Heterogeneity studies identify a subset of sporadic colorectal cancers without evidence for chromosomal or microsatellite instability

Abstract

Two apparently independent mechanisms of instability are recognized in colorectal cancer, microsatellite instability and chromosomal instability. Evidence from colorectal cancer cell lines indicates the presence of either, or both, types of instability in the vast majority. Here, we sought to determine the prevalence of such instability in primary sporadic colorectal cancers. Microsatellite instability was established by demonstration of ovel clonal, nongerm-line alleles in at least two of four tested loci. Chromosomal abnormalities were identified by comparative genomic hybridization (CGH) and flow cytometric analysis of nuclear DNA content. Tumours harbouring chromosomal instability were distinguished from those with stable but aneuploid karyotypes by comparing chromosomal defects at multiple sites throughout each cancer. This analysis allowed assessment of both the number of chromosomal abnormalities and their heterogeneity throughout the tumour. The results confirm that microsatellite instability is consistently associated with multiple, repeated changes in microsatellites throughout the growth of the affected colorectal carcinomas. There were also several carcinomas in which major structural or numerical abnormalities in chromosomes had clearly continued to arise during tumour growth. However, a substantial subset of tumours showed neither microsatellite instability nor multiple, major chromosomal abnormalities. We suggest that the development of a proportion of colorectal cancers proceeds via a different pathway of carcinogenesis not associated with either of the currently recognized forms of genomic instability.

Characterization of a new cytogenetic subtype of ductal breast carcinomas

“…One hypothesis is that rearrangements arise in cells that enter mitosis before double-strand breaks are repaired; the genes implicated being those involved in double-strand break repair. However, other mechanisms such as telomere erosion, DNA hypomethylation and dysfunction of p53 may exist, permitting the growth of cells that have sustained chromosome translocation, deletion and amplification events (Georgiades et al, 1999;Soulie et al, 1999). It remains to establish whether the underlying rate of numerical and structural chromosome alterations is different in the two groups of tumors or whether the observed chromosome patterns are simply a consequence of different selective pressures.…”

Array-CGH analysis of microsatellite-stable, near-diploid bowel cancers and comparison with other types of colorectal carcinoma

“…Second, some have proposed that low-level MSI may exist in many cancers within the CIN þ group (Iino et al, 1999). Third, a group of microsatellite-stable, near-diploid, (MSIÀCINÀ) colorectal carcinomas has been described (Georgiades et al, 1999;Curtis et al, 2000). This phenotype, also known as MACS (microsatellite and chromosome stable), was originally reported by Georgiades et al (1999) in four colorectal carcinomas.…”

“…Third, a group of microsatellite-stable, near-diploid, (MSIÀCINÀ) colorectal carcinomas has been described (Georgiades et al, 1999;Curtis et al, 2000). This phenotype, also known as MACS (microsatellite and chromosome stable), was originally reported by Georgiades et al (1999) in four colorectal carcinomas. Subsequent studies have confirmed that MSIÀ, neardiploid colorectal cancers do exist, and have variously suggested that they account for up to a third of all bowel cancers, have aggressive behaviour and occur more often than expected in a familial context (Hawkins et al, 2001;Giaretti et al, 2003).…”

Microsatellite-stable diploid carcinoma: a biologically distinct and aggressive subset of sporadic colorectal cancer

“…However, a recent study has demonstrated that a percentage of colorectal carcinomas show neither pattern of genetic instability, and may represent a potentially distinctive form of the disease (Georgiades et al, 1999). The authors postulated that these seemingly genetically stable tumours may have developed through an as yet uncharacterized unique molecular pathway.…”