Specific patterns of chromosomal abnormalities are associated with RER status in sporadic colorectal cancer

Abstract

Current opinion of the genetic events driving colorectal tumourigenesis focuses on genomic instability. At least two apparently independent mechanisms are recognized, microsatellite instability and chromosomal instability. The genetic defects underlying each type of instability are only partially understood and controversy remains as to the role of p53 in the generation of chromosomal defects in colorectal cancer. This study sought to clarify the relationships between chromosomal abnormalities and defects of both p53 and mismatch repair. Extensive chromosomal analysis was undertaken, using¯ow cytometry and comparative genomic hybridization, of a series of sporadic colorectal cancers which had been grown to early passage as subcutaneous xenografts in SCID mice. Overall levels of chromosomal defects were observed to be low in RER+ cancers compared with RERx and distinctive patterns of chromosomal anomalies were found to be associated with both the RER+ and RERx phenotype. No particular level or pattern of chromosomal anomalies appeared to be associated with p53 status, supporting recent observations that abnormal p53 function is not suf®cient to cause chromosomal anomalies in colorectal tumours.

Comprehensive characterization of HNPCC-related colorectal cancers reveals striking molecular features in families with no germline mismatch repair gene mutations

“…Omitting the colorectal adenomas (33:1, 79:1), our MMR gene mutation negative series showed seven chromosomally stable (CINÀ) carcinomas among 14 MSS carcinomas (50%) examined by CGH. This high frequency of stable carcinomas was highly significant when compared to published data on sporadic MSS colorectal cancers (P ¼ 0.006; Table 5) or xenografted MSS colorectal cancers (2/27, P ¼ 0.004; Curtis et al, 2000).…”

“…Accordingly, marked stability of chromosome number and structure (measured by karyotyping or CGH) was associated with mismatch repair defects in both sporadic (Schlegel et al, 1995;Curtis et al, 2000;Abdel-Rahman et al, 2001) and HNPCC-related (Muleris et al, 1995) colorectal carcinomas. This association holds even when there is clear proof of active Wnt signaling due to APC or CTNNB1 mutations in these tumors (Abdel-Rahman et al, 2001; see also Rowan et al (2000) for the APC/ CTNNB1 status in MSI cell lines).…”

High rate of CAD gene amplification in human cells deficient in MLH1 or MSH6

“…PALA sensitivity, defined as the concentration of PALA that inhibits cell growth by 50% (ID 50 ), was determined as described by Perry et al (15). Selection for resistance was performed at a PALA concentration of 3 times the ID 50 concentration by using medium deficient in deoxyribonucleosides and ribonucleosides that was supplemented with 10% (vol͞vol) dialyzed FBS (HyClone).…”

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.…”