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PubMed1997

Allelic imbalance and microsatellite instability in resected Duke's D colorectal cancer.

Hepatic resection is the treatment of choice for selected patients with liver metastases from colorectal cancer (CRC). Although the 5-year survival rate among patients after liver resection is 25-45%, 55-75% of patients die from progressive disease. The purpose of this study was to characterize molecular genetic alterations, including microsatellite instability and allelic imbalance, in patients with potentially curative resected liver metastases from CRC and to correlate these molecular features with clinical and pathologic characteristics. We examined DNA from formalin-fixed, paraffin-embedded archival tumor specimens from 141 surgically resected hepatic metastases from CRC. We used microsatellite markers localized to chromosome arms 5q, 8p, 10q, 15q, 17p, 18p, and 18q in a polymerase chain reaction-based assay. Allelic imbalance at each locus and the presence of tumor microsatellite instability were correlated with clinicopathologic features of the tumor and clinical course of the patient. Microsatellite instability at multiple loci was seen in only 2.5% of resected liver metastases, a frequency significantly lower than that previously detected for primary CRC. Additionally, these findings had no significant correlation with disease-free survival or overall survival. Allelic imbalance at one or more loci was seen in 87% of informative tumors. Allelic imbalance on chromosome 17p was seen in 84% of informative tumors, and its presence was associated with a significantly poor disease-free survival (p = 0.015) and overall survival (p = 0.05). These data suggest that allelic imbalance on chromosome 17p is an independent prognostic parameter in patients with potentially curative resected liver metastases from CRC. Such alterations could provide a useful stratification criterion for adjuvant therapy for patients who have undergone curative resection of liver metastases from CRC.

Adult↗
PubMed2002

Molecular basis for stool-based DNA tests for colorectal cancer: a primer for clinicians.

Cancers develop as a result of alterations in genes that regulate growth, survival, and other cellular behaviors. Colorectal cancers develop through one of at least three different pathways, termed chromosomal instability, microsatellite instability, and the CpG island methylator phenotype. Although there is some overlap, these pathways tend to inactivate different sets of tumor suppressor genes and tend to have somewhat different biological behaviors. Tumor cells and DNA are shed into the fecal stream, and uniquely mutated genes can be identified that would indicate the likely presence of a neoplasm in the gastrointestinal tract. By understanding the pathways to tumor development, the target genes involved, and the mechanisms underlying genomic instability, it will be possible to implement strategies to detect and treat the different types of colorectal cancer.

Colorectal Neoplasms↗
PubMed2005

Defective DNA mismatch repair determines a characteristic transcriptional profile in proximal colon cancers.

BACKGROUND & AIMS: Colon cancers with defective DNA mismatch repair (MMR) have peculiar molecular, pathologic, and clinical features, including high-level microsatellite instability, conspicuous lymphocytic infiltration, preferential location in the proximal colon, and better prognosis. Our aim was to characterize the transcriptional profile of this colon cancer subset. METHODS: An oligonucleotide microarray containing 12,625 probes was used to evaluate gene expression in 25 proximal colon cancers, 10 samples of normal colon mucosa, and 14 colon cancer cell lines. Transcriptional profiles of MMR-deficient cancers and cell lines were compared with those of their MMR-proficient counterparts. RESULTS: Unsupervised analysis of microarray data showed that MMR status exerts a predominant influence on the gene expression profile of proximal colon cancers. Hierarchical clustering divided the cancers into 2 groups corresponding almost perfectly with their MMR status. Supervised analysis identified numerous gene expression changes that represent a genetic signature of MMR-deficient colon cancers. Changes in genes involved in apoptosis and the immune response were consistent with the better prognosis of MMR-deficient cancers. In MMR-deficient cancers and cell lines, 4-1BBL, a crucial gene in the anti-tumor immune response, was, respectively, 2.4 and 6.0 times more expressed than in their MMR-proficient counterparts. This difference was confirmed by quantitative reverse-transcription polymerase chain reaction and flow cytometric assessment of 4-1BBL protein expression in colon cancer cell lines. Our analysis also showed novel possible gene targets of microsatellite instability. CONCLUSIONS: MMR inactivation produces distinct changes in the cellular messenger RNA pool, which is consistent with a unique tumorigenesis pathway.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Effects of oxidative and alkylating damage on microsatellite instability in nontumorigenic human cells.

Microsatellite instability is a phenomenon that is well characterized in mismatch repair-deficient tumor cell lines, including the potential etiological role of endogenous DNA damage. However, our understanding of microsatellite mutational mechanisms in repair-proficient, nontumorigenic cells is limited. We determined microsatellite mutation frequencies for human lymphoblastoid cells using an episomal DNA shuttle vector in which a (TTCC/AAGG)(9) microsatellite is inserted in-frame within the herpes simplex virus thymidine kinase (HSV-tk) gene. The responses of plasmid-bearing cells to reactive oxygen species or alkylating agents were compared after treatment with hydrogen peroxide (H(2)O(2)) and N-ethyl-N-nitrosourea (ENU). H(2)O(2) treatment induced a statistically significant increase in overall HSV-tk mutation frequency relative to controls, with catalase reducing the effect. H(2)O(2) treatment increased the mutation frequency within the microsatellite and the HSV-tk coding region to a similar extent (five and six-fold, respectively, relative to the control). Mutational specificity analyses demonstrated that the proportion of mutations within the microsatellite is not statistically different among the H(2)O(2), catalase, and PBS treatment groups. In contrast, treatment of cells bearing the microsatellite vector with ENU altered the mutational spectrum, relative to solvent control. ENU induced the expected base substitutions within the HSV-tk coding region, but did not increase the microsatellite mutation frequency. The low level of microsatellite mutagenesis observed after reactive oxygen species (ROS) insult likely reflects the normal repair processes of these nontumorigenic, repair-competent cells. Our ex vivo experiments demonstrate the manner in which repetitive DNA in normal human cells might respond to endogenous mutagens.

Alkylating Agents↗
PubMed2006

Msh2 deficiency leads to chromosomal abnormalities, centrosome amplification, and telomere capping defect.

Msh2 is a key mammalian DNA mismatch repair (MMR) gene and mutations or deficiencies in mammalian Msh2 gene result in microsatellite instability (MSI+) and the development of cancer. Here, we report that primary mouse embryonic fibroblasts (MEFs) deficient in the murine MMR gene Msh2 (Msh2(-/-)) showed a significant increase in chromosome aneuploidy, centrosome amplification, and defective mitotic spindle organization and unequal chromosome segregation. Although Msh2(-/-) mouse tissues or primary MEFs had no apparent change in telomerase activity, telomere length, or recombination at telomeres, Msh2(-/-) MEFs showed an increase in chromosome end-to-end fusions or chromosome ends without detectable telomeric DNA. These data suggest that MSH2 helps to maintain genomic stability through the regulation of the centrosome and normal telomere capping in vivo and that defects in MMR can contribute to oncogenesis through multiple pathways.

Animals↗
PubMed1999

Loss of heterozygosity and microsatellite instability in hepatocellular carcinoma in Taiwan.

Elucidation of the basic genetic changes of human hepatocellular carcinoma is important for the understanding and treatment of this cancer. We used microsatellite polymorphism markers to study 30 cases of hepatocellular carcinoma (34 tumours) on all human chromosomes. DNA from 34 pairs of hepatocellular carcinomas and corresponding non-tumour parts was prepared. Loss of heterozygosity (LOH) and microsatellite instability on 23 chromosomes were investigated by 231 sets of microsatellite markers. More than 20% LOH was shown for loci on 16q (47.1%), 13q (32.4%), 17p (32.4%), 5q (26.5%), 11p (23.5%) and 9p (20.6%). The commonly affected regions were mapped to 16q12.1, 16q12.2, 16q24, 13q12.1-32, 17p13, 5q32, 5q34, 5q3, 11p15, 11q23-24 and 9p21. Hepatitis B virus carriers had a significantly higher frequency of LOH on chromosomes 5q, 11p and 16q. Furthermore, larger tumour size tended to have higher frequency of LOH at D16S409 locus (16q12.1). Microsatellte instability was only found in 12 of 231 markers and the frequency is very low. These data suggest that the chromosomes 16q, 13q, 17p, 5q, 11p and 9p might participate in hepatocarcinogenesis. However, microsatellite instability might play little role in the development of this cancer in Taiwan.

Adult↗
PubMed2007

Alterations in cell proliferation and apoptosis in colon cancers with microsatellite instability.

Colon cancers with microsatellite instability (MSI) demonstrate a host immune response characterized by tumor infiltrating lymphocytes (TILs) that may exert effects upon tumor cell apoptosis and cell proliferation. Accordingly, we compared rates of apoptosis and cell proliferation in colon cancers with defective DNA mismatch repair and their association with phenotypic features and clinical outcome. Primary Astler-Coller stage B2 and C colon carcinomas (n = 329) were analyzed for MSI and for hMLH1 and hMSH2 protein expression. Apoptosis (TUNEL assay) and p53 expression were also analyzed by immunohistochemistry, and TILs were quantified by morphology. DNA ploidy and proliferation (PI: S phase + G(2)M) were evaluated using flow cytometry. MSI-H (n = 58) colon cancers showed increased TILs that were significantly associated with increased apoptosis, higher apoptosis to proliferation (AI/PI) ratios, reduced proliferative indices (PI) and diploid DNA content. Increased TILs (p = 0.036) and reduced PI (p = 0.042), but not AI or AI/PI, were associated with improved disease-free survival. Tumors with MSI-H (p = 0.032) or loss of hMLH1 or hMSH2 proteins (p = 0.040), or diploidy (p = 0.0015), had better adjusted overall survival rates. Interestingly, similar rates of cell turnover and overlapping survival rates were found in diploid MSS/MSI-L tumors and in MSI-H cases. In conclusion, higher apoptosis/proliferation ratios and reduced cell proliferation are phenotypic features of MSI-H tumors that are associated with increased TILs, indicating an activated immune response that may contribute to their favorable survival rates.

Adult↗
PubMed2006

Expression and mutation of SMAD4 in poorly differentiated carcinoma and signet-ring cell carcinoma of the colorectum.

Poorly differentiated adenocarcinoma (Por) and signet-ring cell carcinoma (Sig) are rare but highly malignant types of colorectal cancer. To explore their genetic backgrounds we investigated TGF-beta type II receptor (TGF-beta RII) and SMAD4 in the TGF-beta signaling pathway, and to identify their mutator phenotype we examined microsatellite instability (MSI) status. Loss of SMAD4 expression was significantly more frequent in Por (12 of 38; 31%) and Sig (4 of 5; 80%) tumors than in well (Well) and moderately differentiated (Mod) carcinomas (p = 0.04, 0.003, respectively). Mutation of the SMAD4 gene was detected in 2 of 26 Por tumors. MSI was positive in 14 of the 38 Por tumors and in 1 of the 5 Sig tumors, but in none of the Well or Mod tumors examined. We also found mutation of TGF-beta RII, a putative target of MSI, in 10 of 35 Por tumors (28.6%), but in none of 3 Sig tumors. As a whole, about 50% of the Por tumors and 80% of the Sig tumors showed abnormalities of either TGF-beta RII or SMAD4 expression. This suggests that disruption of the TGF-beta signaling pathway may play a central role in the pathogenesis of Por and Sig tumors of the colorectum.

Adenocarcinoma↗
PubMed2000

MSH2-deficient murine lymphomas harbor insertion/deletion mutations in the transforming growth factor beta receptor type 2 gene and display low not high frequency microsatellite instability.

High-frequency microsatellite instability (MSI), defined as more than 20% unstable loci, is an inconsistent finding in hematologic malignancies; consequently, the significance of deficient DNA mismatch repair (MMR) to their pathogenesis has been questioned. To further investigate the relationship between MMR deficiency and genomic instability in hematologic malignancies, this study evaluated MSH2-/- murine lymphomas for insertion/deletion (ID) mutations within the transforming growth factor (TGF)-beta receptor type II (TbetaR-II) gene and MSI at 10 neutral microsatellites. The lymphomas displayed ID mutations within short mononucleotide runs of TbetaR-II at a high frequency, whereas nonmalignant tissue from corresponding animals lacked mutations. Loss of TbetaR-II transcripts and protein was seen in 6 of 7 murine lymphomas harboring acquired TbetaR-II mutations. In the analysis of paired nonmalignant and tumor DNA samples, low-frequency but not high-frequency MSI was found. Low-frequency MSI occurred in 8 of 20 lymphomas and 12 displayed microsatellite stability. MSI was even less frequent in nonmalignant tissue as only 3 of 20 samples displayed low-frequency MSI and 17 displayed stability. Evaluation of 20 single cell clones from the MSH2-/- lymphoma cell lines R25 and L15 identified high-frequency MSI in 4 and 2 clones, respectively. The remaining clones showed low-frequency MSI or stability. These findings suggest that acquired TbetaR-II mutations represent important inactivating events in tumor pathogenesis following MSH2 deficiency. Furthermore, for some hematolymphoid malignancies, the evaluation of cancer-associated genes for ID mutations may represent a more sensitive marker of MMR deficiency than evaluation of neutral microsatellites for high-frequency MSI. (Blood. 2000;95:1767-1772)

Animals↗
PubMed2005

Aberrations in the mismatch repair genes and the clinical impact on oesophageal squamous carcinomas from a high incidence area in South Africa.

AIMS: To investigate the incidence of genetic aberrations in the DNA repair genes in a cohort of oesophageal cancers. METHODS: One hundred oesophagectomy samples of squamous cell carcinoma were studied. Normal and tumour DNA were isolated using a standard phenol/chloroform extraction procedure. Six recommended microsatellite loci with high informativity were analysed. The following markers were used: D2S123 (2p), D3S659 (3p), D3S1255 (3p), Bat 25 (4q), Bat 26 (2p), and Bat 40 (1p). The results were analysed using software attached to an automated DNA sequencer. The molecular data were then correlated with clinicopathological parameters. RESULTS: The incidence of microsatellite instability and loss of heterozygosity was very low. There was no significant correlation between the clinicopathological and molecular data. However, D2S123 genetic abnormalities were seen more frequently in both moderately and well differentiated tumours than in poorly differentiated tumours (p = 0.033). Follow up data were available for only 67 of the 100 patients. Fifty patients were alive and 17 patients had died. CONCLUSION: Low frequencies of genetic aberrations in these mismatch repair loci are found in squamous carcinomas of the oesophagus from a high incidence area in South Africa.

Adult↗
PubMed2002

Allelic variation of BAT-26 and BAT-40 poly-adenine repeat loci in North Indians.

Analysis of mononucleotide repeats BAT-26 and BAT-40 in North Indians revealed that there were germline polymorphisms at both the loci. We evaluated BAT-26 and BAT-40 in 100 normal healthy individuals from North India. The DNA from normal blood was PCR amplified using primers flanking the BAT-26 and BAT-40 loci. The allelic variation of BAT-26 and BAT-40 ranged between 117-130 and 94-112 bp respectively. The most frequent BAT-26 allele was 122 bp, which corresponded to 26 repeats and had a frequency of 32% while that of BAT-40 was 109 bp corresponding to 39 repeats with a frequency of 26%. These results suggest that polymorphisms in these poly-adenine repeat loci limit their applicability in studying the microsatellite instability in cancers.

3-Hydroxysteroid Dehydrogenases↗
PubMed2005

Heterozygous ATR mutations in mismatch repair-deficient cancer cells have functional significance.

ATR (ataxia telangiectasia and Rad3-related) function is necessary for the proper response to commonly used chemotherapeutic agents. Heterozygous truncating mutations in exon 10 of the ATR gene have been described in numerous cancers exhibiting microsatellite instability. We show that truncating mutations of ATR are capable of acting in a dominant-negative manner to abrogate ATR-dependent Chk1 phosphorylation and cell-cycle arrests after DNA damage. In addition, endometrial cell lines harboring ATR mutations are defective for ATR-dependent responses. These findings imply that ATR mutations play an important role in the development and clinical behavior of a subset of microsatellite instability-positive endometrial, colon, and stomach cancers.

Amino Acid Sequence↗
PubMed2004

[Relationship between microsatellite alterations on chromosome 8 and clinicopathological characteristics in hepatocellular carcinoma].

OBJECTIVE: To study the features of microsatellite alterations and their association with clinicopathological characteristics of hepatocellular carcinoma (HCC). METHODS: Ten high-polymorphic microsatellite markers on chromosome 8 were selected to detect the loss of heterozygosity (LOH), microsatellite instability (MSI) and allelic imbalance (AI) in 56 HCCs using automatic capillary array electrophoresis DNA analysis system. RESULTS: LOH was found in 37 of 56 HCCs (66.1%) on at least 10 locus. The three most frequently altered loci were D8S261 (53.5%, 23/43), D8S1721 (52.5%, 21/40) and D8S1771 (52.5%, 21/40). LOH on D8S277 was significantly higher in cases with positive serum HBsAg than in those with negative HBsAg (P < 0.01). Similarly, LOH on D8S261, D8S298 and D8S1733 occurred more frequently in patients with negative HBsAg than those with positive HBsAg (P < 0.01). LOH on D8S298 and D8S1771 were more frequent in tumors larger than 3 cm in size (P < 0.05 and P < 0.01 respectively). LOH frequencies of D8S1721 were significantly higher in cases with absent or partially encapsulated tumor than in those with intact tumor capsule (P < 0.05). LOH on D8S298 and D8S1771 were more frequently detected in tumors with intrahepatic metastasis than those without (P < 0.01). MSI was found in 12.5% (7/56) cases. AI was found in 19.6% (11/56) of all cases examined. CONCLUSIONS: Microsatellite alterations on chromosome 8 were frequent in HCC. LOH, possibly representing alterations of the tumor suppressor pathway, may play an important role in hepatocarcinogenesis. MSI, reflecting a dysfunction of the mismatch repair pathway, may also contribute to this process, but in a less significant way. LOH at some particular loci is associated with certain clinicopathological parameters of human HCC.

Adult↗
PubMed2004

DNA methyltransferase Dnmt1 and mismatch repair.

We have examined the relationship between DNA mismatch repair and deficiency of DNA methylation in a mouse embryonic cell line, Dnmt1-/- ES, with homologous deletion of the gene coding for the maintenance DNA methyltransferase Dnmt1. With the use of a sensitive PCR for the assay of two mononucleotide- and three dinucleotide microsatellite markers that exhibited instabilities in mismatch repair-deficient cells, significantly higher frequencies of instability were detected at three of the five markers in Dnmt1-/- ES than the wild-type ES. The data suggest that Dnmt1 enzyme plays an integrating role in DNA replication and/or repair. The implication that Dnmt1 enzyme and/or cytosine methylation may participate in the strand discrimination of mismatch repair during eukaryotic DNA replication is discussed.

Animals↗
PubMed1997

Molecular genetic analysis of a patient with hereditary nonpolyposis colorectal cancer syndrome.

Hereditary nonpolyposis colorectal cancer types I and II constitute approximately 5% to 10% of the cases of colorectal cancer annually. Recognition of its clinical features and identification of affected families are imperative for appropriate medical and surgical management. Furthermore, molecular analysis can be performed in such families because the DNA mismatch repair genes have been identified as being mutated, thereby leading to microsatellite instability. We describe a 33-year-old woman with ovarian, uterine, and colorectal cancer, whose family, on close examination, had features consistent with hereditary nonpolyposis colorectal cancer. The patient had evidence of microsatellite instability in her colon cancer.

Adult↗
PubMed2006

Mismatch repair polymorphisms and colorectal polyps: hMLH1-93G>A variant modifies risk associated with smoking.

BACKGROUND AND AIM: Mutations in the mismatch repair (MMR) enzymes hMLH1 and hMSH6 are known causes of hereditary nonpolyposis colorectal cancer and act by inducing a mutator phenotype characterized by microsatellite instability. The aim of our study was to determine if polymorphisms in the DNA MMR genes hMLH1 and hMSH6 are associated with an increased risk of colorectal polyps, and to evaluate interactions with exposures known to cause DNA damage. METHODS: In a Minnesota-based case-control study of individuals with adenomas (N=401), hyperplastic polyps (N=195), or both adenomas and hyperplastic polyps (N=123) versus polyp-free controls (N=624), we investigated the role of hMLH1-93G>A, hMLH1 I219V, and hMSH6 G39E polymorphisms in increasing the risk of colorectal polyps. Polytomous multivariate logistic regression analysis was used, adjusting for age, sex, body mass index, postmenopausal hormone use, aspirin use, and NSAID use. RESULTS: Overall, no evidence of an association between any of the three polymorphisms or hMLH1 haplotypes and colorectal polyps was observed. However, risk associated with the hMLH1-93A variant differed by smoking: smoking-associated risks were stronger among those with variant -93AA or -93AG genotypes, showing a twofold greater risk of adenoma with >25 pack-years of smoking compared with nonsmokers, and a corresponding eightfold greater risk of hyperplastic polyps (genotype smoking: p-interaction=0.02 for hyperplastic polyps and p-interaction=0.08 for adenomas). CONCLUSIONS: These data are consistent with the observation that smoking is associated with MMR in colorectal neoplasia and suggest that the risk increase with smoking may differ by hMLH1-93G>A genotype.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Edd, the murine hyperplastic disc gene, is essential for yolk sac vascularization and chorioallantoic fusion.

EDD is the mammalian ortholog of the Drosophila melanogaster hyperplastic disc gene (hyd), which is critical for cell proliferation and differentiation in flies through regulation of hedgehog and decapentaplegic signaling. Amplification and overexpression of EDD occurs frequently in several cancers, including those of the breast and ovary, and truncating mutations of EDD are also observed in gastric and colon cancer with microsatellite instability. EDD has E3 ubiquitin ligase activity, is involved in regulation of the DNA damage response, and may control hedgehog signaling, but a definitive biological role has yet to be established. To investigate the role of Edd in vivo, gene targeting was used to generate Edd knockout (Edd(Delta/Delta)) mice. While heterozygous mice had normal development and fertility, no viable Edd-deficient embryos were observed beyond E10.5, with delayed growth and development evident from E8.5 onward. Failed yolk sac and allantoic vascular development, along with defective chorioallantoic fusion, were the primary effects of Edd deficiency. These extraembryonic defects presumably compromised fetal-maternal circulation and hence efficient exchange of nutrients and oxygen between the embryo and maternal environment, leading to a general failure of embryonic cell proliferation and widespread apoptosis. Hence, Edd has an essential role in extraembryonic development.

Allantois↗