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 disease-free 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.

Figure 1.

Frequencies of gains and losses throughout the genome in 183 gastric cancers with a median absolute deviation of chromosome 2 value <0.18. Clones are sorted by position on chromosome (1–22). Vertical lines represent transitions between chromosomes; dashed-vertical lines mark centromere positions.

Figure 2.

Kaplan–Meier survival plot of 55 patients with lymph node–negative gastric cancer and 128 patients with lymph node–positive gastric cancer. Patients without lymph node metastasis have a significantly better survival outcome than patients with lymph node–positive gastric cancer (p < .001). 0, lymph node–negative gastric cancer; 1, lymph node–positive gastric cancer.

Figure 3.

Kaplan–Meier survival plot. Patients with gastric cancers harboring loss of one of the 11 chromosomal regions have a significantly better survival outcome than patients with gastric cancers without loss of one of the 11 chromosomal regions (log rank, 9.76; p = .002). 0, no loss; 1, loss.

Figure 4.

Kaplan–Meier survival plot. Patients with loss of heat shock protein 90 (HSP90) expression have a better survival outcome than patients with strong HSP90 protein expression (log rank, 6.24; p = 0.04). 1, negative or mild positive; 2, moderate positive; 3, strong positive.