Abstract 3609: Differential gene expression is associated with response to chemoradiation and relapse-free and overall survival in rectal adenocarcinoma
Authors: Lee Michael S. , Carlson Cheryl , Calvo Benjamin F. , O'Neil Bert H. , Bortone Dante S. , Vincent Benjamin G. 
Published: August 2018

Background: Neoadjuvant chemoradiation is a standard therapy for stage II-III rectal adenocarcinoma, and the degree of pathologic response observed upon resection informs prognosis. However, there is a need to identify novel biomarkers of response to chemoradiation and survival after chemoradiation, particularly using modern next-generation sequencing methods.

Methods: We prospectively collected pretreatment endoscopic tumor biopsies from 43 patients with stage II-IV rectal adenocarcinoma prior to neoadjuvant chemoradiation with concurrent fluoropyrimidine. Tumor samples were fresh frozen, and subsequently RNA was extracted, paired end libraries for mRNA sequencing (RNASeq) were prepared using TruSeq RNA Access library prep kits (Illumina), and samples were sequenced on Illumina HiSeq. Differentially expressed genes were determined using DESeq2 and Ingenuity pathway analysis (Qiagen) was performed. Additionally, the association between “claudin-low”-like gene sets established in breast and bladder cancers and clinical outcomes was determined.

Results: Among the 36 patients with adequate RNA quality, 7 had a pathologic complete response (pCR) and 29 did not, with 22 differentially expressed genes with false discovery rate (FDR) &lt;0.1 between the two cohorts, including EME2 (2.0-fold change, FDR p-value 0.00627). At 5 years of follow-up, 11 patients had known relapse and 11 were known to be relapse-free, with 33 differentially expressed genes with FDR&lt;0.1 between the two cohorts. Pathway analysis demonstrated that p53 signaling and Wnt/β-catenin signaling pathways were associated with relapse, while dendritic cell maturation and Toll-like receptor signaling pathways were associated with relapse-free survival. Rectal cancers with greater expression of a “claudin-low”-like signature had significantly inferior relapse-free survival (HR 1.79, 95% CI 1.07-3.00) and overall survival (HR 1.91, 95% CI 1.17-3.12) on univariate Cox proportional hazards model.

Conclusions: There are multiple differentially expressed genes associated with response to neoadjuvant chemoradiation in rectal adenocarcinoma. EME2, which forms an endonuclease that cleaves stalled replication forks, was one of the most differentially expressed genes overexpressed in patients with pathologic complete response and thus is a rational target for further investigation. Extension of “claudin-low” gene expression signatures to rectal cancers may serve as a new prognostic biomarker. Further investigation into the association of gene expression subtypes and responses to neoadjuvant chemoradiation is warranted.

Citation Format: Michael S. Lee, Cheryl Carlson, Benjamin F. Calvo, Bert H. O'Neil, Dante S. Bortone, Benjamin G. Vincent. Differential gene expression is associated with response to chemoradiation and relapse-free and overall survival in rectal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3609.