Bulk and Single-Cell Next-Generation Sequencing: Individualizing Treatment for Colorectal Cancer

Abstract

The increasing incidence combined with constant rates of early diagnosis and mortality of colorectal cancer (CRC) over the past decade worldwide, as well as minor overall survival improvements in the industrialized world, suggest the need to shift from conventional research and clinical practice to the innovative development of screening, predictive and therapeutic tools. Explosive integration of next-generation sequencing (NGS) systems into basic, translational and, more recently, basket trials is transforming biomedical and cancer research, aiming for substantial clinical implementation as well. Shifting from inter-patient tumor variability to the precise characterization of intra-tumor genetic, genomic and transcriptional heterogeneity (ITH) via multi-regional bulk tissue NGS and emerging single-cell transcriptomics, coupled with NGS of circulating cell-free DNA (cfDNA), unravels novel strategies for therapeutic response prediction and drug development. Remarkably, underway and future genomic/transcriptomic studies and trials exploring spatiotemporal clonal evolution represent most rational expectations to discover novel prognostic, predictive and therapeutic tools. This review describes latest advancements and future perspectives of integrated sequencing systems for genome and transcriptome exploration to overcome unmet research and clinical challenges towards Precision Oncology.

Keywords: colorectal cancer; genomic and transcriptomic landscapes; intra-tumor heterogeneity; liquid biopsies; next-generation sequencing.

Figure 1

Putative clinical implications emerging from the breakthrough exploration of intra-patient intratumor and circulating heterogeneity. (a) Step-wise delineation of translational and clinical implications via genome and transcriptome sequencing. (b) Medium-term clinical expectations: Progress from genomic and transcriptomic studies to sequencing of bulk multi-regional primary and metastatic tumor tissue and matched serial cfDNA within appropriately designed clinical trials promises to realize the initial phase of Precision Oncology. Innovative future translational research: Emerging advances in single-cell exploration of genomic and transcriptional heterogeneity could enable the precise selection of drug combinations.