Microsatellite instability in sporadic carcinomas of the proximal colon: Association with diploid DNA content, negative protein expression of p53, and distinct histomorphologic features

Förster, Stefan; Sattler, Hans-Peter; Hack, M.; Romanakis, Konstantinos; Rohde, V.; Seitz, Gerhard; Wullich, Bernd

doi:10.1016/s0039-6060(98)70223-5

Cited by 66 publications

(32 citation statements)

References 13 publications

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“…Patients with colorectal carcinoma, coincident with germ-line mutation in mismatch repair genes, tend to develop near-diploid cancers with few chromosomal aberrations, often without p53 mutation, and this is the pattern observed here Bocker et al, 1996;Cottu et al, 1996;Feeley et al, 1999;Forster et al, 1998;Ionov et al, 1993;Konishi et al, 1996;Lothe et al, 1993;Olschwang et al, 1997;Remvikos et al, 1995;Schlegel et al, 1995). Previous studies have suggested that loss of p53 function is associated with chromosomal instability, favouring the development of aneuploidy, polyploidy, chromosomal breaks and ampli®cation (Bischo et al, 1990;Bou er et al, 1995;Carder et al, 1993;Donehower et al, 1995;Fukasawa et al, 1997;Harvey et al, 1993;Livingstone et al, 1992;Meling et al, 1993;Purdie et al, 1994;Tsukada et al, 1993;Yin et al, 1992).…”

supporting

confidence: 52%

Chromosomal instability and p53 inactivation are required for genesis of glioblastoma but not for colorectal cancer in patients with germline mismatch repair gene mutation

et al. 2000

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We have previously reported high-frequency microsatellite instability (MSI-H) and germ-line mismatch repair gene mutation in patients with unusually young onset of high-grade glioma. Some of these patients developed metachronous MSI-H colorectal cancer and conformed to the diagnosis of Turcot's syndrome. Frameshift mutation of TGFbRII was present in all the colorectal carcinomas but not in brain tumours. We further characterized the genetic pathways of tumour evolution in these metachronous gliomas and colorectal carcinomas. All MSI-H glioblastomas had inactivation of both alleles of the p53 gene and showed over-expression of the p53 protein while none of the colorectal carcinomas had p53 mutation or protein over-expression. Flow cytometry and comparative genomic hybridization revealed that all glioblastomas were chromosomal unstable with aneuploid DNA content, and with a variable number of chromosomal arm aberrations. In contrast, the colorectal carcinomas had diploid or near-diploid DNA content with few chromosomal arm aberrations. The pattern of chromosomal aberrations in the two organs was di erent. Loss of 9p was consistently observed in all glioblastomas but not in colorectal carcinomas. Epidermal growth factor receptor ampli®cation was absent in all glioblastomas and colorectal carcinomas. Our results suggest that both the frequency of p53 mutation and its e ects di er greatly in the two organs. Following loss of mismatch repair function, p53 inactivation and chromosomal instability are not necessary for development of colorectal carcinoma, but are required for genesis of glioblastoma. Oncogene (2000) 19, 4079 ± 4083.

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confidence: 52%

Chromosomal instability and p53 inactivation are required for genesis of glioblastoma but not for colorectal cancer in patients with germline mismatch repair gene mutation

et al. 2000

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“…In fact, bax expression can be lost upon frameshift mutations in a tract of 8 deoxyguanosines in the bax gene, frequently present in MMP (Rampino et al, 1997;AbdelRahman et al, 1999). It has been reported that the MMP in colorectal cancer is associated with response to 5-FU treatment (Nelson, 1998), and that patients with mismatch repair deficiency have a better clinical outcome (Bubb et al, 1996;Forster et al, 1998;Lukish et al, 1998;Liang et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Expression of apoptosis-related markers and clinical outcome in patients with advanced colorectal cancer

Paradiso¹,

Simone²,

Lena³

et al. 2001

Br J Cancer

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SummaryThe clinical relevance of bax and bcl-2 protein expression has been investigated in 84 patients with recurrent or metastatic colorectal cancer submitted to a chemotherapy regimen including methotrexate and fluorouracil/leucovorin. Cytoplasmic immunostaining of bax and bcl-2 was present in 65.5% and 38%, respectively, of the tumours. No association was found between bax and bcl-2 or between p53 and bax or bcl-2 protein expression. Moreover, the biomarkers were unrelated to patient and tumour characteristics known to affect the clinical outcome of colorectal cancer patients. In general, the apoptosis-related markers did not appear indicative of short-and long-term clinical response nor of prognosis. Bcl-2-negative lesions were more frequent among patients who reached an objective clinical response, which is in agreement with previously reported data regarding other tumour types. When the interrelationship between p53 and bax expression was examined, a better response rate (40%) was found for patients whose tumours did not express p53 and bax, and a better prognosis (2-year probability of overall survival 75%) for patients with p53-positive and bax-negative tumours. In the present series of patients with advanced colorectal cancer submitted to systemic chemotherapy we did not find a clear association between expression of apoptosis-related markers and clinical outcome, even in the subset of patients in which the apoptotic index as determined by the TUNEL approach was investigated.

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“…The direct association between increased transcription of MLH1 and MSH2 with MSI might suggest that their activity is at least in part co-ordinated, perhaps as an attempt to control the higher mutation rate in MSI-H. An intriguing finding was the reduction in p53 transcription in MSI-H compared to normal bowel, and MSS or MSI-L cancers. While studies on p53 mutation in MSI have shown conflicting results, there is a consensus that p53 has an inverse relationship with MSI (Cottu et al, 1996;Breivik et al, 1997;Olschwang et al, 1997;Forster et al, 1998;Iacopetta et al, 1998). The basis for the apparent reduced rate of p53 mutations in the higher 'mutator' phenotype of MSI-H has remained unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Since overexpression of MLH1 and MSH2 induces apoptosis (Zhang et al, 1999), the relationships between these genes and the mutation and function of the tumour-suppressor gene p53 have been of interest. There appears to be an inverse relationship between MSI 'severity' (status) and p53 mutation (Cottu et al, 1996;Breivik et al, 1997;Olschwang et al, 1997;Forster et al, 1998;Iacopetta et al, 1998), which seems paradoxical as a greater rate of p53 mutation in higher 'mutator phenotype' MSI-H cancers might be expected. The mechanism underlying this effect is unclear but might relate to the degree of DNA methylation and consequently gene activity in the MMR genes (Cunningham et al, 1998;Kuismanen et al, 1999), although this has not been described.…”

mentioning

confidence: 99%

Activity (transcription) of the genes for MLH1, MSH2 and p53 in sporadic colorectal tumours with micro-satellite instability

et al. 2004

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Micro-satellite instability (MSI) is relevant in the management of colorectal cancers (CRC) and relies on analysis of gene mutations, or production of the proteins involved in DNA mismatch repair (e.g. MLH1, MSH2). p53 mutation is also relevant in MSI, but high-level CRC (MSI-H) demonstrate fewer mutations than low-level (MSI-L) or stable (MSS) cancers. Recently, the importance of gene activity (transcription) in MSI has been identified, where rather than being mutated genes have been downregulated. In this study, 67 sporadic CRC and eight samples of normal bowel were analysed for MSI status (by SSCP) and levels of MLH1, MSH2 and p53 gene transcription (by RT -PCR and scanning densitometry). Micro-satellite instability correlated with gender and site, with more MSI-H CRC in females (Po0.02) and in the right colon (Po0.04). In MSI-H, p53 transcription was markedly reduced (Po0.003). Compared to normal bowel, MLH1 transcription was elevated in all cancers (Po0.01), while MSH2 transcription was elevated only in MSI-H (Po0.04). There was a direct correlation between MLH1 and MSH2 transcription (Po0.001). Although fewer mutations are reported in MSI-H than MSI-L/MSS, these results suggest that reduced p53 transcription might account for decreased tumour suppression in MSI-H. The direct correlation between MLH1 and MSH2 transcription suggests that control of these genes might be coordinated.

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Microsatellite instability in sporadic carcinomas of the proximal colon: Association with diploid DNA content, negative protein expression of p53, and distinct histomorphologic features

Cited by 66 publications

References 13 publications

Chromosomal instability and p53 inactivation are required for genesis of glioblastoma but not for colorectal cancer in patients with germline mismatch repair gene mutation

Chromosomal instability and p53 inactivation are required for genesis of glioblastoma but not for colorectal cancer in patients with germline mismatch repair gene mutation

Expression of apoptosis-related markers and clinical outcome in patients with advanced colorectal cancer

Activity (transcription) of the genes for MLH1, MSH2 and p53 in sporadic colorectal tumours with micro-satellite instability

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