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At least 937 records · Page 52Linked to original sources
PubMed2001

High frequency of mitochondrial DNA mutations in glioblastoma multiforme identified by direct sequence comparison to blood samples.

In an earlier study, we showed that heteroplasmy in the mitochondrial genome of gliomas sometimes occurs in a D-loop polycytosine tract. We extended this study by pairwise comparisons between glioma samples and adjacent brain tissue of 55 patients (50 glioblastomas, 1 astrocytoma WHO grade III, 4 astrocytomas WHO grade II). We used a combination of laser microdissection and PCR to detect and quantify variations in the polycytosine tract. New length variants undetectable in the adjacent brain tissue were observed in 5 glioblastomas (9%). In 2 of these cases, samples from a lower tumor stage (WHO grade II) could be analyzed and revealed the early occurrence of these mutations in both cases. Since the mitochondrial D-loop contains additional repeats and highly polymorphic non-coding sequences, we compared 17 glioblastomas with the corresponding blood samples of the same patients by direct sequencing of the complete D-loop. In 6 of these tumors (35%), instability was detected in 1 or 2 of 3 repeat regions; in 1 of these repeats, the instability was linked to a germline T-to-C transition. Furthermore, of 2 tumors (12%) 1 carried 1 and the other 9 additional transitions. In the latter patient, 6.7 kb of the protein coding mtDNA sequence were analyzed. Six silent transitions and 2 missense mutations (transitions) were found. All base substitutions appeared to be homoplasmic upon sequencing, and 89% occurred at known polymorphic sites in humans. Our data suggest that the same mechanisms that generate inherited mtDNA polymorphisms are strongly enhanced in gliomas and produce somatic mutations.

Adult↗
PubMed2006

The role of telomeres and telomerase in the pathology of human cancer and aging.

Cellular senescence, the state of permanent growth arrest, is the inevitable fate of replicating normal somatic cells. Postulated to underlie this finite replicative span is the physiology of telomeres, which constitute the ends of chromosomes. The repetitive sequences of these DNA-protein complexes progressively shorten with each mitosis. When the critical length is bridged, telomeres trigger DNA repair and cell cycle checkpoint mechanisms that result in chromosomal fusions, cell cycle arrest, senescence and/or apoptosis. Should senescence be bypassed at such time, continued cell divisions in the face of dysfunctional telomeres and activated DNA repair machinery can result in the genomic instability favourable for oncogenesis. The longevity and malignant progression of the thus transformed cell requires coincident telomerase expression or other means to negate the constitutional telomeric loss. Practically then, telomeres and telomerase may represent plausible prognostic and screening cancer markers. Furthermore, if the argument is extended, with assumptions that telomeric attrition is indeed the basis of cellular senescence and that accumulation of the latter equates to aging at the organismal level, then telomeres may well explain the increased incidence of cancer with human aging.

Aging↗
PubMed2004

Novel and diverse functions of the DNA mismatch repair family in mammalian meiosis and recombination.

The mismatch repair (MMR) family is a highly conserved group of proteins that function in genome stabilization and mutation avoidance. Their role has been particularly well studied in the context of DNA repair following replication errors, and disruption of these processes results in characteristic microsatellite instability, repair defects and, in mammals, susceptibility to cancer. An additional role in meiotic recombination has been described for several family members, as revealed by extensive studies in yeast. More recently, the role of the mammalian MMR family in meiotic progression has been elucidated by the phenotypic analysis of mice harboring targeted mutations in the genes encoding several MMR family members. This review will discuss the phenotypes of the various mutant mouse lines and, drawing from our knowledge of MMR function in yeast meiosis and in somatic cell repair, will attempt to elucidate the significance of MMR activity in mouse germ cells. These studies highlight the importance of comparative analysis of MMR orthologs across species, and also underscore distinct sexually dimorphic characteristics of mammalian recombination and meiosis.

Animals↗
PubMed2002

Limited proliferation and telomere dysfunction following telomerase inhibition in immortal murine fibroblasts.

Telomerase is a ribonucleoprotein enzyme that functions to maintain telomeres, the terminal DNA that protects chromosomal integrity, regulating cellular replicative life span. Telomerase is not expressed in most normal human somatic cells but is active in stabilizing telomeres of certain self-renewing cell populations and most malignant cells, making the enzyme an appealing target for anticancer therapy. We describe here a novel cross-species approach to telomerase inhibition. Ectopic expression of the human telomerase catalytic reverse transcriptase component in murine cells inhibited endogenous murine telomerase activity. Using this approach, telomerase inhibition in immortal murine fibroblasts resulted in critical telomere shortening, leading to slowed proliferation, abnormal morphology, altered cell cycle, and telomere dysfunction with cytogenetic instability, followed by apoptotic cell death. Subpopulations of two telomerase-inhibited clones escaped widespread apoptosis, showing proliferative recovery in culture despite persistently inhibited telomerase activity with progressive telomere shortening and dysfunction. This study, by targeting immortal murine cells for telomerase inhibition, demonstrates the importance of telomerase to murine cell immortalization and telomere maintenance. Moreover, the murine model used here should prove useful in further evaluating telomerase inhibition as an anticancer therapy.

3T3 Cells↗
PubMed1998

Gap junction expression following UVC-induced neoplastic transformation in human hybrid cell lines.

Decreased connexin gene expression and loss of the capacity for either homologous or heterologous intercellular communication has been associated with neoplastic transformation. We tested the hypothesis that loss of gap junctional intercellular communication (GJIC) correlates with tumorigenic potential in the HeLa x skin fibroblast human hybrid cell system. Connexin gene expression, gap junction function and tumorigenicity were determined for the non-tumorigenic somatic hybrid cell line (CGL1) and a series of UVC-induced tumorigenic cell lines derived from CGL1. CGL1 and the parental skin fibroblasts express connexin43 (alpha1 gap junction gene) mRNA and protein, form gap junctional plaques and have functional gap junctions. UVC-irradiation of CGL1 cells produced a cell line (UV12) with an aggressive tumorigenic phenotype, which lost connexin43 expression as well as both homologous and heterologous GJIC and was in this respect similar to HeLa cells. However, the phenotype of UV12 cells exhibited some instability and revertants to a less aggressive tumorigenic phenotype were isolated. These cells expressed connexin43 mRNA and protein, and demonstrated homologous GJIC. Furthermore, cells reconstituted from a tumor derived from this revertant cell line retained significant connexin43 expression and homologous GJIC, although they exhibited an aggressive tumorigenic phenotype. Thus, functional homologous GJIC cannot be dissociated from tumorigenicity in this system. However, heterologous GJIC between these same UVC-induced tumorigenic cell lines and normal human skin fibroblasts was reduced, whereas the non-tumorigenic hybrid cells showed extensive heterologous GJIC. In summary, re-acquisition of connexin43 expression and homologous GJIC does not restore the non-tumorigenic phenotype in UVC-induced tumorigenic HeLa skin fibroblast human hybrid cells. However, reduction of heterologous GJIC does correlate with tumorigenicity in this cell system.

Cell Communication↗
PubMed2003

Mitochondrial DNA damage in non-melanoma skin cancer.

Mitochondrial DNA (mtDNA) damage, predominantly encompassing point mutations, has been reported in a variety of cancers. Here we present in human skin, the first detailed study of the distribution of multiple forms of mtDNA damage in nonmelanoma skin cancer (NMSC) compared to histologically normal perilesional dermis and epidermis. We present the first entire spectrum of deletions found between different types of skin tumours and perilesional skin. In addition, we provide the first quantitative data for the incidence of the common deletion as well as the first report of specific tandem duplications in tumours from any tissue. Importantly, this work shows that there are clear differences in the distribution of deletions between the tumour and the histologically normal perilesional skin. Furthermore, DNA sequencing of four mutation 'hotspot' regions of the mitochondrial genome identified a previously unreported somatic heteroplasmic mutation in an SCC patient. In addition, 81 unreported and reported homoplasmic single base changes were identified in the other NMSC patients. Unlike the distribution of deletions and the heteroplasmic mutation, these homoplasmic mutations were present in both tumour and perilesional skin, which suggests that for some genetic studies the traditional use of histologically normal perilesional skin from NMSC patients may be limited. Currently, it is unclear whether mtDNA damage has a direct link to skin cancer or it may simply reflect an underlying nuclear DNA instability.

Aged↗
PubMed2001

Identification of homozygous deletions at chromosome 16q23 in aflatoxin B1 exposed hepatocellular carcinoma.

Loss of heterozygosity (LOH) represents the most frequent genetic alteration observed in hepatocellular carcinoma (HCC). Chromosome 16q is of particular interest as it exhibits LOH in 29% of HCC tumors and is frequently lost in breast, prostate, ovarian and gastric carcinomas. We genotyped 157 HCC tumors for 17 microsatellite markers distributed on chromosome 16q and determined a common region of LOH localized between the markers D16S518 and D16S504. By refining the boundaries of two interstitial LOH and two homozygous deletions, the critical region was delimited to 180 kb between D16S3096 and D16S3029. This region is located in intron 8 of the WWOX/FOR gene, but a search for mutations in all coding exons of this gene in 27 HCC tumors and cell lines did not reveal any tumor somatic alterations. Furthermore, by RT-PCR, no abnormal transcripts of this WWOX/FOR gene was detected in nine HCC cell lines. Finally, analysis of the p53 gene mutations with the clinical parameters of all tumors revealed that the two homozygous deletions have occurred in tumors presenting a R249S mutation. Our data revealed a relationship between chromosome 16q homozygous deletions and R249S p53 mutations in tumors where the patient had been exposed to aflatoxin B1 (P=0.002). These results are consistent with a role of aflatoxin B1 in the instability of chromosome 16q at the fragile site FRA16D. However, the nature of the specific gene that is altered during hepatocarcinogenesis remains to be elucidated.

Aflatoxin B1↗
PubMed2005

Clinical value of mitochondrial mutations in colorectal cancer.

PURPOSE: Prognostic factors that could select high-risk recurrence colorectal cancer patients and predict chemosensitivity are needed. Since mutations of mitochondrial DNA (mtDNA) have been described in different types of cancers and since they may play a role in response to anticancer agents, we investigated in a population-based series of colorectal cancer patients the clinical value of mtDNA mutations. PATIENTS AND METHODS: The displacement loop (D-loop) region of mtDNA was sequenced on a series of 365 patients recorded in the Digestive Cancer Registry of Côte-d'Or (France) between 1998 and 2000. Clinicopathologic characteristics were correlated to the presence of a D-loop mutation. Survival rates were compared with the log-rank test. A multivariate survival analysis was performed. RESULTS: D-loop mutations were found in 38.3% of the tumors. The 3-year survival rate was 53.5% in patients with D-loop mutation versus 62.1% in patients without (P = .05). After adjustment for age, stage, and microsatellite instability status, the relative risk of death in patients with D-loop mutation was 1.40 (95% CI, 1.02 to 1.93; P = .034) as compared with those without. In stage III colon cancers, adjuvant chemotherapy was beneficial only for patients without D-loop mutation (3-year survival, 78.3% v 45.4%, P < .02). In those with D-loop mutation who received adjuvant chemotherapy, the relative risk of death was 4.30 (95% CI, 1.23 to 15.00; P < .02). CONCLUSION: The D-loop region is a hotspot for somatic mutations in colorectal tumors. Moreover, presence of tumor D-loop mutation appears to be a factor of poor prognosis in colorectal patients and a factor of resistance to fluorouracil-based adjuvant chemotherapy in stage III colon cancers.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

High incidence of somatic mitochondrial DNA mutations in human ovarian carcinomas.

To investigate the potential role of somatic mitochondrial DNA (mtDNA) mutations in tumorigenesis, the occurrence of mutations in mtDNA of ovarian carcinomas was studied. We sequenced the D-loop region of mtDNA of 15 primary ovarian carcinomas and their matched normal controls. Somatic mtDNA mutations were detected in 20% (3 of 15) tumor samples carrying single or multiple changes. Complete sequence analysis of the mtDNA genomes of another 10 pairs of primary ovarian carcinomas and control tissues revealed somatic mtDNA mutations in 60% (6 of 10) of tumor samples. Most of these mutations were homoplasmic, and most were T-->C or G-->A transitions, but one represented a differential length within a run of identical C residues. A region of mtDNA sequence including the 16S and 12S rRNA genes, the D-loop and the cytochrome b gene, may represent the zone of preferred mtDNA mutation in ovarian cancer. The high incidence of mtDNA mutations found in ovarian carcinomas and other human cancers suggests that genetic instability of mtDNA might play a significant role in tumorigenesis.

DNA, Mitochondrial↗
PubMed1992

[Schizophrenia and factitious cheilitis: a case report].

Factitious Cheilitis is a rare skin disorder which has been seen in patients with emotional disturbances, particularly in cases with neurotic and personality disorders. However, there have been no reports of factitious cheilitis seen in cases of schizophrenia. This study reports on a case of schizophrenic disorder, where the patient was observed to develop factitious cheilitis whilst subject to unstable psychiatric conditions. The case reported here is of a 59 year-old female widow, who has experienced the delusion of being controlled, the delusion of being possessed. Been subject to auditory hallucination and vague somatic pain for eight years and had a very poor psychotropic drug compliance. Observation revealed frequent licking of the lips unrelated to drug-induced dyskinesia, but as a possibly linked response to hallucination whilst subject to an intense unstable emotional and painful state. Factitious cheilitis was proved with biopsy of the lips and pathological findings of acanthosis, hyperkeratosis and parakeratosis. After psychiatric and dermatologic care, her cheilitic condition improved. This study demonstrates that factitious cheilitis can be seen in a schizophrenic patient, specifically where hallucination and emotional instability coupled with long-term licking of the lips can result in factitious cheilitis. The relationship of skin disorder and psychiatric illness is discussed.

Cheilitis↗
PubMed2005

Unequal segregation of parental chromosomes in embryonic stem cell hybrids.

Chromosome segregation was studied in 14 intra- and 20 inter-specific hybrid clones generated by fusion of Mus musculus embryonic stem (ES) cells with fibroblasts or splenocytes of DD/c mice or Mus caroli. As a control for in vitro evolution of tetraploid karyotype we used a set of hybrid clones obtained by fusion of ES cells (D3) with ES cells (TgTP6.3). Identification of the parental chromosomes in the clones was performed by microsatellite analysis and in situ hybridization with labeled species-specific probes. Both analyses have revealed three types of clones: (i) stable tetraploid, observed only for ES x ES cell hybrids; (ii) bilateral loss of chromosomes of both ES and somatic partners; (iii) unilateral segregation of chromosomes of the somatic partner. Observed unilateral segregation was extensive in ES-splenocyte cell hybrids, but lower in ES-fibroblast hybrid clones. Developmental state of the somatic partner is presumably responsible for directional chromosome loss. Nonrandom segregation implies that initial differences in the parental homologous chromosomes were not immediately equalized implying at least transient persistence of the differentiated epigenotype.

Animals↗
PubMed2004

ATR, Claspin and the Rad9-Rad1-Hus1 complex regulate Chk1 and Cdc25A in the absence of DNA damage.

The ATR and Chk1 kinases are essential to maintain genomic integrity. ATR, with Claspin and the Rad9-Rad1-Hus1 complex, activates Chk1 after DNA damage. Chk1-mediated phosphorylation of the Cdc25A phosphatase is required for the mammalian S-phase checkpoint. Here, we show that during physiological S phase the regulation of the Chk1-Cdc25A pathway depends on ATR, Claspin, Rad9, and Hus1. Human cells with chemically or genetically ablated ATR showed inhibition of Chk1-dependent phosphorylation of Cdc25A, and they accumulated Cdc25A without external DNA damage. Furthermore, siRNA-mediated depletion of Claspin, Rad9 and Hus1 also stabilized Cdc25A. ATR ablation also inhibited the activatory phosphorylation of Chk1 on serine 345. Thus, the ATR-Chk1-Cdc25A pathway represents an integral part of physiological S-phase progression, and interference with this mechanism undermines viability of somatic mammalian cells. DNA damage further activates and switches this pathway from its constitutively operating "surveillance mode" compatible with DNA replication into an "emergency" checkpoint response.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Telomerase as tumor marker.

Telomerase, a critical enzyme responsible for continuous cell growth, is repressed in most somatic cells except proliferating progenitor cells and activated lymphocytes, and activated in approximately 85% of human cancer tissues. Telomerase activity is a useful cancer-cell detecting marker in some types of cancers in which almost all cases show telomerase activation. In other types in which telomerase becomes upregulated according to tumor progression, it is a useful prognostic indicator. Detection of human telomerase reverse transcriptase (hTERT) mRNA or protein in various clinical samples is also applicable. However, careful attention should be paid to the false negative results due to the instability of this enzyme or hTERT mRNA and the existence of polymerase chain reaction inhibitors as well as the false-positive results due to the contamination by normal cells with telomerase activity. If these pitfalls are avoided, in situ detection of hTERT mRNA or protein will facilitate the reliability of telomerase as a tumor marker.

Animals↗
PubMed1999

Ligase-based detection of mononucleotide repeat sequences.

Up to 15% of all colorectal cancers are considered to be replication error positive (RER(+)) and contain mutations at hundreds of thousands of microsatellite repeat sequences. Recently, a number of intragenic mononucleotide repeat sequences have been demonstrated to be targets for inactivating genes in RER(+)colorectal tumors. In this study, thermostable DNA ligases were tested for the ability to detect alterations in microsatellite sequences in colon tumor samples. Ligation profiles on mononucleotide repeat sequences were determined for four related thermostable DNA ligases, Thermus thermophilus ( Tth ) ligase, Thermus sp. AK16D ligase, Aquifex aeolicus ligase and the K294R mutant of the Tth ligase. While the limit of detection for point mutations was one mutation in 1000 wild-type sequences, the ability to detect a single base deletion in a 10 base mononucleotide repeat was one mutation in 100 wild-type sequences. Furthermore, the misligation error increased exponentially as the length of the mono-nucleotide repeat increased, and was 10% of the correct signal for a 19 base mononucleotide repeat. A fluorescent ligase-based assay [polymerase chain reaction/ligase detection reaction (PCR/LDR)] correlated with results obtained using a radioactive assay to detect instability within the TGF-beta Type II receptor gene. PCR/LDR was also used to detect the APCI1307K mononucleotide repeat allele which has a carrier frequency of 6.1% in Ashkenazi Jewish individuals. In a blind study, 30 samples that had been typed for the presence of the APCI1307K allele were tested. The PCR/LDR results correlated with those obtained using sequencing and allele-specific oligonucleotide hybridization for 16 samples carrying the mutation and 13 wild-type samples. Ligation assays that characterize mononucleotide repeats can be used to rapidly detect somatic mutations in tumors, and to screen for individuals who have a hereditary predisposition to develop colon cancer.

Adenomatous Polyposis Coli↗
PubMed1984

Observations in studies of quantitative kinetics of tritium labelled hematoporphyrin derivatives (HpDI and HpDII) in the normal and neoplastic rat brain model.

Increasing interest has developed in the use of the photodynamic agent, Hematoporphyrin derivative (HpD) for photoradiation therapy (PRT) as adjunctive therapy of malignant glial tumors of the brain. HpD, injected systemically, is preferentially taken up and retained by neoplastic tissue. Early studies of such uptake have largely relied on gross fluorescence as evidence of tissue uptake. In this study HpD was labelled with a tritiated radioisotope (3H) in order to quantify tissue uptake in visceral and in normal and neoplastic brain tissues in a rat brain model. 3H-HpD was injected intravenously at a 10 mg/kg dose into 30 Sprague-Dawley rats (Group A) without tumors in order to clarify method. Separately, 3H-HpD of like dosage was injected into 20 Fischer-344 rats (Group B), 5 control and 15 with a 9L gliosarcoma implanted in the left anterior cerebral cortex. Post injection sacrifice occurred at 6, 24 and 48 hours. From the Sprague-Dawley group multiple somatic and cerebral specimens were assayed. Differential areas within the brain showed no significant difference in uptake. The tumor area, peritumoral margin, and distant uninvolved areas of the Fischer-344 9L rats were likewise assayed. Definite uptake of normal visceral and cerebral tissue occurred with a markedly higher uptake differential in tumor areas. Such differential was relatively consistent from trial to trial, but multiple separate values obtained in the respective study groups were often unreliabe in their reproducibility and at variance with previously reported tissue level studies. These findings implied an instability of 3H-HpD, subsequently confirmed chromatographically as contamination probably due to time related degradation and exchange. Therefore, 3H-HpD appears to inherently carry such a risk for contamination. The compound Photofrin II (HpDII) represents a chromatographic fraction of HpD (HpDI), currently considered its most photodynamically active and purest component. Tritiated Photofrin II was used for quantification. An assay was performed with 5 Fischer-344 9L brain tumor rats (Group C), sacrificed at 24 hours. Photofrin II provided results more reliably reproducible. Contamination, degradation, and exchange of 3H-Photofrin II did not appear to occur. Neoplastic brain levels of the Photofrin II isotope were higher than in the HpD studies, and highly fluorescent. Normal brain values were consistently minimal and without fluorescence. The differential tumor/brain ratio in Photofrin II was consequently much higher. The isolated active substrate of HpDI and HpDII (Photofrin II) appears to be the compound DiHematoporphyrin Ether (DHE).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Human insulin-like growth factor binding protein-1 (hIGFBP-1) transgenic mice: insights into hIGFBP-1 regulation and actions.

Three hemizygous transgenic (Tg) mouse lines were generated with a fusion gene composed of the mouse metallothionein promoter (mMT-1) and a full length human insulin-like growth factor binding protein-1 (hIGFBP-1) cDNA that was truncated in its 3' untranslated (3'UT) region. The transgene was ectopically expressed in the brain of each line and resulted in postnatal brain-growth retardation that was manifested by 2 weeks of age. Despite the expression of the transgene in multiple other tissues and high serum hIGFBP-1 concentrations in two of the three lines, studies designed to detect alterations in somatic growth, in reproduction and in glucose metabolism revealed few other abnormalities. Unexpectedly, however, we found that the regulation of the transgene shared characteristics with that of the native gene, despite the fact that it lacked the endogenous gene's 5' regulatory region, as well as most of its 3' UT region. Our studies suggest that factors controlling mRNA stability are important to regulation of both the native and transgene, and that an AU-rich element 17 base pairs (bp) from the end of coding sequence is responsible for the instability of the transgene and in part for instability of the endogenous gene.

Animals↗
PubMed2002

Distinct regions of loss of heterozygosity on 22q in different sites of head and neck squamous cell carcinomas.

BACKGROUND: Frequent loss of heterozygosity (LOH) has been reported in many types of cancer, including head and neck carcinomas. Somatic deletions involving specific chromosomal regions are strongly associated with inactivation of the allele of a tumor suppressor gene located within the deleted region. In most studies concerning LOH in head and neck squamous cell carcinomas (HNSCC) the different anatomical sites are not distinguished. The behavior of tumors arising at various sites differs significantly, however, suggesting different intrinsic tumor properties. In this study we compared the LOH on 22q and its relationship to clinicopathological parameters at the three major sites of HNSCC: oral cavity, larynx and pharynx. MATERIAL/METHODS: LOH and microsatellite instability (MSI) were studied using seven polymorphic microsatellite markers mapped to the 22q11-q13.3 region in 37 oral, 32 laryngeal, and 31 pharyngeal carcinomas. RESULTS: Two separate regions of LOH were identified in the laryngeal (22q11.2-12.1) and oral cavity (22q13.1-13.31) tumors. When the different anatomical sites were compared, a statistically significant difference was found between the presence of LOH at D22S421 (p<0.001), D22S315 (p=0.014) and D22S929 (p=0.026) in the laryngeal tumors. CONCLUSIONS: These data suggest that distinct regions on 22q are involved in LOH in oral cavity and laryngeal tumorigenesis, but do not support a similar association between the development of pharyngeal tumors and genes located on 22q. These findings implicate the presence of different tumor suppressor genes mapping to distinct regions on chromosome 22q in oral and laryngeal carcinomas.

Alleles↗
PubMed2002

Genes involved in DNA repair are mutational targets in endometrial cancers with microsatellite instability.

Microsatellite instability (MSI) is observed in a subset of endometrial cancers (ECs) and is attributed to defects in mismatch repair. Mismatch repair deficiency allows for accumulation of mutations in the coding repeats of key target genes, which may be involved in the initiation and progression of MSI+ EC. We examined genes implicated in DNA repair pathways in 38 MSI-high (MSI-H), 10 MSI-low, 25 microsatellite stable ECs, and a selected panel of associated premalignant hyperplasias. Genetic alterations were correlated to histopathological data, including tumor grade and stage. Somatic frameshift mutations were observed in hMLH3, hMSH3, hMSH6, CHK1, and BAX genes in MSI-H endometrial hyperplasias and cancers, whereas mutations in ATR and CDC25C were observed only in MSI-H ECs. Increased mutation frequency in DNA damage response pathway genes including ATR, CHK1, and BAX demonstrated a significant trend with advancing tumor grade (P < 0.05). Our observations of the same mutations at short coding mononucleotide repeats in both premalignant lesions and tumors and association of increased frequency of mutation accumulation with advancing tumor grade suggest that these alterations may play a role in the development and progression of MSI+ EC.

Adenocarcinoma↗