Microsatellite instability in sporadic colorectal carcinoma is not an indicator of prognosis

Feeley, K M; Fullard, John F.; Heneghan, Michael A.; Smith, Terry L.; Maher, Michael; Murphy, Ronan P.; O'Gorman, T

doi:10.1002/(sici)1096-9896(199905)188:1<14::aid-path323>3.0.co;2-q

Cited by 72 publications

(34 citation statements)

References 14 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).…”

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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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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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“…Salahshor et al (1999) found an obvious trend towards a better outcome of their MSI-H collective, but this was not statistically significant. Feeley et al (1999) could not see any impact of microsatellite status on patients' survival at all, but the validity of this study is limited by the low number of MSI-H cases. In summary, however, most studies revealed a longer disease-free and overall survival for patients with MSI-H CRC compared to MSS CRC (Watson et al, 1998;Gryfe et al, 2000;Samowitz et al, 2001).…”

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confidence: 75%

Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases

et al. 2005

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Colorectal carcinomas (CRCs) with high microsatellite instability (MSI-H) share clinicopathological features distinctly different from their microsatellite stable (MSS) counterparts. Unlike MSS cancers, MSI-H CRCs occur predominantly in the right-sided colon and are often characterised by a strong lymphocyte infiltration. A poor differentiation pattern is found in most MSI-H CRCs, even though patients with MSI-H carcinomas seem to have a significantly longer survival after surgical resection. To clarify which factors contribute to the obvious paradoxon of a more favourable prognosis of MSI tumours, several clinical and histopathological features as well as the microsatellite status were evaluated in 120 colorectal cancer cases fulfilling clinical criteria (Bethesda) indicative for familial colorectal cancer. Microsatellite instablity status and lymphocyte infiltration were related to tumour stage and patients' follow-up. Statistical analysis confirmed well-known relations, such as enhanced lymphocyte infiltration accompanied by Crohn's like reaction (CLR) in MSI-H cancers (CLR þ in 27 out of 47 MSI-H vs 14 out of 71 MSS CRCs, Po0.001). However, after stratification for depth of local invasion and penetration of the primary tumour, T3 tumours displaying MSI had a significantly lower rate of distant metastases (M1 in four out of 35 MSI-H vs 20 out of 41 MSS CRCs, Po0.001). A similar tendency was observed for CLR-positive CRCs (M1 in six out of 29 CLR þ vs 17 out of 45 CLRÀ CRCs, P ¼ 0.13). In a logistic regression model, the MSI-H phenotype and the presence of CLR were independent predictors of a low UICC stage (P ¼ 0.006 and 0.04, respectively). These data, together with the recent definition of highly immunogenic neo-antigens expressed in MSI-H tumour cells, suggest that MSI-H CRCs elicit a protective host response that may prevent metastasis formation.

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“…3,[8][9][10][11] This low mutational incidence is also accompanied by a decreased incidence of loss of heterozygosity (LOH), 1,3,12 which is reflected at the cytogenetic level in frequent (pseudo)diploidy. [13][14][15][16] The PTEN tumor suppressor gene is located on chromosome 10q23, consists of 9 exons and encodes a protein product of 403 amino acids with phosphatidylinositol, tyrosine and serine/threonine protein phosphatase activity. [17][18][19] Its relation with cancer appears to be centered mainly on its capability to antagonize the phosphatidylinositol 3,4,5-trisphosphate (PIP3) kinase activity, modulating negatively the PIP3-Akt signaling pathway.…”

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confidence: 99%

The relationship between microsatellite instability and PTEN gene mutations in endometrial cancer

Bilbao

Rodríguez

Ramírez

et al. 2006

Intl Journal of Cancer

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Microsatellite instability (MSI) and mutations in the PTEN gene are among the molecular alterations involved in endometrial carcinogenesis. There is conflicting information regarding to their role in this type of tumor. For this reason, we have studied both molecular lesions in a large population-based series of 205 patients with sporadic endometrial cancer. MSI was found in 41 (20.0%) of the tumors and PTEN mutations were found in 74 (36.1%). There were differences in genotype between tumors with and without MSI. Tumors with MSI showed both a higher frequency of PTEN mutations (58.5% vs. 30.4%) (p 5 0.002, Fisher's exact test) and a higher number of insertions or deletions (I/D) of one nucleotide within the mononucleotide tracts of the PTEN gene (45.8% vs. 11.4% out of all I/D, p 5 0.005). Conversely, G:C to A:T transitions in CpG dinucleotides were found mostly in microsatellite stable tumors (57.7% vs. 18.2% out of all single-base substitutions, p 5 0.037). Overall, 67.6% of tumors with mutated PTEN exhibited multiple mutations or allelic imbalance (AI). Multiple PTEN mutations in the same tumor were more frequent in tumors with MSI (60% vs. 25.7%); by contrast the presence of AI accompanying PTEN mutation was higher in microsatellite stable tumors (74.3% vs. 40%) (p 5 0.028). In addition, patients with both genetic alterations were diagnosed at more advanced stage of progression (54.2% for MSI vs. 20.0% for MSS, p 5 0.006), and exhibited a worse prognosis (hazard ratio [95% confidence interval]: 3.0 [1.1-13.1], p 5 0.034, log-rank test) than patients with only the PTEN gene mutated. Our data suggest that the DNA mismatch repair system status influences: (i) both the frequency and the mutational spectrum of PTEN; (ii) the nature of one of the hits that inactivate this tumor-suppressor gene; and (iii) the clinical condition and behavior of the patients. ' 2006 Wiley-Liss, Inc.Key words: microsatellite instability; PTEN mutation; endometrial cancer Microsatellite instability (MSI) is caused by defects in the DNA mismatch repair (MMR) system, either by mutations or by epigenetic events leading to gene silencing. 1,2 Tumors with MSI are characterized by a massive instability in simple repeated sequences and mutations in many cancer-related genes, particularly those with simple repeated sequences in their coding regions. [3][4][5][6][7] Tumors with MSI display a strong microsatellite mutator phenotype (MMP), which underlies a mutational pathway for gastrointestinal cancer that differs in genotype and phenotype from cancers with microsatellite stability (MSS).The MMP pathway for colon cancer possesses several peculiar characteristics in genotype. These tumors show a paradoxically low incidence of mutations affecting the prototypical cancer genes for colon cancer, namely the APC and p53 tumor suppressor genes and the K-ras oncogene. 3,[8][9][10][11] This low mutational incidence is also accompanied by a decreased incidence of loss of heterozygosity (LOH), 1,3,12 which is reflected at the cytogenetic level in freque...

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Microsatellite instability in sporadic colorectal carcinoma is not an indicator of prognosis

Cited by 72 publications

References 14 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

Microsatellite instability in colorectal cancer is associated with local lymphocyte infiltration and low frequency of distant metastases

The relationship between microsatellite instability and PTEN gene mutations in endometrial cancer

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