Genomic instability occurs in colorectal carcinomas but not in adenomas

Abstract

Genomic instability, as demonstrated by the presence of additional alleles at short tandemly repeated (STR) loci, has recently been observed in colorectal tumours from individuals with hereditary nonpolyposis colorectal cancer (HNPCC), and in some sporadic tumours. These neoplasms have been called replication error positive (RER+). In this study, we confirm the presence of genomic instability in a proportion of unselected colorectal carcinomas but find no evidence of instability in adenomas. We further report replication errors in a tetranucleotide sequence, and in STRs within two tumour suppressor genes. 108 colorectal adenocarcinomas and 46 adenomas were analysed for the presence of variant bands at 4-15 microsatellite markers. Seven (6.5%) of carcinomas were RER+, four of which originated from the proximal colon. Analysis of the adenomas and of matched adenoma-carcinoma and carcinoma-metastatic samples from four patients suggests that the replication errors may occur during the development of carcinomas but are rare in adenomas.

Allelic loss mapping and physical delineation of a region harboring a putative thymic lymphoma suppressor gene on mouse chromosome 12

“…The commonly lost region is indicated by a bar above markers. Numbers on a thin line below the bars indicate lymphomas retaining both alleles in 251 informative lymphomas examined cancers and neuroblastomas (Suzuki et al, 1989;Young et al, 1993;Chang et al, 1995;Bandera, 1997). Therefore, a human homolog of the candidate tumor suppressor gene in Tlsr4 may be involved in the development of some of those human tumors, although the types of mouse and human tumors are di erent.…”

“…The D12Mit279 locus in the vicinity of Tlsr4 showed allelic loss at a frequency of as high as 62% and the frequency was not a ected by the presence or absence of a p53-de®cient allele in irradiated mice (Matsumoto et al, 1998). Interestingly, the Tlsr4 interval on mouse chromosome 12 is homologous to human chromosome 14q32 ± 33 where frequent allelic losses have been found in a variety of tumors: ovarian tumors (Bandera, 1997), colorectal carcinomas (Young et al, 1993), neuroblastomas (Suzuki et al, 1989) and invasive bladder cancer (Chang et al, 1995). Therefore, analysis of Tlsr4 may lead to isolation of a candidate of the tumor suppressor gene not only in Tlsr4 but also in the human 14q32-33 region.…”

Microsatellite deletions in the c-myb transcriptional attenuator region associated with over-expression in colon tumour cell lines

“…DNA mis-match repair defects have been found to occur in approximately 17% of sporadic (nonhereditary) cancers (Aaltonen et al, 1994;Ionov et al, 1993;Lothe et al, 1993;Young et al, 1993;Kim et al, 1994;Thibodeau et al, 1993) and up to 86% of tumours from hereditary non-polyposis colorectal cancer (HNPCC) patients (Aaltonen et al, 1993, …”

“…Approximately 17% of sporadic colon tumours and up to 85% of tumours from hereditary non-polyposis colorectal cancer (HNPCC) patients show evidence of microsatellite instability (MSI) which arises from defects in the DNA mismatch repair mechanisms (Aaltonen et al, , 1994Lothe et al, 1993;Young et al, 1993;Wu et al, 1994;Kim et al, 1994). Recent studies suggest that one common type of mutation, occuring in tumours and tumour cell lines with mismatch repair defects, is a reduction in the length of mononucleotide tracts (Ionov et al, 1993;Markowitz et al, 1995;Chen et al, 1995;Bubb et al, 1996).…”

MYC oncogenes and human neoplastic disease

“…Scattered reports have suggested that individuals bearing the`short' (S) allele either have an increased incidence of certain tumors and/or that such tumors manifest a more aggressive behavior. The associated neoplasms include soft-tissue sarcomas (Kato et al, 1990), oral cancers (Saranath et al, 1990), colorectal cancers (Young et al, 1994), nonHodgkin's lymphoma (Crossen et al, 1994), breast cancer (Champeme et al, 1992), and non-SCLC lung cancer (Kawashima et al, 1988). In contrast, at least one report has suggested that the`SS' genotype protects against hepatocellular cancer (Taylor et al, 1993).…”