Genetic Alterations of Metastatic Colorectal Cancer

Abstract

Genome sequencing studies have characterized the genetic alterations of different tumor types, highlighting the diversity of the molecular processes driving tumor development. Comprehensive sequencing studies have defined molecular subtypes of colorectal cancers (CRCs) through the identification of genetic events associated with microsatellite stability (MSS), microsatellite-instability-high (MSI-H), and hypermutation. Most of these studies characterized primary tumors. Only recent studies have addressed the characterization of the genetic and clinical heterogeneity of metastatic CRC. Metastatic CRC genomes were found to be not fundamentally different from primary CRCs in terms of the mutational landscape or of genes that drive tumorigenesis, and a genomic heterogeneity associated with tumor location of primary tumors helps to define different clinical behaviors of metastatic CRCs. Although CRC metastatic spreading was traditionally seen as a late-occurring event, growing evidence suggests that this process can begin early during tumor development and the clonal architecture of these tumors is consistently influenced by cancer treatment. Although the survival rate of patients with metastatic CRC patients improved in the last years, the response to current treatments and prognosis of many of these patients remain still poor, indicating the need to discover new improvements for therapeutic vulnerabilities and to formulate a rational prospective of personalized therapies.

Keywords: colorectal cancer; genomic alterations; metastasis; tumor evolution; tumor heterogeneity.

Figure 1

Frequency of the most recurrent gene alterations observed in metastatic CRC patients. The data on the frequency of the major genetic alterations were reported by Priestly et al. [23] and were based on the wide-genome sequencing analysis of 372 metastatic CRC patients.

Figure 2

Frequency of the most recurrent genetic alterations observed in metastatic CRC patients (data reported by Yaeger et al., 2018) [24]. Top Panel: most recurrent genetic alterations observed in the whole population of metastatic CRC patients; Middle Panel: most recurrent genetic alterations observed in the population of metastatic CRC patients subdivided into MSI-H and MSS; Bottom Panel: tumor location in metastatic CRC patients exhibiting either MSI-H or MSS.