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Results for “DNA MICROSATELLITE INSTABILITY”

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PubMed2000

Frequent chromosomal instability but no microsatellite instability in hepatocellular carcinomas.

Microsatellite instability (MSI) phenotype, caused by a deficiency of DNA mismatch repair genes, has been detected in a subset of tumors in the gastrointestinal tract. However, it is not clear how MSI is involved in the tumorigenesis of hepatocellular carcinomas (HCC). Results with HCC are controversial, with positive results published with American and European tumors, but negative with Japanese tumors. We report the absence of MSI in 39 Korean HCCs after analysis with 6 mononucleotide- and over 150 dinucleotide-repeat markers. Only one such dinucleotide-repeat (D2S213) exhibited a reproducible shift in mobility, representing a somatic mutation present in only some of the tumor cells. This may be the result of a spontaneous error of replication due to the intrinsic mutability of these unstable sequences and without any connection to true genomic instability. In support of this interpretation, no frameshift mutations were found at the coding repeats of target genes for the microsatellite mutator phenotype including TGF-betaRII, BAX, hMSH3, and hMSH6. In contrast, we observed frequent allelic losses on chromosomes 4q, 8p, 16q, and 17p by the analysis of dinucleotide repeats (microallelotyping), reflecting a high degree of tumor chromosomal instability, which was significantly associated to the tumor differentiation (p=0.036, Fisher's exact test). These results suggest that, unlike chromosomal instability, widespread MSI plays no role in the development or progression of HCC.

Adolescent↗

PubMed2000

Absence of microsatellite instability in transitional cell carcinoma of the bladder.

OBJECTIVES: To investigate the prevalence of the microsatellite instability related to mismatch repair (MMR) gene defects using a panel of six microsatellite markers, as recommended by a recent workshop on microsatellite instability in colon cancer, because it is still unclear whether abnormalities in DNA MMR genes are involved in transitional cell carcinoma (TCC) of the bladder. METHODS: Three mononucleotide repeats (BAT26, TGFbetaRII, and BAX) were studied in 33 TCC samples and in four bladder cancer cell lines. Three dinucleotide repeats (D2S123, D5S346, and D17S250) were studied in 21 of these 33 TCC samples. RESULTS: No alteration was detected either in the 33 TCC samples analyzed or in the four bladder cancer cell lines (T24, J82, 647V, and 1207) studied. A difference between normal and tumor DNA was observed in only 1 of 21 tumor samples for D17S250. CONCLUSIONS: These data indicate that microsatellite instability is very uncommon in TCC of the bladder.

Aged↗

PubMed2003

Tumor-specific immunological recognition of frameshift-mutated peptides in colon cancer with microsatellite instability.

Colorectal cancers with microsatellite instability (MSI+ CRCs) caused by dysfunction of DNA mismatch repair have unique clinicopathological characteristics including good prognosis with T-cell infiltration in tumor. To identify tumor antigens that induce immune response against MSI+ CRC, SEREX (serological analysis of recombinant cDNA expression cloning) was applied. By screening a lambda phage cDNA library constructed from three MSI+ CRC cell lines with serum from a patient with MSI+ CRC with abundant T-cell infiltrates in tumor, 64 antigens were isolated. Immunogenicity of each antigen was evaluated by screening sera from patients with various cancers and from healthy individuals, and specific IgG antibodies (Abs) for 49 antigens were detected only in MSI+ CRC patients. A frameshift mutation in the repetitive G sequences (microsatellite) in the coding region of CDX2, one of the identified antigens, was found in the tumor tissue of the patient who had anti-CDX2 serum Ab. The Ab recognized both the COOH-terminal tumor-specific peptides created by the frameshift mutation and the NH(2)-terminal normal peptides of CDX2 when Western blot analysis was performed using various bacterial recombinant CDX2 proteins including the normal and altered peptides, which indicated that immune response could be raised against tumor-specific peptides generated through MSI. The anti-CDX2 Ab was detected only in the patient with the CDX2 frameshift mutation in tumor and disappeared 7 years after the curative resection, suggesting that this immune response may also be useful as a tumor marker. No altered subcellular localization and transcription ability was demonstrated in the mutated CDX2, although decreased expression was suggested in immunohistochemical analysis. Therefore, tumor-specific peptides generated by MSI may be involved in antitumor immune responses and may be useful for the development of diagnostic and therapeutic methods for patients with MSI+ CRC.

Amino Acid Sequence↗

PubMed2005

The increase of mitochondrial DNA content in endometrial adenocarcinoma cells: a quantitative study using laser-captured microdissected tissues.

OBJECTIVE: Microsatellite instability (MSI) is a frequent genetic event in the D-loop region (which controls mitochondrial DNA (mtDNA) replication) of mitochondrial genome of endometrial cancer. We therefore investigated the relationship between mtMSI and mtDNA content in endometrial cancer. METHODS: Tumor tissues from 65 cancer patients and normal tissues from 41 non-cancer patients were used in this study. Pure endometrial adenocarcinoma cells and normal endometrial glandular epithelial cells were collected by laser capture microdissection, and analyzed for levels of mtDNA copy number by real-time quantitative PCR. RESULTS: Our data show that mtDNA copy number was not related with age in both endometrial cancer and normal endometrium cells. Great inter-individual variations in mtDNA copy number in endometrial cancer group were found; and mtDNA content was significantly larger than that in normal endometrium group. About 2-fold increase of mtDNA copy number was found in endometrial adenocarcinoma compared with normal endometrial glandular epithelium (P = 0.001). In particular, the analysis also shows that the copy number of mtDNA in the cases that carried the mtMSI at nucleotide position 303 was significantly higher than that of the negative cases (P = 0.048). CONCLUSIONS: Our data indicate that mtDNA copy number increased during endometrial cancer development. There is also a correlation between the mtDNA instability and mtDNA content in endometrial cancer cells. Role of mitochondrial genome changes in carcinogenesis warrants further investigation.

Adenocarcinoma↗

PubMed1997

Poorly differentiated colonic adenocarcinoma, medullary type: clinical, phenotypic, and molecular characteristics.

Clinicopathological evidence has accumulated that colorectal adenocarcinoma with minimal or no glandular differentiation constitutes two entities with different prognosis. In a series of 20 predominantly nonglandular, poorly differentiated adenocarcinomas, histological features, DNA content, p53 protein expression, Ki-ras mutation, and microsatellite instability were analyzed and correlated to the biology of the tumors. In addition, the presence of Epstein-Barr virus (EBV) transcripts was tested by RNA in situ hybridization and EBV DNA was demonstrated by nested polymerase chain reaction. Histologically, 13 tumors showed small uniform cells and 7 tumors showed large pleomorphic cells. Tumors with uniform cells exhibited more commonly an expansive growth pattern (69.2% versus 0%; P < 0.025) and a dense peritumor lymphoid infiltrate (84.6% versus 14.3%; P < 0.01) resembling their gastric counterpart, solid or medullary carcinoma. These tumors showed less frequent lymph node as well as hematogeneous metastases than pleomorphic carcinomas. In addition, they were usually diploid (84.6% versus 28.6%; P < 0.05) and lacked stabilization of the p53 protein (0% versus 42.9%; P < 0.05). No significant difference between the medullary and the pleomorphic tumor type was found with respect to bcl2 expression and the occurrence of Ki-ras mutations at codon 12. In contrast, microsatellite instability was almost totally restricted to poorly differentiated adenocarcinomas of the medullary type (100% versus 14.3%; P < 0.001). Finally, polymerase chain reaction revealed EBV DNA in 5 tumor specimens, which was, however, restricted to the peritumor lymphoid infiltrate as shown by in situ hybridization. Correlation with the biology of the tumors revealed that only one patient with the uniform cell type died due to metastastic disease during the follow-up period (median, 31 months), which was the case in five of the seven patients with the pleomorphic-type carcinoma (P < 0.025). Our results clearly indicate that the poorly differentiated colonic carcinoma with minimal or no glandular structures constitute two different entities, a medullary and a pleomorphic variant, which markedly differ in their phenotype, genotype, and prognosis.

Adult↗

PubMed2005

BRAF mutations in colorectal carcinoma suggest two entities of microsatellite-unstable tumors.

BACKGROUND: Alterations of BRAF have been implicated in the carcinogenesis of colorectal tumors with microsatellite instability (MSI). These alterations were attributed to defective DNA mismatch repair, which underlies MSI. It was the objective of this study to clarify the role of BRAF in colorectal carcinoma with MSI. METHODS: After sequencing for BRAF and KRAS in 82 colorectal tumor samples with or without MSI, mismatch repair protein expression was analyzed by immunohistochemistry, and promoter methylation of hMLH1 was analyzed with a methylation-specific polymerase chain reaction. Results were correlated with the germline status of hMLH1 or hMSH2 and clinical characteristics. RESULTS: BRAF was mutated more often in tumors with MSI than in tumors without MSI (27% vs. 5%; P = 0.016). The most prevalent BRAF alteration, V599E, occurred only in tumors with MSI. BRAF V599E was associated with more frequent hMLH1 promoter methylation (P = 0.07) and loss of hMLH1 (P = 0.02). The median age of patients with BRAF V599E was older compared with the median age of patients without this mutation (P = 0.001; 78 vs. 49 yrs). No BRAF alterations occurred in patients with germline mutations of mismatch repair genes. Five novel BRAF mutations were identified. CONCLUSIONS: Although BRAF V599E was common in colorectal carcinomas with MSI, it was not a consequence of deficient mismatch repair. The current data showed instead that the BRAF V599E mutation was associated only with a subgroup of colorectal carcinomas with MSI that were obtained from older patients without hereditary nonpolyposis colorectal carcinoma and showed epigenetic silencing of hMLH1. These results indicated that tumors with MSI caused by epigenetic MLH1 silencing have a distinct mutational background from that of tumors with genetic loss of mismatch repair, suggesting that there are two genetically distinct entities of microsatellite-instable tumors.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Prognostic significance of CpG island methylator phenotype and microsatellite instability in gastric carcinoma.

PURPOSE: The influence of molecular characteristics in prognosis of gastric cancer remains unclear. The aim of this study was to evaluate the prognostic value of the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) in gastric cancer. EXPERIMENTAL DESIGN: We studied the methylation profiles of tumor suppressor gene p16, DNA mismatch repair gene hMLH1, and four CpG islands (MINT1, MINT2, MINT25, and MINT31) using bisulfite/methylation-specific PCR, and MSI using five microsatellite markers in 83 resected gastric carcinomas. The CIMP and MSI status were compared with clinicopathologic features and overall survival. RESULTS: Concordant methylation of multiple genes/loci (CIMP-high) was present in 31% of tumors and in 4% of non-neoplastic mucosa, CIMP-low in 55% and 17%, and CIMP-negative in 13% and 79%, respectively (P < 0.001). The prevalence of MSI-high, MSI-low, and MS-stable in tumor was 19%, 17%, and 64%, respectively. MSI status was closely associated with hMLH1 hypermethylation and CIMP status (P = 0.001). In univariate analysis, overall survival was predicted by pathologic stage (P < 0.0001), R0 resection (P = 0.0002), MINT31 methylation (P = 0.04), and CIMP-high status (P = 0.04). MSI status of tumor was not a significant predictor of prognosis. Although CIMP status seemed to be a prognostic predictor of gastric cancer, only pathologic stage remained a significant predictor of prognosis on multivariate analysis (P < 0.001). CONCLUSIONS: Our results indicate that there is an association between CIMP status and MSI status in gastric cancer. Concordant methylation of multiple genes/loci (CIMP-H) is associated with better survival but is not an independent predictor of prognosis in resected gastric cancer.

Adaptor Proteins, Signal Transducing↗

PubMed2005

[The first molecular analysis of a Hungarian HNPCC family: a novel MSH2 germline mutation].

BACKGROUND: Hereditary nonpolyposis colorectal cancer is an inherited disease characterized by onset at an early age, an excess of synchronous and metachronous large bowel tumors and a variety of extracolorectal malignancies. Basal and squamous cell carcinomas of the skin are not customarily included in the tumor spectrum of the syndrome. The disease is caused by a germline mutation in one of the DNA mismatch repair genes, most commonly MSH2 or MLH1, and typically presents with microsatellite instability and frequent loss of mismatch repair protein expression in the tumor tissue. PATIENT: The case of a 62-year old woman who had a history of colon cancer at the age of 46 years, endometrial cancer at the age of 56 years, baso-squamous, and squamous cell cancer of the face at the ages of 53, 54, 62 and 58 years, respectively, and rectal cancer at 60 is reported. Her family fulfills the Amsterdam criteria for the diagnosis of hereditary nonpolyposis colorectal cancer. The baso-squamous cell, the squamous cell, the endometrial and the rectal cancers were assessed for the microsatellite instability status and the expression of the MSH2 and MLH1 mismatch repair proteins, and the p53 tumor suppressor protein by immunohistochemistry. Mutational screening using an automated capillary DNA sequencer was performed by the direct genomic sequencing of 17 fragments of the MSH2 gene, which covers promoter, all exons and flanking intronic regions. RESULTS: All cancers displayed microsatellite instability and were positive for the p53 protein. The immunohistochemical staining in the baso-squamous cell, the squamous cell, the rectal and endometrial cancers were negative for MSH2 and positive for MLH1 proteins. DNA sequencing analysis revealed a mutation c.2292G > A in exon 14 of the MSH2 gene, which is altering the 764. amino acid, the tryptophan to STOP codon (p.W764X). Thus the MSH2 protein is presumably truncated by 171 aminoacids. CONCLUSION: To the best of authors' knowledge, this is the first molecular characterization of a Hungarian hereditary nonpolyposis colorectal cancer family. According to the Human Mutation Database and International Collaborative Group of HNPCC Database, this mutation is novel, has not been reported previously. Cutaneous baso-squamous and squamous cell cancers may present as part of the HNPCC phenotype. Detection of the loss of mismatch repair protein expression and mismatch repair gene mutation mapping, represents a significant improvement of the diagnosis of this syndrome in Hungary. These examinations identify the mutation carriers who are at an increased risk of developing cancers.

Adaptor Proteins, Signal Transducing↗

PubMed1995

Somatic mutations in the hMSH2 gene in microsatellite unstable colorectal carcinomas.

Microsatellite instability is frequently seen in tumors from patients with hereditary nonpolyposis colorectal cancer (HNPCC). Germline mutations in the mismatch repair gene hMSH2 account for approximately 50% of these cases. Tumors from sporadic cases also exhibit this microsatellite instability phenotype, although at a lower frequency, and very few somatically derived mutations have so far been reported in such tumors. In this study DNA from 23 primary colorectal carcinomas (four familial and 19 sporadic cases) exhibiting microsatellite instability were screened for mutations in the hMSH2 gene using constant denaturant gel electrophoresis (CDGE). Among the sporadic cases, five (26%) were found to have somatically derived mutations. One tumor revealed two different mutations, possibly leading to a homozygous inactivation of the gene. One of the four familial cases was classified as having HNPCC, and a germline as well as a somatic mutation were found in this tumor. These results demonstrate that a considerable proportion of sporadic colorectal cancers with microsatellite instability, have somatic mutations in the hMSH2 gene.

Adult↗

PubMed2000

Genetic alterations in DNA diploid, aneuploid and multiploid colorectal carcinomas identified by the crypt isolation technique.

Loss of heterozygosity (LOH) and microsatellite instability (MSI) commonly occur in colorectal carcinomas. However, the role of these genetic alterations in determining DNA ploidy status of tumors (diploid, aneuploid and multiploid) remains unclear. In the present study, we attempted to clarify the relationship between genetic alterations and DNA ploidy status. Crypt isolation coupled with DNA cytometric sorting and polymerase chain reaction assay (17 microsatellite markers) were used to study allelic losses and MSI in 59 colorectal carcinomas (diploid, 15; aneuploid, 10 and multiploid, 34). Of the 15 diploid carcinomas, 6 exhibited MSI in which allelic losses were rarely found. The other 9 diploid tumors mostly exhibited allelic losses, but none displayed MSI status. Whereas allelic losses frequently occurred in the aneuploid carcinomas and the aneuploid populations of multiploid carcinomas, they were rarely detected in the diploid populations of multiploid carcinomas. MSI status was not observed in aneuploid carcinomas nor in either population of multiploid carcinomas. Although multiploid carcinomas genetically resemble aneuploid carcinomas in the expression of the severe LOH phenotype, the genetic alterations seen in the diploid populations of multiploid carcinomas may differ from those of diploid carcinomas. Furthermore, all diploid, aneuploid and both the diploid and aneuploid fractions of the multiploid tumors that were non-MSI exhibited a high rate of LOH, suggesting that LOH is independent of the tumor's ploidy status.

Adenocarcinoma↗

PubMed2001

Microsatellite stability in human post-mortem tissues.

Human identification and forensic criminal casework may involve DNA profiling of decomposed material. Somatic microsatellite (STR) instability may lead to false exclusions and theoretically to false inclusions, both in criminal cases and in human identification. Hence, the somatic and postmortal stability of the actual sequences is crucial to the reliability of such analyses. Somatic STR stability in human tissues has been documented in small series only and the effect of postmortal tissue decomposition on microsatellite stability remains to be elucidated. On this basis, we have systematically searched for somatic STR mutations in 26 deceased humans without signs of decomposition at autopsy and 25 autopsy cases with obvious signs of postmortal decomposition. A blood sample and six tissue samples were collected from each case. Seven STRs were chosen for study, the tetranucleotides HUMVWA31/A, HUMTH01, HUMF13A1, and HUMFES/FPS, and the hyperpolymorphic markers HUMAPOAI1, D11S554 and HUMACTBP2. Denaturing gel electrophoresis was performed on an ABD Prism 377 gene sequencer with Genescan 672 software (Applied Biosystems, Inc.). The bone DNA profile of each case was chosen as the standard DNA profile. All cases gave profiles from additional tissues. By intraindividual comparison of DNA profiles in the cases without signs of degradation we find that the short repetitive sequences under study are stable, that is without evidence of somatic mutations. The cases with varying degree of decomposition display postmortal microsatellite stability, we detect no somatic mutations or other possible postmortal changes that could lead to between-organ non-matches. In conclusion, PCR-based STR analyses are suitable in human identification and forensic casework dealing with different tissues, even when the substrate is heavily decomposed.

Autopsy↗

PubMed2004

Analysis of chromosomal instability in focal cortical dysplasia of Taylor's balloon cell type.

Focal cortical dysplasias (FCD) represent a frequent finding in patients with chronic intractable epilepsy. Neuropathological hallmarks include localized dyslamination of the neocortex and neuronal heterotopias in white matter. Balloon cells, similar to those occurring in cortical tubers of patients with tuberous sclerosis (TSC) are observed in numerous patients. These lesions were classified as FCD type IIb (FCD IIb). Recent findings indicate an accumulation of TSC1 polymorphisms as well as loss of heterozygosity (LOH) and/or microsatellite instability (MSI) at the TSC1 locus on chromosome 9q in FCD IIb. Here, we tested the hypothesis of whether chromosomal instability constitutes a genome-wide phenomenon in this patient cohort. Seven microsatellite markers based on a reference panel recommended by the international workshop on microsatellite instability were analyzed in 14 surgical FCD IIb specimens. DNA from single laser-microdissected cells, i.e., balloon cells versus control neurons obtained from adjacent cortex was harvested for PCR amplification and subsequent fluorescent fragment length gel electrophoresis. Our analysis revealed only rare instances of LOH and MSI at genomic loci on 2p and 17q, whereas no alterations were found at informative markers on chromosomes 1p, 5q and 18q. In addition, no loss of repair protein expression (MSH2 or MLH1) has been identified in balloon cell nuclei of FCD IIb specimens. The present data suggest solitary LOH and MSI events at genomic localizations others than the TSC1 locus to occur in FCD IIb. Our findings lend further support to the hypothesis that the molecular pathogenesis of FCD IIb is associated with TSC1.

Chromosomal Instability↗

PubMed2003

Hydrogen peroxide-induced microsatellite instability in the Escherichia coli K-12 endogenous tonB gene.

Damage to DNA by reactive oxygen species may be a significant source of endogenous mutagenesis in aerobic organisms. Using an endogenous tonB gene as a mutation selective marker in Escherichia coli, we have examined whether endogenous oxidative mutagenesis can contribute to genetic instability. We have also used oxyR(+) and oxyR(-) strains to evaluate how hydrogen peroxide scavenging system can contribute to genetic instability. The highest mutation frequency induced by hydrogen peroxide was 3.8x10(-6) at 600 microM and 5.3 x 10(-6) at 40 microM in oxyR(+) and oxyR(-), respectively. Hydrogen peroxide induced minus frameshift mutations predominantly followed by transversions (G:C-->T:A, G:C-->C:G, and A:T-->T:A). The types and the nature of the mutations did not differ between strains. Frameshift mutations occurred at G:C and A:T sites equally, and in repeated and non-repeated sequences equally. It is evident that endogenous oxidative damage to DNA can increase the frequency of strand slippage intermediates occurring during DNA replication and contribute to genomic instability. Our results further indicate that oxyR regulon does not take part in the DNA-repair pathway against oxidative damage induced by hydrogen peroxide.

Bacterial Proteins↗

PubMed2002

Hypermethylation of HPP1 is associated with hMLH1 hypermethylation in gastric adenocarcinomas.

The HPP1 gene was initially discovered because of its frequent hypermethylation in hyperplastic colon polyps, but it is also hypermethylated in colorectal adenomas and carcinomas. Expression of the DNA mismatch repair gene hMLH1 is diminished or absent in some hyperplastic polyps, and it has been suggested that HPP1 inactivation is associated with the progression of microsatellite-unstable colorectal tumors. We sought then to determine the prevalence of HPP1 silencing by DNA methylation in gastric adenocarcinomas and to define any association of this event with microsatellite instability (MSI) or hMLH1 hypermethylation. Thirty-two matched normal-gastric adenocarcinoma DNA pairs were studied for MSI status and hypermethylation of HPP1 and hMLH1. Five (100%) of 5 MSI-H tumors, 2 (50%) of 4 MSI-L tumors, and 8 (35%) of 23 MSS tumors demonstrated HPP1 hypermethylation. Eight (25%) of 32 tumors (5 of 5 MSI-H, 2 of 4 MSI-L, and 1 of 23 MSS) showed evidence of hMLH1 hypermethylation. All (8 of 8) of these hMLHI-methylated tumors demonstrated concomitant methylation at the HPP1 locus: there were no cases of hMLH1 methylation occurring in the absence of HPP1 methylation. In gastric adenocarcinoma, hypermethylation frequently targets HPP1. Moreover, hMLH1 hypermethylation occurs predominantly in the setting of HPP1 hypermethylation. HPP1 hypermethylation may represent an early event in mismatch repair-deficient gastric tumorigenesis.

Adaptor Proteins, Signal Transducing↗

PubMed2002

Emerging pathways in colorectal-cancer development.

The past decade has seen the emergence of new pathways in the development of colorectal cancer. There is now clear evidence that subsets of these tumours do not show chromosomal instability and do not follow the suppressor pathway. Instead, about 15% of colorectal cancers are characterised by microsatellite instability (MSI). This feature arises through defective DNA mismatch repair, which is related either to a germline mutation (as in hereditary non-polyposis colorectal carcinoma) or to failure to express a mismatch-repair gene. CpG-island methylation has been linked to sporadic cancers with a high frequency of MSI. This type of methylation leads to loss of gene expression when it occurs in the promoter region of a gene. Tumours may have high or low type C (cancer-related) CpG-island methylation. When methylation affects hMLH1 (mismatch repair gene), the resultant cancer has high MSI.

Biopsy, Needle↗

PubMed2000

Microsatellite instability in sporadic parathyroid adenoma.

Parathyroid adenomas are usually benign uniglandular tumors, and inactivation of several tumor suppressor genes, notably the MEN 1 gene, or activation of oncogenes have been implicated in the tumorigenesis. Genomic instability, indicative of the involvement of DNA mismatch repair genes, has not been previously described in parathyroid adenomas. A single large parathyroid adenoma was resected from an 8.5-yr-old Brazilian patient with no personal or family history of other endocrinopathies. Analysis of paired tumor-nontumor DNA using 23 microsatellite markers, located on chromosomes 1, 10, and 11 was carried out. Microsatellite instability was detected in nine markers (D1S191, D1S212, D1S413, D1S2848, RET, D11S901, D11S903, INSR, and INT2), whereas no allelic loss was detected with any of the analyzed markers. Immunohistochemical analysis of retinoblastoma protein expression revealed low levels of expression, but no histopathological signs of malignancy. We conclude that in this single, apparently sporadic parathyroid adenoma, DNA mismatch repair genes might be involved in parathyroid tumorigenesis.

Adenoma↗

PubMed1996

Microsatellite instability in preinvasive and invasive head and neck squamous carcinoma.

To investigate the extent and significance of microsatellite instability in head and neck carcinogenesis we analyzed DNA extracted from normal squamous epithelium, severe dysplasia, and corresponding carcinoma specimens from 20 patients by multiplex polymerase chain reaction. Loci on chromosomes 3p, 5p, 5q, 8p, 9p, 9q, 11q, 17p, 17q, 18p, 18q were selected for analysis. Our results show that three of the dysplasias (15.0%) and six of the invasive carcinoma (30.0%) manifested instability at multiple loci. Two of the dysplastic lesions had identical alterations in the corresponding carcinomas and one showed instability differences in only two of eight loci. Normal squamous epithelium lacked microsatellite instability. No apparent association between smoking, alcohol use, or family history of cancer and instability was found in this small cohort. Invasive carcinomas with instability were relatively more poorly differentiated and had a higher stage and a high proliferative fraction. Our study indicates that microsatellite instability is 1) noted in a small subset of dysplastic lesions of head and neck squamous epithelium and 2) present in approximately one-third of invasive lesions, usually with aggressive characteristics, and may clinically be a late event associated with tumor progression.

Aged↗

PubMed2001

Molecular genetics of ulcerative colitis-associated colon cancer in the interleukin 2- and beta(2)-microglobulin-deficient mouse.

Mice deficient in beta(2)-microglobulin and interleukin 2 (beta(2)m(null) x IL-2(null)) spontaneously develop colon cancer in the setting of chronic ulcerative colitis (UC). We investigated mutations of the Apc and p53 genes and microsatellite instability in colonic adenocarcinomas arising in this model. Mutations of the Apc and p53 genes in the regions corresponding to mutation hot spots in human colorectal cancer were determined by sequencing in 11 colonic adenocarcinomas. Microsatellite instability was determined in matched normal and neoplastic DNA at five loci. All 11 adenocarcinomas harbored Apc mutations. Of these 11 tumors, 5 harbored truncating mutations. A total of 67 Apc mutations were found in these 11 tumors; 59 were missense mutations, whereas 8 were frameshift or nonsense mutations. Six of the 11 adenocarcinomas harbored p53 mutations. A total of seven p53 mutations were found in these 11 tumors; all mutations were transitions, 4 of which were C:G-->T:A transitions occurring in codon 229 at cytosine-guanine dinucleotides. Nine adenocarcinomas exhibited microsatellite instability in at least one of the five loci examined; 1 tumor had microsatellite instability in two loci. Molecular genetics, as well as clinical features, of colon cancer in the beta(2)m(null) x IL-2(null) mice are similar to those of human UC-associated colorectal cancer. As such, this model appears to be an excellent animal model to study UC-associated colorectal carcinogenesis.

Adenocarcinoma↗