AUTHOR=Chan Jason , Kinsella Michael , Willis Joseph , Hu Huankai , Reynolds Harry , Delaney Conor , McCulla Andrea , Deharo Steve , Ahdesmaki Miika , Allen Wendy L., Johnston Patrick , Kinsella Timothy J.

TITLE=A Predictive Genetic Signature for Response to Fluoropyrimidine-Based Neoadjuvant Chemoradiation in Clinical Stage II and III Rectal Cancer

JOURNAL=Frontiers in Oncology

VOLUME=3

YEAR=2013

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2013.00288

DOI=10.3389/fonc.2013.00288

ISSN=2234-943X

ABSTRACT=<p><bold>Purpose</bold>: Pre-operative chemoradiation (CRT) is currently the standard of care for patients with clinical stage II and III rectal cancer but only about 45% of patients achieve tumor downstaging and &lt;20% of patients achieve a pathologic complete response. Better methods to stratify patients according to potential neoadjuvant treatment response are needed. We used microarray analysis to identify a genetic signature that correlates with a pathological complete response (pCR) to neoadjuvant CRT. We performed a gene network analysis to identify potential signaling pathways involved in determining response to neoadjuvant treatment.</p><p><bold>Patients and Methods</bold>: We identified 31 T3–4 N0–1 rectal cancer patients who were treated with neoadjuvant fluorouracil-based CRT. Eight patients were identified to have achieved a pCR to treatment while 23 patients did not. mRNA expression was analyzed using cDNA microarrays. The correlation between mRNA expression and pCR from pre-treatment tumor biopsies was determined. Gene network analysis was performed for the genes represented by the predictive signature.</p><p><bold>Results</bold>: A genetic signature represented by expression levels of the three genes EHBP1, STAT1, and GAPDH was found to correlate with a pCR to neoadjuvant treatment. The difference in expression levels between patients who achieved a pCR and those who did not was greatest for EHBP1. Gene network analysis showed that the three genes can be connected by the gene ubiquitin C (UBC).</p><p><bold>Conclusion</bold>: This study identifies a 3-gene signature expressed in pre-treatment tumor biopsies that correlates with a pCR to neoadjuvant CRT in patients with clinical stage II and III rectal cancer. These three genes can be connected by the gene UBC, suggesting that ubiquitination is a molecular mechanism involved in determining response to treatment. Validating this genetic signature in a larger number of patients is proposed.</p>