A Nine-Gene Signature for Predicting the Response to Preoperative Chemoradiotherapy in Patients with Locally Advanced Rectal Cancer

Abstract

Preoperative chemoradiotherapy (PCRT) and subsequent surgery is the standard multimodal treatment for locally advanced rectal cancer (LARC), albeit PCRT response varies among the individuals. This creates a dire necessity to identify a predictive model to forecast treatment response outcomes and identify patients who would benefit from PCRT. In this study, we performed a gene expression study using formalin-fixed paraffin-embedded (FFPE) tumor biopsy samples from 156 LARC patients (training cohort n = 60; validation cohort n = 96); we identified the nine-gene signature (FGFR3, GNA11, H3F3A, IL12A, IL1R1, IL2RB, NKD1, SGK2, and SPRY2) that distinctively differentiated responders from non-responders in the training cohort (accuracy = 86.9%, specificity = 84.8%, sensitivity = 81.5%) as well as in an independent validation cohort (accuracy = 81.0%, specificity = 79.4%, sensitivity = 82.3%). The signature was independent of all pathological and clinical features and was robust in predicting PCRT response. It is readily applicable to the clinical setting using FFPE samples and Food and Drug Administration (FDA) approved hardware and reagents. Predicting the response to PCRT may aid in tailored therapies for respective responders to PCRT and improve the oncologic outcomes for LARC patients.

Pre-Existing Tumoral B Cell Infiltration and Impaired Genome Maintenance Correlate with Response to Chemoradiotherapy in Locally Advanced Rectal Cancer

“…Of note, none of the previously proposed predictive gene lists [ 19 , 20 , 21 , 22 , 24 , 25 , 28 ] were able to classify good and poor responders with reasonable specificity or sensitivity when applied to our cohort ( Supplementary Figure S2 ). Recently, the largest and most recent LARC cohort was published (Park et al [ 28 ]). Unfortunately, the small number of genes evaluated by the cohort prevented most of our inferential analyses to perform properly and could not be adequately evaluated.…”

Validation of Gene Expression-Based Predictive Biomarkers for Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer

“…Although the present study again demonstrated that the gene expression signatures derived from microarray technologies were not capable of discriminating non-responders from responders, most recent studies have extensively searched for promising candidates to predict nCRT response in LARC using more robust expression assays and platforms. For instance, multi-gene expression assays developed on the NanoString nCounter system may provide more accurate prediction to nCRT response in LARC [ 39 , 40 ]. DNA-based molecular markers, including mutations in KRAS or TP53 and microsatellite instability (MSI), may also be associated with responses to neoadjuvant treatment in LARC [ 41 , 42 , 43 ].…”

Significance of TERT Genetic Alterations and Telomere Length in Hepatocellular Carcinoma

“…Protein–protein interactions were analyzed using CBS probe PINGS TM (Protein Interaction Network Generation System, KR100957386B1; Daejon, Korea) to identify the genes interacting with TERT . CBS probe PINGS TM uses five modules (protein–protein interactions, Path-finder, Path-linker, Path-maker, and Path-lister) to identify interacting genes, interaction distance, and interaction frequency [ 23 ].…”