Department of Experimental Clinical Oncology, Aarhus University Hospital , Aarhus , Denmark.
Acta Oncol. 2013 Oct;52(7):1327-35. doi: 10.3109/0284186X.2013.818247. Epub 2013 Aug 19.
Gastroesophageal cancers are heterogeneous diseases with a poor outcome. Prognostic and predictive factors are needed to improve patient survival. Hypoxia is an adverse prognostic factor and is associated with resistance to chemo- and radiotherapy in various cancers. However, knowledge on the impact of hypoxia in gastroesophageal cancer is limited. The aim of this study was to evaluate potential prognostic factors in terms of a subset of hypoxia-responsive genes and clinicopathological parameters in patients with gastroesophageal cancer.
Ninety-five patients with loco-regional gastroesophageal cancer treated with curative intent were retrospectively analyzed. Based on formalin-fixed paraffin-embedded diagnostic biopsies gene expressions of 15 hypoxia-induced and pH-independent genes from a previously described hypoxia gene expression classifier was quantified. The prognostic impact was evaluated for overall survival (OS) and disease-specific survival (DSS). Uni- and multivariate Cox proportional hazards model was used to identify hypoxia-responsive gene expression and clinicopathological parameters as prognostic markers.
An unsupervised hierarchical clustering of hypoxia regulated genes showed two well-differentiated patient clusters: One cluster of tumors with high gene expression and another with low gene expression, indicating a more hypoxic genotype versus a less hypoxic genotype respectively. As the group of esophageal squamous cell carcinomas (ESCC) alone showed intra-group heterogeneity this group was ranked according to the gene expression of the 15 genes. The most hypoxic third showed a trend towards a poorer outcome in terms of OS [HR = 0.48 (CI 0.21-1.07), p = 0.07] and DSS [HR = 0.48 (CI 0.18-1.24), p = 0.13]. Treatment response was identified as an independent prognostic factor for DSS in the group of ESCC [HR = 0.21 (CI 0.05-0.95), p = 0.04].
Gene expression analysis of 15 hypoxia-responsive genes was identified as a promising prognostic marker in patients with ESCC. Further studies confirming these results in larger patient cohorts are needed.
评估胃食管癌症患者的预后和预测因素，以改善患者的生存。方法：回顾性分析 95 例局部胃食管癌症患者。根据福尔马林固定石蜡包埋的诊断性活检，使用先前描述的缺氧基因表达分类器定量了 15 个缺氧诱导和 pH 独立基因的基因表达。评估整体生存率（OS）和疾病特异性生存率（DSS）的预后影响。采用单因素和多因素 Cox 比例风险模型，确定缺氧反应基因表达和临床病理参数作为预后标志物。结果：缺氧调节基因的无监督层次聚类显示，存在两种分化良好的患者群：一种是高基因表达肿瘤群，另一种是低基因表达肿瘤群，分别代表更缺氧的基因型和较少缺氧的基因型。由于食管鳞状细胞癌（ESCC）组本身存在组内异质性，因此根据 15 个基因的表达对该组进行了排序。最缺氧的第三组在 OS[HR=0.48(CI 0.21-1.07),p=0.07]和 DSS[HR=0.48(CI 0.18-1.24),p=0.13]方面的结果显示出较差的趋势。在 ESCC 组中，治疗反应被确定为 DSS 的独立预后因素[HR=0.21(CI 0.05-0.95),p=0.04]。结论：15 个缺氧反应基因的基因表达分析被确定为 ESCC 患者有前途的预后标志物。需要进一步的研究来确认这些结果在更大的患者群体中。
