Abstract
Purpose: 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 <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.Patients and Methods: 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.Results: 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).Conclusion: 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.
Highlights
TREATMENT OF LOCALLY ADVANCED RECTAL CANCER An estimated 40,340 new cases of rectal cancer will be diagnosed in 2013 [1]
We found a genetic signature that was found to be correlated with pathological complete response (pCR) and was independent of clinical factors
PATIENT CHARACTERISTICS Two sample groups were identified from a sub-population of 31 rectal cancer patients with varying response to 5-FU and radiotherapy (Table 1)
Summary
TREATMENT OF LOCALLY ADVANCED RECTAL CANCER An estimated 40,340 new cases of rectal cancer will be diagnosed in 2013 [1]. Rectal cancer is a highly treatable and often curable disease when localized. The 2-year local recurrence rates after surgery alone for Stage II and III rectal cancers are
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