Pharmacogenomic interrogation of colorectal cancer using next-generation whole exome sequencing

The promise of individualized therapy for cancer patients can be fulfilled by utilizing pharmacogenetic information to assistant in therapy selection when multiple treatment options are available. Recent advances in genetic and genomic technologies to interrogate cancer genomes coupled with a greater understanding of the gene variants that influence response to chemotherapy, point to the nearby future where pharmacogenetic information can be integrated into clinical practice. For histologically similar colorectal cancers, which can have profoundly different outcomes related to the molecular heterogeneity of the tumors, a detailed understanding of this heterogeneity has the potential to be used to understand the molecular factors impacting resistance to chemotherapy, with the eventual goal of being able to guide therapy selection. Therefore, next-generation whole exome sequencing was used to assess the distribution of pharmacogenomic important gene variants in a cohort of colorectal tumors in order to determine their potential influence on chemotherapy outcome in known colorectal molecular subtypes. Next generation whole exome sequencing was performed on 244 colorectal adenocarcinomas and matched normal samples as part of The Cancer Genome Atlas (TCGA) project. The whole exome data was interrogated for the presence of gene variants known to influence the response to chemotherapeutic agents. These gene variants were derived from a list of important pharmacogenomic genes available at the Pharmacogenomics Knowledge Base (www.pharmgkb.org). Furthermore, we interrogated additional gene variants that have previously been reported to influence the response to standard colorectal chemotherapy agents, such as 5-fluorouracil, oxaliplatin and irinotecan. Overall, the whole exome profiling of colorectal cancers with matched normal samples enabled the simultaneous interrogation of a wide range of pharmacogenomically relevant gene variants that have the potential to influence the response to chemotherapy. In addition, utilization of next-generation sequencing technologies also enables the assessment of non-SNP gene variants such as focal amplification and deletion of important pharmacogenomic genes. Integration of pharmacogenonetic gene variants with the known molecular subtypes of colorectal cancer can potentially be used to guide chemotherapy choices and thus bringing us one step closer to fulfilling the promise of individualized therapy.