Optimising methods for determining RER status in colorectal cancers

Stone, Joanne; Tomlinson, Ian; Houlston, Richard S.

doi:10.1016/s0304-3835(99)00324-9

Cited by 22 publications

(15 citation statements)

References 11 publications

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“…Multiple informative markers located close to APC, TP53, and CDKN2A were available for some patients; in these cases, LOH was called if it was shown by at least 2 of the 3 available markers. Microsatellite instability was assessed using multiplexed assay for the BAT-25 and BAT-26 mononucleotide repeats 29 ; the presence of microsatellite instability in a sample precluded reliable LOH analysis. Primer details are listed in Supplementary Table 2.…”

Section: Methodsmentioning

confidence: 99%

Field Cancerization in the Intestinal Epithelium of Patients With Crohn's Ileocolitis

et al. 2012

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Background & Aims Tumors that develop in patients with Crohn's disease tend be multifocal, so field cancerization (the replacement of normal cells with non-dysplastic but tumorigenic clones) might contribute to intestinal carcinogenesis. We investigated patterns of tumor development from pretumor intestinal cell clones. Methods We performed genetic analyses of multiple areas of intestine from 10 patients with Crohn's disease and intestinal neoplasia. Two patients had multifocal neoplasia; longitudinal sections were collected from 3 patients. Individual crypts were microdissected and genotyped; clonal dependency analysis was used to determine the order and timing of mutations that led to tumor development. Results The same mutations in KRAS, CDKN2A(p16), and TP53 that were observed in neoplasias were also present in nontumor, nondysplastic, and dysplastic epithelium. In 2 patients, carcinogenic mutations were detected in nontumor epithelium 4 years before tumors developed. The same mutation (TP53 p.R248W) was detected at multiple sites along the entire length of the colon from 1 patient; it was the apparent founder mutation for synchronous tumors and multiple dysplas-tic areas. Disruption of TP53, CDKN2A, and KRAS were all seen as possible initial events in tumorigenesis; the sequence of mutations (the tumor development pathway) differed among lesions. Conclusions Pretumor clones can grow extensively in the intestinal epithelium of patients with Crohn's disease. Segmental resections for neoplasia in patients with Crohn's disease might therefore leave residual pretumor disease, and dysplasia might be an unreliable biomarker for cancer risk. Characterization of the behavior of pretumor clones might be used to predict the development of intestinal neoplasia.

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Section: Methodsmentioning

confidence: 99%

Field Cancerization in the Intestinal Epithelium of Patients With Crohn's Ileocolitis

et al. 2012

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“…[27][28][29] To determine the linkage of Bax-frameshift mutations to high MSI and global MMR deficiency, we perfomed a PCR fragment-length analysis for BAT-25 and BAT-26. Informative results were obtained in 113 of the 116 tumors and eight tumors (6.9%) were identified as microsatellite instable, which is in line with frequencies for BAT-25/BAT-26 microsatellite instable tumors as reported by other groups.…”

Section: Analysis For Msimentioning

confidence: 99%

Combined p53/Bax mutation results in extremely poor prognosis in gastric carcinoma with low microsatellite instability

et al. 2003

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Gastric cancer is highly refractory to DNA-damaging therapies. We therefore studied both gene mutation and protein expression of p53 and Bax in a cohort of 116 patients with gastric cancer who underwent R0-resection with a curative intent. Bax mutation was independent from severe microsatellite instability (MSI), that is, global mismatch repair deficiency as determined by analysis of BAT-25/BAT-26 microsatellite markers. Thus, Bax-frameshift mutation is a feature of tumors with low MSI. In contrast and as expected, no p53 mutations were observed in the microsatellite instable tumors. p53 Mutation or p53 overexpression did not have an impact on disease prognosis. p53-Inactivation was, however, associated with an extremely poor prognosis in the subgroup of patients with Bax-mutated tumors. Thus, we show for the first time that the combined mutation of p53 and Bax, two key regulators of the mitochondrial apoptosis pathway, results in an extremely aggressive tumor biology and poor clinical prognosis.

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“…[15][16][17] Microsatellite instability is also a distinctive feature in nearly 15-20% of sporadic colorectal tumors. [18][19][20] Replication-error-positive phenotype has been detected recently in other solid tumors [21][22][23][24] and in various lymphomas and leukemias. [25][26][27][28][29][30] The involvement of microsatellite instability in the pathogenesis of gastric lymphoma of MALT type is controversial, as both negative and positive findings were reported.…”

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confidence: 99%

Microsatellite instability in gastric MALT lymphoma

et al. 2004

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The role of microsatellite instability and defects in DNA mismatch repair mechanism in the pathogenesis of gastric lymphoma of mucosa-associated lymphoid tissue (MALT) type is still controversial, as both negative and positive findings have been reported. This may be explained mainly by arbitrary selection of the tested loci, the use of various techniques of microsatellite instability analysis and by different definitions of replication error positive phenotype. The aim of our study was to evaluate the instability at selected microsatellite markers using the GeneScan Analysis Software. DNA from paraffin-embedded tissue blocks of 13 previously untreated patients with localized gastric MALT lymphoma was extracted. Five microsatellite markers, which are located in hMSH2, hMLH1, P16, APC and MLL loci, were selected from the genetic database. We found genetic instability in tumors of 9/13 patients with gastric MALT lymphoma (69%). Seven of them had replication-error-positive phenotype (54%). Microsatellite instability was found in 39% of the samples in the MLL locus, 39% in the APC, 46% in the P16, 23% in the hMLH1 and none in the hMSH2. This study demonstrates that microsatellite instability has more prominent role in pathogenesis of gastric MALT lymphoma than reported to date. We suggest that microsatellite instability should be analyzed with markers adjacent to chromosomal loci that are involved in lymphomas. Our findings support the 'Real Common Target genes' theory of high rate of microsatellite instability in specific genes, which are associated with related tumors.

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Optimising methods for determining RER status in colorectal cancers

Cited by 22 publications

References 11 publications

Field Cancerization in the Intestinal Epithelium of Patients With Crohn's Ileocolitis

Field Cancerization in the Intestinal Epithelium of Patients With Crohn's Ileocolitis

Combined p53/Bax mutation results in extremely poor prognosis in gastric carcinoma with low microsatellite instability

Microsatellite instability in gastric MALT lymphoma

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