Abstract
Esophageal cancer (EC) is a very aggressive tumor, and no reliable prognostic markers exist especially for resectable advanced neoplasia. The principal aim of this study was to investigate the association of germline polymorphisms in nucleotide excision repair (NER) pathway genes with the overall survival (OS) of patients with advanced EC. As a second aim, we also studied the association of NER gene variants with response to cisplatin-based chemotherapy. Among the EC patients referred to our Institution between 2004 and 2012, we selected a cohort of 180 patients diagnosed with a clinical tumor stage ranging from IIB and IVA. Patients were genotyped for four NER variants, two in the ERCC1 (rs11615 and rs3212986) and two in the ERCC2/XPD (rs1799793 and rs13181) genes. Kaplan–Meier analyses and Cox proportional hazards model were used to evaluate the associations of the selected variants with OS; association with response to neoadjuvant therapy was investigated using logistic regression. Results showed that the ERCC1 rs3212986 and the ERCC2/XPD rs1799793 were significantly associated with shorter OS. On the contrary, response association analysis displayed that, while rs11615 and rs3212986 in ERCC1 were associated with response, both ERCC2/XPD variants were not. By creating survival prediction models, we showed that the rs3212986 and the rs1799793 have a better predictability of the tumor stage alone. Furthermore, they were able to improve the power of the clinical model (AUC = 0.660 vs. AUC = 0.548, p = 0.004). In conclusion, our results indicate that the ERCC1 rs3212986 and the ERCC2/XPD rs1799793 could be used as surrogate markers for a better stratification of EC patients with advanced resectable tumor.
Highlights
Esophageal cancer (EC) is a highly lethal malignancy, usually diagnosed at an advanced stage [1]
The first aim of this study was to define a possible association between variants in Excision repair cross-complementing 1 (ERCC1), and ERCC2/XPD genes and overall survival (OS) of patients with advanced resectable EC; as a second aim, we evaluated the association of the same genetic variants with response to cisplatin-based neoadjuvant chemotherapy
To avoid the confounding effect of clinical stage that could hide the effects of constitutive genetic variants, we excluded from our cohort patients with stage I, IIA and IVB, and restricted the OS association study to 180 patients diagnosed with a clinical stage ranging from IIB to IVA
Summary
Esophageal cancer (EC) is a highly lethal malignancy, usually diagnosed at an advanced stage [1]. EADC is thought to arise from an Constitutive Prognostic Markers in EC acquired precursor condition known as Barrett’s esophagus caused by chronic gastro-esophageal reflux [2, 3]. Other EADC risk factors, shared by ESCC, include tobacco and alcohol consumption, habits that lead to a chronic inflammation status [4]. One of the mechanism involved in cancer-related inflammation is the induction of genetic instability resulting in random DNA alterations [5, 6]. DNA repair genes and their constitutive variants have been indicated as a possible cause of the inter-individual variability to chemotherapy and patient outcome or as a factor that could modify the risk of tumor development [7,8,9,10,11,12,13,14]
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