Losses of Chromosome 5q and 14q Are Associated with Favorable Clinical Outcome of Patients with Gastric Cancer

Abstract

Purpose. To improve the clinical outcome of patients with gastric cancer, intensified combination strategies are currently in clinical development, including combinations of more extensive surgery, (neo)adjuvant chemotherapy, and radiotherapy. The present study used DNA copy number profiling to identify subgroups of patients with different clinical outcomes. We hypothesize that, by identification of subgroups, individual treatment strategies can be selected to improve clinical outcome and to reduce unnecessary treatment toxicity for patients with gastric cancer.Experimental Design. DNA from 206 gastric cancer patients was isolated and analyzed by genomewide array comparative genomic hybridization. DNA copy number profiles were correlated with lymph node status and patient survival. In addition, heat shock protein 90 (HSP90) expression was analyzed and correlated with survival in 230 gastric cancer patients.Results. Frequent (>20%) DNA copy number gains and losses were observed on several chromosomal regions. Losses on 5q11.2-q31.3 and 14q32.11-q32.33 (14% of patients) were correlated with good clinical outcome in univariate and multivariate analyses, with a median diseasefree survival interval of 9.2 years. In addition, loss of expression of HSP90, located on chromosome 14q32.2, was correlated with better patient survival. Conclusion. Genomewide DNA copy number profiling allowed the identification of a subgroup of gastric cancer patients, marked by losses on chromosomes 5q11.2-q31.3 and 14q32.11-q32.33 or low HSP90 protein expression, with an excellent clinical outcome after surgery alone. We hypothesize that this subgroup of patients most likely will not benefit from (neo)adjuvant systemic treatment and/or radiotherapy, whereas anti-HSP90 therapy may have clinical potential in patients with HSP90-expressing gastric cancer, pending validation in an independent dataset. The Oncologist 2012;17:653-662

Regulation and function of the human HSP90AA1 gene

“…Remarkably, in a number of tumors the HSP90AA1 gene is homozygously deleted, suggesting that these tumors may have a reduced level of malignancy. This hypothesis is supported by a comparative genome-wide analysis of 206 gastric cancer patients that reported loss of HSP90AA1 is indeed associated with favorable outcomes after surgery alone (Buffart et al 2012), and is in agreement with other studies reporting that the absence of Hsp90α in tumor biopsies may serve as a biomarker for positive clinical outcomes (Gallegos et al 2008; Cheng et al 2012). …”

Gastric cancer and gene copy number variation: emerging cancer drivers for targeted therapy

“…52 Its protein product negatively regulates WNT signaling and its inactivation leads to β-catenin accumulation and transcriptional activation of genes (MYC, cyclin D1) related to cell proliferation. 53,54 As reported, the chromosome locus of APC is frequently deleted in GCs, [55][56][57][58][59] and its decreased copy number significantly associated with lymph node invasion and metastasis in GC patients. 55 Moreover, APC deletion was principally found in advanced GCs, suggesting that it might be involved in the progression but not initiation of GCs.…”

MiR-19a promotes epithelial-mesenchymal transition through PI3K/AKT pathway in gastric cancer

“…The carcinogenesis of GC is complicated, and most patients experienced asymptomatic presentation in the early stage, resulting metastases at diagnosis. Surgical intervention, chemotherapy and radiotherapy remain to be the most curative treatment options for metastases, but the results of such trials always lead to incidence of postoperative relapse, metastasis and clinical responses [2,3]. To improve the clinical outcome of GC treatment, it is important to clarify GC pathogenesis and to investigate the genes responsible for the progress, metastasis of gastric cancer [4].…”