly associated with nodal spread and is an independent prognostic marker for gastric cancer. Additionally, we postulate that immunohistochemical detection of HDAC as a companion diagnostic method might predict treatment response to HDIs, thereby enabling selection of patients for this specific targeted treatment in gastric cancer.

Introduction

Gastric cancer is the fourth most common cancer and the second leading cause of cancer-related death worldwide, surpassed only by lung cancer.1, 2 5-year survival depends on tumour stage at the time of diagnosis, and is fairly high for patients with localised disease (62%), but dramatically decreases when the tumour has already spread to regional lymph nodes (22%) or distant organ sites (3%).³ Unfortunately, most patients with gastric cancer are diagnosed in an advanced stage when local or distant metastases are already present.³ Gastrectomy with or without accompanying adjuvant radiotherapy and with or without chemotherapy is the treatment of choice, promising complete cure in patients with early-stage disease. However, more than half of the patients receiving potential curative surgery will eventually relapse. For them and for most patients presenting with advanced disease, the therapeutic options are systemic chemotherapy, radiotherapy, or both.² Since currently used chemotherapy and radiotherapy regimens have poor efficacy in the metastatic stage, for these patients, treatment-resistant disease progression usually leads to tumour-related death within a year of treatment. Therefore, new molecular-targeted therapeutic approaches in the treatment of gastric cancer are urgently needed.

In the past few years, evidence has accumulated showing that modifications of acetylation status have a central role in gastric carcinogenesis.4, 5 Post-translational modifications of the N-terminal tails of core histones by histone acetyltransferases (HATs) and histone deacetylases (HDACs) are known to change profoundly the nucleosomal conformation of tumour cells and healthy cells alike. By this mechanism, aberrant activation of histone deacetylases in tumour cells leads to transcriptional repression of a diverse set of genes mainly involved in the regulation of proliferation, migration, angiogenesis, differentiation, invasion, and metastasis.6, 7 Equally important for tumour biology is the ability of HATs and HDACs to acetylate and deacetylate many tumour-relevant non-histone proteins directly, which alters their functional activity, subcellular localisation, and interaction partners.⁸ So far, 18 HDAC isoforms, grouped in four classes, have been described in human beings.⁷ The best characterised and probably biologically most relevant HDACs are the NAD+ independent class I HDAC 1, 2, and 3 isoenzymes.

Many HDAC inhibitors (HDIs) belonging to different chemical classes have been developed and are currently being tested in the treatment of a large variety of human tumours.⁷ Suberoylanilide hydroxamic acid (SAHA or vorinostat) is the first member of this family of new drugs that has been approved for the treatment of cutaneous T-cell lymphoma in second-line and third-line treatment.⁹

HDIs have been shown to have activity against many cancer cells, including gastric-cancer cells10, 11, 12 in vitro and in animals, mainly by inducing cancer-cell death.13, 14 HDIs have also been shown to sensitise cancer cells to radiation¹⁵ and act synergistically with other anticancer drugs.16, 17

In this context, surprisingly little is known about the specific expression of important HDAC isoforms in gastric-cancer tissue. We aimed to address this paucity of translational information and identify the expression patterns of HDAC 1, 2, and 3 in gastric adenocarcinomas in two large and well-characterised independent patient cohorts. The expression patterns were correlated with clinicopathological data and patient survival.

Section snippets

Patients

143 patients of a series of 321 consecutive patients with gastric cancer who had undergone total or partial gastrectomy at the Otto-von-Guericke University (Magdeburg, Germany) between 1995 and 2005 comprised the training cohort, whereas the validation cohort comprised 150 patients of a series of 217 consecutive patients with gastric cancer who had undergone total gastrectomy at the Charité University Hospital (Berlin, Germany) between 1995 and 2002. Only patients with histologically confirmed

Results

The clinicopathological characteristics of the patients are given in Table 1, Table 2.

The training cohort consisted of 143 patients. Survival data were available for 49 of these patients; follow-up data were missing for the other patients because these patients were not resident near the hospital in Magdeburg where they underwent gastrectomy. Of the 49 patients, 25 patients died during follow-up. Median follow-up for those patients still alive at the endpoint of analysis was 21·6 months (range

Discussion

In this study, we recorded and independently confirmed class I HDAC isoforms HDAC1, HDAC2, and HDAC3 to be highly expressed in tumours of most patients with gastric cancer. We showed that high expression of all three of these isoforms together was significantly associated with nodal tumour spread and decreased overall patient survival.

To our knowledge, this is the first detailed systematic report on class I HDAC expression in two large independent patient series of gastric cancer. Until now,

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Fast track — ArticlesAssociation of patterns of class I histone deacetylase expression with patient prognosis in gastric cancer: a retrospective analysis

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Patients

Results

Discussion

Biochem Pharmacol

Cancer Lett

Genomics

Cancer Cell

Trends in the incidence of gastric cancer in Japan and their associations with Helicobacter pylori infection and gastric mucosal atrophy

Gastric Cancer

Gastric cancer: epidemiology, pathology and treatment

Ann Oncol

Cancer statistics, 2007

CA Cancer J Clin

Deciphering the underlying genetic and epigenetic events leading to gastric carcinogenesis

J Cell Physiol

Histone acetylation and gastrointestinal carcinogenesis

Ann NY Acad Sci

Epigenetic therapy of cancer: past, present and future

Nat Rev Drug Discov