Background Esophageal cancer (ECa) is the 7th most incident cancer and the 6th leading cause of cancer-related death. Most patients are diagnosed with locally advanced or metastatic disease, enduring poor survival. Biomarkers enabling early cancer detection may improve patient management, treatment effectiveness, and survival, are urgently needed. In this context, epigenetic-based biomarkers such as DNA methylation are potential candidates. Methods Herein, we sought to identify and validate DNA methylation-based biomarkers for early detection and prediction of response to therapy in ECa patients. Promoter methylation levels were assessed in a series of treatment-naïve ECa, post-neoadjuvant treatment ECa, and normal esophagus tissues, using quantitative methylation-specific PCR for COL14A1, GPX3, and ZNF569. Results ZNF569 methylation (ZNF569me) levels significantly differed between ECa and normal samples (p < 0.001). Moreover, COL14A1 methylation (COL14A1me) and GPX3 methylation (GPX3me) levels discriminated adenocarcinomas and squamous cell carcinomas, respectively, from normal samples (p = 0.002 and p = 0.009, respectively). COL14A1me & ZNF569me accurately identified adenocarcinomas (82.29%) whereas GPX3me & ZNF569me identified squamous cell carcinomas with 81.73% accuracy. Furthermore, ZNF569me and GPX3me levels significantly differed between normal and pre-treated ECa. Conclusion The biomarker potential of a specific panel of methylated genes for ECa was confirmed. These might prove useful for early detection and might allow for the identification of minimal residual disease after adjuvant therapy.
Background Esophageal cancer (ECa) is associated with high mortality, mostly due to late diagnosis, precluding curativeintent surgery. Hence, neoadjuvant chemoradiation (ChRT) is recommended in most patients regardless of histological subtype. A proportion of these patients, however, achieve complete disease remission and might be spared of radical surgery. The lack of reliable, minimally invasive biomarkers able to detect post‐ChRT disease persistence is, nonetheless, a major drawback. We have previously shown that miRNA promotor methylation enables accurate cancer detection in tissues and liquid biopsies but has been seldom explored in ECa patients. Aims Herein, we sought to unveil and validate novel candidate biomarkers able to detect ECa prior and post ChRT. Materials and Methods Promoter methylation of miR129‐2, miR124‐3 and ZNF569 was assessed, using quantitative methylation‐specific PCR (qMSP), in tissue samples from normal esophagus, treatment‐naïve and post‐ChRT ECa, as well as in liquid biopsies from ECa patients. Results All genes disclosed significantly different promoter methylation levels between ECa and normal esophagus, accurately detecting post‐ChRT disease, especially for adenocarcinoma. Remarkably, miR129‐2me/ZNF569me methylation panel identified ECa in liquid samples with 53% sensitivity and 87% specificity. Discussion MiR129‐2me, miR124‐3me and ZNF569me accurately discriminate ECa, either pre‐ or post‐ChRT, from normal tissue, enabling ECa detection. Furthermore, circulalting methylation‐based biomarkers are promising minimally invasive tools to detect post‐ChRT residual ECa. Conclusion Overall, our results encourage the use of miRNA methylation biomarkers as accurate ECa detection tools as a novel approach for ChRT response monitoring.
Background The aerobic glycolysis as energy source in cancer confers a selective advantage for its proliferation and survival. Previous in vitro studies demonstrated that treatment with [C16Pyr][Amp], a potential anti-cancer drug in prostate, decreased the transcript levels of LDHA and CPT2, both involved in metabolic plasticity. In fact, LDHA and CPT2 were reported to be overexpressed in cancer, with association with poor prognosis and resistance to chemo- and radiotherapy. Since LDHA and CPT2 can be potential therapy resistance biomarkers, the aim of this work was to assess LDHA and CPT2 expression using PCa tissues. Methods LDHA and CPT2 expression was evaluated by immunohistochemistry in 57 PCa tissues, 24 from patients that developed resistance to hormonal therapy and 33 without therapy resistance. For both proteins, percentage of positive tumor cells, intensity of immunostaining, and immunoexpression pattern was determined by a blinded manner. Comparisons between therapy variables and protein expression were assessed using the Chi square test. P < 0.05 indicated a statistically significant difference. Results LDHA expression is significantly associated with therapy resistance (P < 0.001). Moreover, CPT2 pattern’s immunoexpression is also associated with therapy resistant (P < 0.001), being cytoplasmatic expression most frequent in patients that respond to therapy (41%), whereas both nuclear and cytoplasmatic expression is more prevalent in therapy-resistant cases (48%). Conclusions LDHA overexpression is significantly associated with therapy resistance in PCa cases, while CPT2 cell expression distribution might be a predictive marker.
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