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PubMed2004

mtDNA mutations in tumors of the central nervous system reflect the neutral evolution of mtDNA in populations.

Mitochondrial DNA (mtDNA) instability has been observed in different types of cancer, including colorectal, breast, and gastric cancer. The relationship between the occurrence of such alteration and the nuclear microsatellite instability (nMI) status of the neoplastic cells remains controversial. In an attempt to clarify this issue, we sequenced the first and second mtDNA hypervariable regions, and typed the mitochondrial (CA)(n) dinucleotide polymorphism in 69 patients with primary tumors of the central nervous system (CNS), previously screened for nMI. Tumor samples showed 27 D-loop sequence changes (39.1%) compared to the corresponding blood samples. Microsatellite homoplasmic allele mutations were detected in four cases (5.8%). We did not find significant associations of the mtDNA instability status with clinicopathological parameters including sex, age, tumor size, and duration of clinical course. Neither did we find any association between mtDNA and nuclear instabilities, indicating that, at least in CNS tumors, they respond to different DNA repair mechanisms. We have also compiled the mtDNA instabilities previously reported by other authors for several types of tumors, comparing them to mtDNA polymorphisms in human populations. Most of the tumor-associated changes are common human polymorphisms and mutational hotspots. To explain the molecular behavior of mtDNA instability in tumors, we propose a model also common to other biological situations.

Central Nervous System Neoplasms↗
PubMed2003

Frequent microsatellite alterations in a predominantly younger age of onset breast cancer population.

Microsatellite instability (MSI) and loss of heterozygosity (LOH) was investigated in paired tumour and normal tissue DNA from 108 predominantly premenopausal breast cancer patients (under age 45 years at presentation) for 25 simple repeat loci interspersed across 11 chromosomes. MSI was observed at a single locus in 69 (64%) patients; 41 of these had instability at more than one site. Greatest frequency of MSI was at loci D2S1356 (33%), D2S2739 (22%), D3S1766 (21%) and D13S796 (20%). LOH was seen at a single site in 55% of patients and at two or more sites in 27 patients with greatest frequency at D2S1356 (33%), D2S443 (19%) and D17S1299 (18%). Both mutations were found in the same patient but at different loci. Clearly, choice of loci is a determining factor in assessing genomic instability. The relatively high frequency of MSI may also reflect peculiarities of this younger patient population. Occurrence of MSI or LOH was unrelated to clinical stage, nodal status, tumour size or grade or steroid receptor status. It was independent of mutations detected in exons 5-9 of the p53 gene. There was no significant association with survival. The lack of such correlations reflects a random disabling mechanism that may equally affect genes promoting cell death as well as growth.

Adult↗
PubMed2005

Microsatellite megatracts in the maize (Zea mays L.) genome.

Long tracts (megatracts) of (CAG)n, (TAG)n, and (GAA)n microsatellite sequences capable of forming composite DNA segments were found in the maize (Zea mays L.) genome. Some of the (CAG)n and (TAG)n megatracts were organized in clusters of up to 1 Mb on several chromosomes, as detected by fluorescence in situ hybridization (FISH), as well as on extended DNA fibers. Extensive polymorphism was found among different maize inbred lines with respect to the number and size of microsatellite megatract clusters on the A chromosomes. Polymorphism was also common among B chromosomes of different nuclei in the inbred line Zapalote Chico. Different retrotransposable elements were often inserted into the microsatellite tracts. Size variation in some (TAG)n and (GAA)n megatracts was observed in consecutive generations among siblings of the inbred lines, indicating that these loci are highly unstable and predisposed to dynamic mutations similar to those described in mammalian systems.

Blotting, Southern↗
PubMed1997

Involvement of the multiple tumor suppressor genes and 12-lipoxygenase in human prostate cancer. Therapeutic implications.

We performed a detailed and comprehensive study of the involvement of tumor suppressor genes in human prostate cancer. We utilized primers flanking either the restriction fragment length polymorphism (RFLP) or variable number of tandem repeat [VNTR; microsatellite or simple repeat site (SRS)] polymorphic sites to polymerase chain reaction (PCR) amplify the genomic DNA and detect loss of heterozygosity of the target genes. Quantitative reverse transcription (RT)-PCR was performed to measure the mRNA expression levels and PCR/single strand conformational polymorphism (SSCP) and DNA sequencing carried out to detect mutation of the tumor suppressor genes. We found that multiple tumor suppressor genes (e.g., p53, DCC, APC, MCC, BRCA1, and WAF1/CIP1) were inactivated at different frequencies via various mechanisms [e.g., loss of heterozygosity (LOH), loss of expression (LOE), mutation, and inactivation by cellular binding protein]. Several important and novel findings are as following: LOH and LOE of the DCC gene, LOH, LOE, and possible mutation of the APC/MCC genes, LOH of the BRCA1 locus, and mutation of the WAF1/CIP1 gene. For p53 tumor suppressor gene alone, multiple inactivation mechanisms (i.e., LOH, LOE, mutation, and amplification of the cellular inactivating protein MDM2) were identified. A possible involvement of genomic instability or mutator phenotype in human prostate cancer was investigated by microsatellite typing using PCR. A high frequency of microsatellite instability was detected and the microsatellite instability found to correlate with advanced stage and poor differentiation of prostate cancer, suggesting that genes functioning in DNA mismatch repair or general stabilization of the genome may be involved in prostate cancer. The results obtained in this study suggested that multiple tumor suppressor genes (both known and unknown genes) may share the role in prostate cancer; a pattern which has been found in a number of human malignancies such as cancers of the esophagus, colon and breast. In fact, we performed deletion studies aimed at localizing potential tumor suppressor loci on various chromosomal regions. A number of chromosomal regions (i.e., 6p12-24 and 17q21) were found to potentially harbor unidentified tumor suppressor genes. Detailed deletion mapping has localized the potential tumor suppressor loci to a < 2 Mb region centromeric to the BRCA1 gene on chromosome 17q. In addition, we identified a number of novel mechanisms of tumor suppressor gene inactivation, in prostate cancer such as loss of mRNA expression of the DCC, APC, MCC and p53 gene, and mutator phenotype. And for the very first time, we identified somatic mutations of the WAF1/CIP1 gene in primary human malignancy-human prostate cancer. This finding provides the first evidence in primary tumor that the WAF1/CIP1 gene may be a tumor suppressor gene and may be involved in prostate cancer. We identified 12-lipoxygenase (12-LOX) as a potential prognostic marker for human prostate cancer. mRNA expression levels of the 12-LOX gene was measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR) and semi-quantitative in situ hybridization (ISH) in 122 pairs of matched normal and tumor tissues from prostate cancer patients. We found that 12-LOX expression levels were elevated in approximately half of the patients analyzed and the 12-LOX elevation correlates with advanced stage, poor differentiation, and surgical margin positivity. Our data suggest that 12-LOX may serve as a correlative marker for a more aggressive phenotype of prostate cancer and therefore for poor prognosis. We are currently refining our assays for possible clinical applicability. Since not all patients with loss of expression of the DCC gene showed LOH of the DCC locus, there must be other mechanism(s) responsible for loss of expression of the DCC gene. When we analyzed the relationship between DCC loss of expression and 12-LOX elevation in prostate cancer pati

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed2000

Hereditary non-polyposis colorectal cancer associated with disseminated superficial porokeratosis. Microsatellite instability in skin tumours.

A 73-year-old man presented with typical lesions of disseminated superficial porokeratosis (DSP) and multiple seborrhoeic keratoses on his face, trunk and extremities, and later developed a keratoacanthoma on his lip. He belonged to a cancer-prone pedigree susceptible to colonic, uterine and other internal cancers, and had a personal history of early gastric cancer and advanced adenocarcinoma of the descending colon without adenomatous polyps at age 59 years. Polymerase chain reaction amplification of skin samples for seven separate microsatellite polymorphisms revealed microsatellite instability (MSI) at multiple loci in five of six seborrhoeic keratoses and the keratoacanthoma, strongly suggesting underlying defects in DNA mismatch repair. Although no germline mutations in two mismatch repair genes hMSH2 and hMLH1 were found, our patient was recognized as having hereditary non-polyposis colorectal cancer (HNPCC) based on the family history and the findings of the microsatellite analysis of skin tumours. This confirmed the usefulness of detection of MSI in prevalent and readily accessible skin lesions, including non-sebaceous non-dysplastic tumours such as seborrhoeic keratosis in the screening of HNPCC families. Although DSP may also be inherited as an autosomal dominant condition, this particular skin disease appeared to be sporadic in our patient and, to our knowledge, no association of DSP or other forms of porokeratosis with HNPCC has previously been reported. In contrast to the seborrhoeic keratoses and keratoacanthoma, no MSI was observed in two samples from DSP lesional epidermis examined.

Adult↗
PubMed1998

Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1.

Recent studies have demonstrated the presence of microsatellite instability (MSI) in tumors from patients with hereditary nonpolyposis colorectal cancer and in a large number of sporadic tumors. To further characterize the type of alterations at these loci and their frequency of involvement in colon cancer, we studied DNA extracted from paraffin-embedded tissue from 508 patients using 11 microsatellites localized to chromosomes 5, 8, 15, 17, and 18. Overall, MSI at each locus varied in character and frequency and was observed with at least one marker in 191 cases (37.6%). Based on the number of markers displaying instability per tumor, three groups of patients were defined: those with <30% of the markers showing instability (MSI-L,, n = 109, 21.5%); those with > or = 30% (MSI-H, n = 82, 16.1%); and those showing no instability (MSS, n = 317, 62.4%). These groups were tested for correlations with a number of clinical and pathological parameters, including age, sex, stage, ploidy status, and site of tumor. Comparing across the three groups and verified by pair-wise comparisons, the MSI-H group was associated with tumor site (proximal colon, P = 0.001), sex (females, P = 0.005), stage (Dukes' B, P = 0.01), and ploidy status (diploid, P = 0.03). No significant differences were noted between the MSI-L and MSS group for any of the parameters tested. An additional 188 consecutive surgical colorectal cancer cases were examined for the presence of MSI and for the immunohistochemical expression of hMLH1 and hMSH2 proteins. Of this group, 129 (68.6%) were classified as MSS, 17 (9.0%) as MSI-L, and 42 (22.3%) as MSI-H. None of the MSS and none of the MSI-L tumors had altered expression of either hMLH1 or hMSH2. However, the majority of MSI-H (40 of 42, 95%) cases demonstrated absence of staining for these proteins. The most frequently altered protein was hMLH1, occurring in 95% of the tumors with altered expression. Cumulatively, these data suggest that the tumor phenotype MSI-H is distinct from tumor phenotypes MSI-L and MSS, with no apparent differences between MSI-L and MSS. Furthermore, altered hMLH1 protein expression appears to be responsible for the mutator phenotype in the vast majority of MSI-H tumors.

Adaptor Proteins, Signal Transducing↗
PubMed2004

The contribution of genetic and epigenetic changes in granulosa cell tumors of ovarian origin.

PURPOSE: Granulosa cell tumors (GCTs) are relatively rare and are subtypes of the sex-cord stromal neoplasms. A better understanding of the molecular genetics underlying various steps in malignant transformation is critical to success in the battle against this disease. Changes in the status of methylation, known as epigenetic alterations, are one of the most common molecular alterations in human cancers, including GCTs. Chromosomal instability and microsatellite instability (MSI) are common in these GCTs. We tested the hypothesis that C-->T transition polymorphism in the promoter region of cytosine DNA-methyltransferase-3B (DNMT3B) and its altered expression are also associated with hypermethylation of the genes. We also attempted to determine the relationship between MSI of ovarian carcinoma and hMLH1 hypermethylation in these tumors. EXPERIMENTAL DESIGN: We studied chromosome instability in 25 GCTs by detecting gross chromosome rearrangements in cultured peripheral blood lymphocytes. MSI was assessed using six microsatellite markers (BAT25, BAT26, D2S123, D5S346, D11S1318, and D17S250). Using sensitive methylation-specific PCR, we searched for aberrant promoter hypermethylation in a panel of genes including p16, BRCA1, RASSF1A, ER-alpha, TMS1, TIMP3, Twist, GSTP1, AR, and hMLH1. Polymorphism in the DNMT3B gene was assessed by the PCR-RFLP method, and DNMT3B expression was studied by reverse transcription-PCR assay. RESULTS: Chromosome instability was indicated by significantly higher frequencies of chromosome aberrations (6.24%; P < 0.001) compared with controls (2.12%). The most frequently observed changes include trisomy 14 and monosomy 22. MSI has been found in 19 of 25 tumors, and loss of heterozygosity has been found in 9 of 25 tumors. Frequencies of methylation in GCTs were 40% for p16 and ER-alpha; 36% for BRCA1 and RASSF1A; 28% for hMLH1; 24% for TIMP3, Twist, and GSTP1; and 20% in TMS1 and AR. TT genotype was found only in two cases; the remainder were either CC or CT type. There was no significant alteration in the expression of DNMT3B in these patients. CONCLUSIONS: Coexistence of chromosome instability, MSI, and hypermethylation suggests that both genetic and epigenetic mechanisms may act in concert to inactivate the above-mentioned genes in these GCTs. These mechanisms can be an early event in the pathogenesis of these tumors, and it can be a critical step in the tumorigenic process. All these events might play an important role in early clinical diagnosis and in chemotherapeutic management and treatment of the disease. Larger studies may lend further understanding to the etiology and clinical behavior of these tumors.

Chromosome Aberrations↗
PubMed2005

Mismatch repair proteins are activators of toxic responses to chromium-DNA damage.

Chromium(VI) is a toxic and carcinogenic metal that causes the formation of DNA phosphate-based adducts. Cr-DNA adducts are genotoxic in human cells, although they do not block replication in vitro. Here, we report that induction of cytotoxicity in Cr(VI)-treated human colon cells and mouse embryonic fibroblasts requires the presence of all major mismatch repair (MMR) proteins. Cr-DNA adducts lost their ability to block replication of Cr-modified plasmids in human colon cells lacking MLH1 protein. The presence of functional mismatch repair caused induction of p53-independent apoptosis associated with activation of caspases 2 and 7. Processing of Cr-DNA damage by mismatch repair resulted in the extensive formation of gamma-H2AX foci in G(2) phase, indicating generation of double-stranded breaks as secondary toxic lesions. Induction of gamma-H2AX foci was observed at 6 to 12 h postexposure, which was followed by activation of apoptosis in the absence of significant G(2) arrest. Our results demonstrate that mismatch repair system triggers toxic responses to Cr-DNA backbone modifications through stress mechanisms that are significantly different from those for other forms of DNA damage. Selection for Cr(VI) resistant, MMR-deficient cells may explain the very high frequency of lung cancers with microsatellite instability among chromate workers.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Use of microsatellite instability and immunohistochemistry testing for the identification of individuals at risk for Lynch syndrome.

It is now generally recognized that a specific subset of those patients clinically defined as having hereditary non polyposis colon cancer (HNPCC) have germline mutations in any one of several genes involved in DNA mismatch repair (MMR). This important subset of HNPCC families is now defined as having Lynch syndrome. A considerable amount of data has shown that tumors from patients with Lynch syndrome have characteristic features resulting from the underlying molecular involvement of defective MMR, that is, the presence of microsatellite instability (MSI) and the absence of MMR protein expression by immunohistochemistry (IHC). As a result, identifying patients with Lynch syndrome can now be accomplished by testing tumors for these tumor-related changes. Together, MSI and IHC are powerful tools that help identify individuals at risk for having Lynch syndrome and to distinguish these cases from HNPCC cases with other hereditary gene defects. Furthermore, IHC analysis provides valuable clues as to which MMR gene is mutated, allowing for comprehensive mutational analyses of that gene. Here, we discuss the current and historical perspectives regarding MSI and IHC analyses in tumors from sporadic colon cancer and from patients with Lynch syndrome. Given this background, we also provide a testing strategy for the identification of patients at risk for Lynch syndrome and subsequent gene testing.

Base Pair Mismatch↗
PubMed1999

The potential of molecular screening.

Clonal genetic alterations such as tumor suppressor, gene mutations, or microsatellite instability are a hallmark of human cancer. These genetic alterations can be detected in clinical samples using DNA amplification techniques and used for early detection of cancer. This article reviews molecular-based approaches for screening of malignancies commonly encountered by the practicing general surgeon.

Biomarkers, Tumor↗
PubMed1999

Genetic instability and the etiology of somatic PIG-A mutations in paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH) is a hematologic disorder characterized by acquired PIG-A gene mutations that lead to defective bioassembly of glycosylphosphatidylinositol (GPI) anchors and the absence of GPI-linked surface proteins. As the etiology of these acquired PIG-A gene mutations is unknown, we hypothesized that patients with PNH have overall genetic instability and acquire somatic mutations throughout their genome. We first analyzed microsatellite sequences and found equivalent size variation using DNA from GPI-negative granulocytes compared with the DNA of paired GPI-positive B cell lines or normal granulocytes. We next quantitated the frequency of mutations at the hypoxanthine-guanine phosphoribosyl transferase (hprt) gene locus, and found 1 PNH patient with a large increase in hprt mutant frequency (256.7 x 10(-6) vs. 27.8 +/- 19.9 x 10(-6) for normal adults) that was confirmed on 4 independent blood samples. We also quantitated "illegitimate" VDJ genetic recombination events between the T cell receptor V gamma and J beta gene loci, and found a second PNH patient with a large increase (43.5 events per microgram of DNA vs. 1.3 +/- 0.8 events per microgram of DNA for normal adults), confirmed on 4 independent DNA samples. Both of these PNH patients are young females with no history of aplastic anemia. Our data show that PNH patients can have increased numbers of acquired somatic mutations in gene loci distinct from PIG-A. These data suggest that genetic instability may be associated with the development of PIG-A mutations that lead to the clinical picture of PNH.

Adolescent↗
PubMed2025

DNA damage repair gene alterations influence the tumor immune microenvironment in advanced non-small cell lung cancer.

PURPOSE: DNA damage response and repair (DDR) gene alterations contribute to genomic instability and increased tumor immunogenicity, yet their clinical significance in non-small cell lung cancer (NSCLC) remains unclear. Using a large real-world dataset, we evaluated the prevalence of DDR alterations and their relation to the tumor immune microenvironment in metastatic NSCLC. EXPERIMENTAL DESIGN: We retrospectively analyzed real-world data from patients with metastatic NSCLC using the Tempus AI database. Tumors were sequenced with Tempus xT DNA and xR RNA assays and classified based on the presence (DDRmt) or absence (DDRwt) of a pathogenic somatic alteration or copy number deletion in a DDR pathway gene. Associations between DDR alterations and immune cell infiltration, PD-L1 immunohistochemistry, tumor mutational burden (TMB), and microsatellite instability (MSI-H) were examined. RESULTS: Among 14,127 patients (median age&#xa0;=&#xa0;67, 49% female), 5,276 (37%) were DDRmt. There was a higher prevalence of current/former smokers in the DDRmt group (86% vs. 82%; p<0.001). DDRmt tumors were more likely to have higher levels of TMB (median: 5.4 vs. 4.6; p<0.001), MSI-H (1.1&#xa0;% vs.&#xa0;<0.1&#xa0;%; p<0.001), and infiltrating CD8+ T cells (p=0.003) compared to DDRwt tumors. A lower frequency of macrophages (p<0.001) were observed among DDRmt compared with DDRwt tumors with no difference in PDL1 positivity. CONCLUSIONS: Among patients with metastatic NSCLC, 37% present with DDRmt tumors characterized by higher TMB, frequency of MSI-H, and changes in immune cell infiltrates. These findings provide insight into the immunogenic landscape of DDR-altered NSCLC and may inform biomarker selection and therapeutic strategies.

Humans↗
PubMed2006

Thymidylate synthase expression in colon carcinomas with microsatellite instability.

PURPOSE: Colon cancer cells with high-frequency microsatellite instability (MSI-H) display resistance to 5-fluorouracil (5-FU) that can be reversed by restoring DNA mismatch repair (MMR) proficiency. Given that thymidylate synthase (TS) is inhibited by 5-FU, we studied the relationship between MSI and TS expression, and the prognostic effect of these and other markers (i.e., p53 and 17p allelic imbalance). EXPERIMENTAL DESIGN: Dukes' stage B2 and C colon carcinomas (n = 320) from participants in 5-FU-based adjuvant therapy trials were analyzed for MSI and 17p allelic imbalance. Expression of MMR (hMLH1, hMSH2), TS, and p53 proteins were analyzed by immunohistochemistry. Correlations between markers and associations with overall survival were determined. RESULTS: Of 320 cancers studied, 60 (19%) were MSI-H. TS expression variables were similar in MSI-H and microsatellite stable/low-frequency MSI (MSS/MSI-L) cancers, and unrelated to MMR proteins. MSI-H tumors had lower stage (P = 0.0007), fewer metastatic lymph nodes (P = 0.004), and improved overall survival (P = 0.01). Loss of MMR proteins was also associated with better overall survival (P = 0.006). None of the TS variables were prognostic. Histologic grade (P = 0.0008) and nodal status (P = 0.0002) were associated with overall survival, in contrast to 17p allelic imbalance or p53. Only MSI status or loss of MMR proteins, histologic grade, and tumor stage were independent markers for overall survival. CONCLUSIONS: MSI-H tumors show earlier stage at presentation and better stage-adjusted survival rates. MSI status and TS expression were unrelated and TS was not prognostic, suggesting that TS levels cannot explain therapeutic resistance to 5-FU reported in MSI-H colon cancers.

Antimetabolites, Antineoplastic↗
PubMed2006

Tumor-specific hyperactive low-molecular-weight cyclin E isoforms detection and characterization in non-metastatic colorectal tumors.

PURPOSE: Several molecules involved in cancer biology have been studied as potential prognostic markers. Recently, overexpression of cyclin E and its low-molecular-weight (LMW) isoforms has been reported to be the most prominent prognostic marker in breast cancer, surpassing proliferation index, ploidy, and axillary nodal involvement. Furthermore, cyclin E and p53 are considered the main factors controlling the euploid equilibrium in human cells. We investigated the status of cyclin E and p53 in cell lines and tissue samples of colorectal cancer, one of the leading causes of death from a tumor in the Western world. EXPERIMENTAL DESIGN: We analyzed colorectal cancer cells, from established cell lines and patient specimens, to determine the protein levels of cyclin E and p53, and to detect p53 and APC mutations, microsatellite and chromosome instability. In addition, we assessed the presence of cyclin E LMW isoforms and their enzymatic activity. RESULTS: Colorectal cancer cells expressed hyperactive LMW forms both in vitro and in vivo. These tumor-specific isoforms are correlated to genomic instability even in p53-proficient cells, and represented a constant feature in the tumors analyzed. CONCLUSIONS: In colorectal cancer, the formation of cyclin E LMW forms is an early event leading to DNA-damage checkpoint-independent proliferation. Collectively, our results provide evidence that evaluation of LMW forms could represent a novel tool in the molecular characterization of colorectal tumors aimed at identifying sensitive prognostic factors and uncovering subsets of high-risk patients within the traditional categories.

Adenomatous Polyposis Coli Protein↗
PubMed2000

Microsatellite instability at selected tetranucleotide repeats is associated with p53 mutations in non-small cell lung cancer.

Microsatellite alterations are useful clonal markers for the early detection of cancer. An increase in microsatellite instability has been observed at certain tetranucleotide repeat markers (AAAGn) in lung, head and neck, and bladder cancer. However, the genetic mechanism underlying these elevated microsatellite alterations at selected tetranucleotide repeat (EMAST) tumors is still unknown. The p53 gene plays an important role in maintaining genome integrity by repairing damaged DNA. Therefore, we tested 88 non-small cell lung cancers with a panel of 13 microsatellite markers previously shown to exhibit frequent instability and also performed p53 sequence analysis in these tumors. Thirty-one of these 88 cancers (35%) demonstrated a novel allele [EMAST(+)] in > or =1 of these 13 microsatellite markers. p53 mutations were detected in 50 of 88 (57%) cancers and were significantly (P = 0.001) more common in EMAST(+) tumors (25 of 31; 81%) than in EMAST(-) tumors (25 of 57; 44%). Among squamous cell cancers, p53 mutations were detected significantly (P = 0.04) more frequently in EMAST(+) tumors (17 of 19; 89%) than in EMAST(-) tumors (10 of 18; 55%). Similarly, among primary adenocarcinomas, p53 mutations were present in 67% of the EMAST(+) tumors and in 35% of EMAST(-) adenocarcinomas. None of the 31 EMAST(+) tumors demonstrated high frequency microsatellite instability when examined with a reference panel of five mono- and dinucleotide markers. Primary lung cancers with microsatellite alterations at selected tetranucleotide repeats have a high frequency of p53 mutations and do not display a phenotype consistent with defects in mismatch repair.

Adenocarcinoma↗
PubMed2006

Analysis of the differences in structural chromosomal aberrations of the gastric mucosa between H. pylori positive and negative gastric cancer patients: involvement of H. pylori in the onset of gastric cancer and examination of the mechanism in gastric carcinogenesis following H. pylori eradication.

Gene mutations are essential to carcinogenesis. If an evident difference is observed in gastric mucosal chromosomal structure aberrations between H. pylori (Hp)-negative and Hp-positive gastric cancer patients, it may be interpreted as suggesting the involvement of Hp in gene mutations. This study was undertaken to compare chromosomal structural aberrations between Hp-negative and Hp-positive gastric cancer patients and to evaluate the effects of Hp eradication on chromosomal structures in clinical cases. The subjects of this study were 40 patients with gastric cancer divided into four groups: Group A was composed of 12 patients with Hp-negative gastric cancer (well-differentiated gastric cancer in 5 cases and poorly-differentiated in 7 cases), Group B of 8 patients with Hp-negative gastric cancer following Hp eradication (well-differentiated in 4 case and poorly-differentiated in 4 cases), Group C of 13 patients with Hp-positive gastric cancer (well-differentiated in 7 cases and poorly-differentiated in 6 cases) and Group D of 7 patients with gastric cancer (well-differentiated in 5 cases and poorly-differentiated in 2 cases) undergoing Hp eradication at subtotal gastrectomy. In each of the groups A, B and C, the structural chromosomal aberration such as loss of heterozygosity (LOH) and microsatellite instability (MSI) was analyzed. In Group D, changes in structural chromosomal aberrations after Hp eradication as compared to the pre-eradication structures were also analyzed. LOH and MSI were examined by PCR, using DNA extracted from the cancer-affected and intact gastric mucosal tissue specimens from each patient. In A, B and C groups, structural chromosomal aberrations were noted, and these aberrations tended to be more marked in cases of poorly-differentiated gastric cancer in each group. In terms of structural chromosomal aberrations, there was no marked difference between Group A and either Group B or C. Hp eradication resulted in no change in chromosomal structure as compared to the pre-eradication structure in Group D. These results suggest the possibility that Hp eradication does not affect chromosomal structures and Hp is involved in gastric carcinogenesis as an additive environmental factor rather than as a factor acting at the gene level.

Anti-Bacterial Agents↗
PubMed2001

Replication slippage involves DNA polymerase pausing and dissociation.

Genome rearrangements can take place by a process known as replication slippage or copy-choice recombination. The slippage occurs between repeated sequences in both prokaryotes and eukaryotes, and is invoked to explain microsatellite instability, which is related to several human diseases. We analysed the molecular mechanism of slippage between short direct repeats, using in vitro replication of a single-stranded DNA template that mimics the lagging strand synthesis. We show that slippage involves DNA polymerase pausing, which must take place within the direct repeat, and that the pausing polymerase dissociates from the DNA. We also present evidence that, upon polymerase dissociation, only the terminal portion of the newly synthesized strand separates from the template and anneals to another direct repeat. Resumption of DNA replication then completes the slippage process.

Binding Sites↗