The Chromosomal Instability Pathway in Colon Cancer

Abstract

The acquisition of genomic instability is a crucial feature in tumor development and there are at least 3 distinct pathways in colorectal cancer pathogenesis: the chromosomal instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP) pathways. Most cases of colorectal cancer arise through the CIN pathway, which is characterized by widespread imbalances in chromosome number (aneuploidy) and loss of heterozygosity (LOH). It can result from defects in chromosomal segregation, telomere stability, and the DNA damage response, although the full complement of genes underlying CIN remains incompletely described. Coupled with the karyotypic abnormalities observed in CIN tumors are the accumulation of a characteristic set of mutations in specific tumor suppressor genes and oncogenes that activate pathways critical for colorectal cancer initiation and progression. Whether CIN creates the appropriate milieu for the accumulation of these mutations or vice versa remains a provocative and unanswered question. The goal of this review is to provide an updated perspective on the mechanisms that lead to CIN and the key mutations that are acquired in this pathway.

Molecular differences in the microsatellite stable phenotype between left‐sided and right‐sided colorectal cancer

“…For example, RC is more likely to have mucinous histology, to be diploid, and to exhibit a high frequency of MSI and CpG island methylation 7, 9, 12. whereas LC often exhibits a differentiated histology, have chromosomal instability, and are more often aneuploidy 7, 9, 11. Classification based on tumor location is simple, comprehensive and consistent with recent attempts to characterize tumors by pathological and molecular features 8, 9.…”

“…CIN is observed in approximately 80–90% of sporadic CRCs4, 5, 7 and is characterized by an accelerated rate of gains or losses in whole or large portions of chromosomes, resulting in karyotypic variability 11. CIN causes imbalances in chromosome numbers (aneuploidy), sub‐chromosomal genomic amplifications and a high frequency of LOH 11.…”

“…Although CRC with the MSI‐high phenotype preferentially occurs in the right‐sided colon, it is rarely found in the left‐sided colon 8, 9. However, the MSS phenotype is the main molecular phenotype in both LC and RC 10, 11. Previous reports have shown that the MSS phenotype is found in approximately 60–70% of RC and around 90% of LC 3, 7.…”

Grapefruit Juice Suppresses Azoxymethane-induced Colon Aberrant Crypt Formation and Induces Antioxidant Capacity in Mice

“…The acquisition of genomic instability is a crucial feature in tumor development; in colon pathogenesis at least three distinct pathways are known, including microsatellite instability, CpG island methylator phenotypes, and chromosomal instability which can result in chromosome number imbalances and loss of heterozygocity (Pino and Chung, 2010;Migliore et al, 2011). However, in our assay we found no increase in the number of micronuclei in the analyzed blood cells.…”

Immune Cells in Colorectal Cancer: Prognostic Relevance and Role of MSI

“…CIN is observed in 80%-85% of sporadic colorectal cancers; the term refers to an accelerated rate of gains or losses of whole or large portions of chromosomes that results in karyotypic variability from cell to cell. The consequence of CIN is an imbalance in chromosome number (aneuploidy), subchromosomal genomic amplifications, and a high frequency of loss of heterozygosity (LOH) [2].…”