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Replication Errors (replication + error)
Selected AbstractsMicrosatellite Instability and k- ras, p53 Mutations in Thyroid LymphomaCANCER SCIENCE, Issue 3 2000Tetsuya Takakuwa Patho-epidemiological studies showed that thyroid lymphoma (TL) arises in inflammatory lesions of chronic lymphocytic thyroiditis (CLTH). Replication error (RER) is found in inflammatory lesions and associated cancer, suggesting that chronic inflammation could be a risk factor for neoplastic development through causing RER. To clarify whether RER is involved in the pathogenesis of TL, we examined the microsatellite instability (MSI) in 9 cases with CLTH and 19 with TL, including 10 diffuse large B-cell lymphoma (DLBL), 4 follicle center cell lymphoma, 3 marginal zone B-cell lymphoma of extranodal (MALT) type, and 2 lymphoplasmacytic type. Sixteen distinct microsatellite repeats were analyzed. Mutations of p53 and k- ras genes were also examined. When alterations at 2 or more microsatellite loci were judged as positive, only 5 DLBL cases exhibited MSI. The frequency of MSI in DLBL was significantly higher than that in other types of TL and CLTH (P < 0.05). Four of 19 cases (21.1%) showed point mutation of the k- ras gene. The k- ras mutations occurred in the cases with DLBL with RER, and four of five cases with RER had a k- ras mutation, indicating a close association between RER and k- ras mutation. p53 mutations were not found in the CLTH. Two of 19 TL cases showed mutations of p53 gene. There was no significant association between RER and p53 mutation. These findings indicate that genomic instability contributes to the progression of TL from low grade to high grade, but not to the development of low grade lymphoma in CLTH lesions. [source] Microsatellite instability and its relevance to cutaneous tumorigenesisJOURNAL OF CUTANEOUS PATHOLOGY, Issue 5 2002Mahmoud R. Hussein Increasing evidence suggests that human tumors sequentially accumulate multiple mutations that cannot be explained by the low rates of spontaneous mutations in normal cells (2,3 mutations/cell). The mathematical models estimate that for the solid tumors to develop, as many as 6,12 mutations are required in each tumor cell. Therefore, to account for such high mutation rates, it is proposed that tumor cells are genetically unstable, i.e. they have genome-wide mutations at short repetitive DNA sequences called microsatellites. Microsatellite repeats are scattered throughout the human genome, primarily in the non-coding regions, and can give rise to variants with increased or reduced lengths, i.e. microsatellite instability (MSI). This instability has been reported in an increasing number of cutaneous tumors including: melanocytic tumors, basal cell carcinomas and primary cutaneous T-cell lymphomas. Moreover, MSI has been observed in skin tumors arising in the context of some hereditary disorders such as Muir,Torre syndrome, Von Recklinghausen's disease and disseminated superficial porokeratosis. While MSI in some of these disorders reflects underlying DNA replication errors, the mechanism of instability in others is still unknown. Thus far, MSI is considered to be a distinct tumorigenic pathway that reveals surprising versatility. The ramifications for cutaneous neoplasms warrant further investigation. [source] XRCC4 codon 247*A and XRCC4 promoter ,1394*T related genotypes but not XRCC4 intron 3 gene polymorphism are associated with higher susceptibility for endometriosis,MOLECULAR REPRODUCTION & DEVELOPMENT, Issue 5 2008Yao-Yuan Hsieh Abstract DNA repair systems act to maintain genome integrity in the face of replication errors, environmental insults, and the cumulative effects of age. Genetic variants in DNA repair genes such as X-ray repair cross-complementing group 4 (XRCC4) might influence the ability to repair damaged DNA. Herein we aimed to investigate whether some XRCC4-related polymorphisms were associated with endometriosis susceptibility. Women were divided: (1) severe endometriosis (rAFS stage IV, n,=,136) and (2) nonendometriosis groups (n,=,112). The polymorphisms of XRCC4 codon 247, XRCC4 promoter ,1394, and XRCC4 intron 3 insertion/deletion (I/D) polymorphism were amplified by PCR and detected by electrophoresis after restriction enzyme (BBS I, Hinc II) digestions. Genotypes and allelic frequencies in both groups were compared. We observed that XRCC4 codon 247*A and XRCC4 promoter ,1394*T related genotypes, but not XRCC4 intron 3 I/D polymorphism, are associated with higher susceptibility for endometriosis. Distributions of XRCC4 codon 247*C homozygote/heterozygote/A homozygote, and C/A allele in both groups were: (1) 89/9.5/1.5% and 93.7/6.3%; (2) 97.3/2.7/0%, and 98.7/1.3% (P,<,0.05). Proportions of XRCC4 promoter ,1394*T homozygote/heterozygote/G homozygote and T/G allele in both groups were: (1) 94.1/5.2/0.7% and 96.7/3.3%, and (2) 79.4/17.9/2.7% and 88.4/11.6% (P,<,0.005). Proportions of XRCC4*I homozygote/heterozygote/D homozygote and A/C allele in both groups were: (1) 67.6/30.9/1.5% and 83.2/16.8%, and (2) 70.5/24.1/5.4% and 82.6/17.4% (nondifference). We conclude that XRCC4 codon 247*A and XRCC4 promoter ,1394*T related genotypes and alleles, but not XRCC4 intron 3 I/D polymorphism, might be associated with endometriosis susceptibilities and pathogenesis. Mol. Reprod. Dev. 75: 946,951, 2008. © 2008 Wiley-Liss, Inc. [source] Microsatellite instability in esophageal squamous cell carcinoma is not associated with hMLH1 promoter hypermethylationPATHOLOGY INTERNATIONAL, Issue 5 2003Masahiro Hayashi To test whether a subset of esophageal squamous cell carcinomas (SCC) develop through a deficiency in DNA mismatch repair, we examined microsatellite instability (MSI) using 11 microsatellite markers including BAT-26, hMLH1 protein expression by immunohistochemistry, and methylation status of the hMLH1 promoter by methylation-specific polymerase chain reaction (MSP). p53 mutations were also investigated. Microsatellite instability at one or more loci was observed in 40% (12/30) of esophageal SCC tumor samples, although only one of these tumors was categorized as high-frequency MSI (MSI-H) and none showed BAT-26 instability. While immunohistochemistry revealed decreased hMLH1 protein expression in 27% (8/30) of the tumors, hMLH1 promoter hypermethylation was not observed. Absence of hMLH1 protein expression was relatively common in well-differentiated (keratinizing-type) esophageal SCC, but was not associated with hMLH1 promoter hypermethylation. p53 mutation was detected in 37% (11/30) and loss of heterozygosity (LOH) in 90% (27/30) of esophageal SCC samples. Our results suggested that most esophageal SCC develop through defects in tumor suppressor genes (i.e. the suppressor pathway), and that MSI in esophageal SCC probably represent random replication errors rather than being associated with DNA mismatch repair deficiency. [source] Spindles losing their bearings: Does disruption of orientation in stem cells predict the onset of cancer?BIOESSAYS, Issue 6 2010Trevor A. Graham Abstract Recently, Quyn et al. demonstrated that cells within the stem cell zone of human and mouse intestinal crypts tend to align their mitotic spindles perpendicular to the basal membrane of the crypt. This is associated with asymmetric division, whereby particular proteins and individual chromatids are preferentially segregated to one daughter cell. In colonic mucosa containing a heterozygous adenomatous polyposis coli gene (APC) mutation the asymmetry is lost. Here, we discuss asymmetric stem cell division as an anti-tumourigenic mechanism. We describe how hierarchical tissue structures suppress somatic evolution, and discuss the relative merits of template strand retention to limit the accumulation of DNA replication errors. We suggest experiments to determine whether somatic mutations resulting in loss of spindle alignment confer an advantage within the stem cell niche. Finally, we discuss whether lack of spindle alignment constitutes an oncogenic event per se, with particular reference to studies in model organisms, and the timing of chromosomal instability in human cancers. [source] | |||||||||||||