G. Karagkounis1,2, J. DeVecchio2, L. Thai1,2, L. C. Duraes1,2, G. A. Gantt1,2, M. F. Kalady1,2 1Cleveland Clinic,Colorectal Surgery,Cleveland, OH, USA 2Cleveland Clinic,Stem Cell Biology And Regenerative Medicine,Cleveland, OH, USA
Introduction: Neoadjuvant chemoradiation (CRT) is the standard of care for locally advanced rectal cancer. Response is highly variable, from complete pathologic response to no treatment effect. The mechanisms behind CRT resistance remain unclear and the paucity of pretreatment predictors of response leads to a significant proportion of patients undergoing therapies from which they may derive minimal or no benefit. The goal of this study was to identify gene expression profiles associated with rectal cancer resistance to CRT.
Methods: Freshly frozen pretreatment rectal adenocarcinoma biopsies were collected according to an established IRB-approved protocol. Thirty-three patients who underwent standard long course neoadjuvant treatment including 5-FU and external beam radiation were identified. Post-treatment resection specimens were evaluated for response based on American Joint Committee on Cancer (AJCC) criteria. Total tumor mRNA was extracted from pretreatment biopsies and gene expression levels were determined using high-throughput microarrays on an Illumina platform. Gene expression levels between complete responders (AJCC 0) to partial and non-responders (AJCC 1-3) were compared using non-parametric Wilcoxon test. Real-time quantitative PCR (RT-qPCR) was used to validate microarray gene expression levels in the same sample set.
Results: Neuronal pentraxin 2 (NPTX2), a gene normally involved in neuronal development and recently implicated in renal cell carcinoma progression, was found to be significantly downregulated among complete responders (AJCC 0) compared to partial and non-responders (AJCC 1-3) by microarray analysis (fold change 29.8, p=0.02). NPTX2 downregulation among complete responders was confirmed by RT-qPCR (p=0.012), with gradually increasing NPTX2 expression levels through the different AJCC grades (p=0.029).
Conclusion: NPTX2 is relatively under expressed in human rectal adenocarcinomas that are sensitive to neoadjuvant CRT. As response to CRT is a strong predictor of oncological outcomes, NPTX2 expression may serve as an early prognostic biomarker and could serve as a potential target for CRT sensitization. These findings provide an opportunity for further studies to elucidate its biological role in rectal cancer.