A gene panel to predict response to adjuvant chemotherapy and risk of recurrence in colorectal cancer

Abstract

Background: Chemotherapy is the mainstay to treat metastatic colorectal cancer (CRC). However, a sizeable proportion of patients do not respond to treatment, which leads to the recurrence of disease. This study was carried out to identify reliable gene expression-based marker(s) to predict the response to chemotherapy and the risk of recurrence.

Methods: This prospective study involved the collection of tumor tissues (n = 100) and normal tissues (n = 10) from CRC patients who primarily underwent surgical treatment. Global gene expression profiles were generated on microarray (Affymetrix; n = 5) and the next-generation sequencing (NGS) (Illumina; n = 20) platforms. Patients were classified as responders (n = 13; complete response with no relapse) or non-responders (n = 12; recurrence of disease leading to death). Common dysregulated genes identified from both platforms were replicated in an independent set (n = 75; quantitative real-time polymerase chain reaction (qRT-PCR)). The area under the curve (AUC) was generated, and a combinatorial analysis was performed.

Results: A total of 193 and 1351 genes were dysregulated in microarray and NGS datasets, respectively. Of the top common genes (PTGIS, LYVE1, C3, C7, CXCL12, CEACAM6, MUC13, and ST14) that were selected for replication, upregulation of five genes (PTGIS, C3, C7, LYVE1, and CXCL12) were associated with the non-responder group in validation set. Combinatorial analysis and comparison of AUC identified a significant increase (p = 0.03) in AUC by 15.2% (95% confidence interval (CI): 0.01-0.29) for two genes (PTGIS and LYVE1). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 88.9%, 100%, 100%, and 95.6%, respectively.

Conclusion: Assessing upregulation of the PTGIS and LYVE1 genes enables identification of individuals who may not respond to adjuvant chemotherapy and the risk of recurrence. The addition of drugs targeting these genes may improve response and benefit the patients.

Keywords

colorectal cancer / microarray / RNA-seq / adjuvant chemotherapy / prognosis / transcriptome sequencing / gene panel

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The Author(s). Malignancy Spectrum published by John Wiley & Sons Australia, Ltd on behalf of Higher Education Press.