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PubMed2001

Extensive somatic microsatellite mutations in normal human tissue.

Microsatellite (MS) instability occurs in tumors with DNA mismatch repair (MMR) deficiencies but is typically absent in adjacent normal tissue. However, MS mutations have been observed in normal tissues from rare individuals with congenital MMR deficiencies. Autopsy tissues from a 4-year-old with congenital MMR deficiency (MLH1-/-) were examined for MS mutations. Insertions and deletions were observed in CA-repeat MS loci. Approximately 0.26 to 1.4 mutations per MS locus per cell were estimated to be present in normal heart, lymph node, kidney, and bladder epithelium. These findings illustrate that phenotypically normal MMR-deficient cells commonly accumulate MS mutations. Loss of MMR and the accumulation of some MS mutations may occur early in MMR-deficient tumor progression, even before a gatekeeper mutation.

Adaptor Proteins, Signal Transducing↗
PubMed1994

p53 mutations and microsatellite instability in sporadic gastric cancer: when guardians fail.

Genetic instability may underlie the etiology of multistep gastric carcinogenesis. The altered microsatellites observed in tumors with the ubiquitous somatic mutation (USM) phenotype may represent the expression of such instability. Similarly, p53 mutations may allow the accumulation of genetic alterations caused by multiple mechanisms. In 40 sporadic gastric adenocarcinomas, nine tumors (22.5%) with p53 mutations in exons 5-8, and six tumors (15%) with the USM+ phenotype, were detected. None of the tumors had both alterations. The tumors with p53 mutations were predominantly in the proximal stomach whereas the USM+ tumors were predominantly in the distal stomach. The mutant p53 alleles were homogeneously distributed throughout the primary tumors, but usually absent from adjacent normal or dysplastic epithelium, indicating that p53 mutations are typically acquired before the bulk of clonal expansion. The loss of mutant p53 alleles during progression was also rarely observed in metastatic foci. Altered microsatellites were homogeneously present in the USM+ primary and metastatic tumors and one synchronous tubular adenoma, but were not detected in adjacent normal and metaplastic epithelium. These findings also demonstrate that the USM+ phenotype is expressed before the bulk of clonal expansion. In most (5 of 6) USM+ tumors, the sizes of the altered microsatellites differed between regions, indicating that the instability usually persists during clonal expansion. These findings indicate that both p53 mutations and the USM+ phenotype are present prior to the bulk of tumor growth and therefore may contribute to, rather than be a late consequence of, malignant transformation.

Aged↗
PubMed2003

Somatic mitochondrial DNA mutations in adult-onset leukaemia.

Mitochondrial genome instability has recently been demonstrated in a wide variety of human tumours and is implicated in the development of the myelodysplastic syndromes, a heterogeneous group of haematological disorders with an increased risk of malignant transformation. We therefore investigated the incidence of somatic mitochondrial DNA (mtDNA) mutations in patients with adult-onset leukaemia. We sequenced the entire mitochondrial genome from both normal tissue (buccal epithelial cells) and the leukaemia from 24 patients with adult-onset leukaemia. Somatic mtDNA mutation was present in nine individuals ( approximately 40%) and in each case the tumour genome differed from the normal genome sequence by a single sequence change. Using PCR-RFLP analysis and real-time PCR, we have studied in detail the mutation present in one patient with acute lymphatic leukaemia, demonstrating that the mutation is associated specifically with the leukaemia.

Adolescent↗
PubMed1995

Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability.

Microsatellite instability has been observed in both sporadic and hereditary forms of colorectal cancer. In the hereditary form, this instability is generally due to germline mutations in mismatch repair (MMR) genes. However, only one in ten patients with sporadic tumours exhibiting microsatellite instability had a detectable germline mutation. Moreover, only three of seven sporadic tumour cell lines with microsatellite instability had mutations in a MMR gene, and these mutations could occur somatically. These results demonstrate that tumours can acquire somatic mutations that presumably do not directly affect cell growth but result only in genetic instability. They also suggest that many sporadic tumours with microsatellite instability have alterations in genes other than the four now known to participate in MMR.

Adult↗
PubMed2001

Somatic beta-catenin mutation in gastric carcinoma--an infrequent event that is not specific for microsatellite instability.

We screened 90 cases of gastric carcinoma (GCA) samples for beta-catenin exon 3 mutation and assessed its possible relationship with microsatellite instability (MSI). Three mutations were detected in two samples, including a single mutation in an intestinal type and double mutations in a diffuse type GCA. One of the mutations found in the diffuse type GCA sample was a non-sense mutation at codon 68 (CAG-->TAG). This novel mutation was predicted to disrupt the binding of beta-catenin to alpha-catenin and may be related to the diffuse type morphology. The other two mutations were missense mutations involved or related to the GSK-3beta phosphorylation site, which have been reported previously. No MSI can be demonstrated in the two cases with beta-catenin mutation. Our results suggested that beta-catenin mutation was infrequent in GCA and appeared not specific for MSI.

Adult↗
PubMedDate not supplied

Molecular patterns of nuclear and mitochondrial microsatellite alterations in breast tumors.

The widespread distribution of microsatellite sequences within the human genome has allowed researchers to identify alternative patterns of microsatellite alterations in cancer cells. Among them, aneuploid patterns of nuclear microsatellites, pseudo-diploid microsatellite instability patterns, and also patterns of microsatellite instability within the mitochondrial genome. In this context, while aneuploid patterns of multiple genomic gains and losses had already been described in breast tumors, data on nuclear microsatellite instability still remain controversial and limited data on mitochondrial instability are available. In order to clarify this, we undertook an extensive analysis of nuclear and mitochondrial microsatellite alterations in breast ductal adenocarcinomas, stratified by grades. No instability was detected in any of the 40 dinucleotide microsatellites analysed nor in bat26 and APDelta3 mononucleotide repeats, clearly concluding that microsatellite instability is not a feature of ductal breast tumorigenesis. Instead, microsatellites defined a clear pattern of aneuploid genomic gains and losses among which, losses of BRCA1 at D17S855 and gains of plakoglobin at D17S846 significantly associated to grade III tumors and poor prognosis. On the other hand, mitochondrial instability at the transcription control region was also detected in 10.8% of cases. None of the new mitochondrial variants was found in the normal tissue counterparts, confirming that these new variants arise as sporadic somatic mutations in the tumor cells. Also, no association was found between heteroplasmy in the normal tissue and mitochondrial instability in the tumors. We therefore suggest that these new variants arise in tumors as a consequence of the progressive accumulation of slippage somatic mutations and the intrinsic instability of these microsatellite sequences. Finally, our results also confirm that mitochondrial instability does not associate with nuclear MSI.

Adult↗
PubMed1999

Genetic testing and counseling for hereditary forms of colorectal cancer.

The discovery of genes responsible for inherited forms of colorectal cancer have the potential to improve cancer risk assessment and counseling. Germline mutations (nonsense, frameshift) of APC are associated with familial adenomatous polyposis, an autosomal dominant syndrome, clinically characterized by young onset, hundreds of adenomatous polyps in the colon, and increased risk for extracolonic tumors. Mutations in APC are also associated with forms of attenuated familial adenomatous polyposis. Germline mutations in five mismatch repair related genes (hMSH2, hMLH1, hMSH6, hPMS1, and hPMS2) cause hereditary nonpolyposis colorectal cancer and are associated with increased risk of somatic genetic alterations and high DNA microsatellite instability. Hereditary nonpolyposis colorectal cancer is characterized by young onset colorectal cancer, proximal colon location, and increased risk of extracolonic cancers. A missense mutation in APC (I1307K) is associated with some familial colorectal cancer in Ashkenazic Jews. For persons at risk for hereditary forms of colorectal cancer, testing algorithms and gene test interpretations depend on identification of the pedigree germline gene mutation. Careful evaluation of the kindred for characteristic aggregation of tumor types among affected individuals and the availability of affected persons for testing are important issues in implementing genetic testing and follow-up management. Case reports illustrate the importance of genetic counseling as a component of cancer genetic risk assessment. The genetic counseling process includes exploration of patient risk perception, sources of anxiety related to cancer risk, patient education (specific cancer-related issues, prevention/intervention options), discussion of possible gene test options, test limitations, and consequences of various gene test outcomes.

Adenomatous Polyposis Coli↗
PubMed1992

Tissue specificity and stability of mosaicism in Pallister-Killian +i(12p) syndrome: relevance for prenatal diagnosis.

We ascertained +i(12p) mosaicism during third trimester in a case of polyhydramnios and diaphragmatic hernia. Primary cultures of amniocytes had colonies with +i(12p), colonies without +i(12p), and mixed colonies with 46/47,+i(12p). The likely explanation was instability and loss of i(12p) during somatic divisions of amniocytes. Fetal blood in third trimester retained +i(12p) in 13% of cells. A review of mosaicism in published cases indicates that factors influencing the presence of +i(12p) include tissue type and in vitro and in vivo age. In blood, amniocyte, and probably bone marrow cultures, +i(12p) is less stable than in fibroblast-like cultures derived from skin and other tissues. Young cultures at early passage are more likely to have +i(12p) than old cultures. Cultures from young (especially fetal) donors are more likely to retain +i(12p) than cultures from adult donors. These rules will be important in determining appropriate tissues for diagnosis and interpretation of mosaicism in this disorder.

Adult↗
PubMed1994

Identification of mutations in DNA polymerase beta mRNAs from patients with Werner syndrome.

Werner syndrome (WS) is a rare autosomal recessive disorder characterized by prematurely aged appearance. Genetic linkage analysis has placed the relevant gene in subchromosomal band 8p12. DNA polymerase beta gene has been mapped to chromosome 8p12-11 and thought to be involved in DNA repair and possibly in recombination. Somatic cells from WS patients exhibit chromosomal instability, a markedly reduced replicative life span and slow growth. The functions of DNA polymerase beta gene and its position prompted us to examine this gene in WS patients. We have found the novel DNA polymerase beta cDNA species in blood samples from WS patients, which contain 107 bp insertions or 87 bp deletions in the catalytic domain of DNA polymerase beta. These mutations change the structure of DNA polymerase beta and thus the capacity of the DNA repair system would be impaired, which may account for the high mutation rate observed in WS.

Amino Acid Sequence↗
PubMed1984

Generation of phenotypic diversity and progression in metastatic tumor cells.

The emergence of diversified tumor cell subpopulations in malignant neoplasms accounts for their heterogeneous cellular phenotypes and virtually ensures that some tumor cells will ultimately evolve with the most favorable properties for their enhanced abilities to survive, grow, invade and metastasize (tumor progression). The rates of cellular phenotypic diversification appear to vary greatly among different tumors and within the same tumor, and they are probably controlled, at least in part, by cellular instability due to chromosomal defects and random somatic mutational events, the rates of which are known to be higher in more malignant cells, and by epigenetic events, which may vary widely depending on the nature of the tumor cells and their microenvironments. As tumor progression proceeds, the most malignant cell subpopulations appear to lose their responsiveness to changes in tumor microenvironment while maintaining their high rates of phenotypic diversification. Tumor and normal cell-cell and cell-extracellular matrix interactions, as well as tumor cell nutrients, oxygen, hormones, growth factors, inducers and other regulatory molecules provide individual malignant cells with microenvironmental signals that could act through epigenetic cellular modifications, such as DNA methylation, and transcriptional, posttranscriptional, translational and posttranslational controls, or combinations of these. In addition, integration of viral gene sequences or viral modification of host DNA in critical regions could affect phenotypic stability. Finally, manipulation of tumor cells by antitumor therapy can also have profound effects on the rates of phenotypic diversification of the surviving tumor cells. A model for generating cellular phenotypic diversity based on the proposed mechanism for rapid generation of immunoglobulin molecular diversity in B cells may be applicable to malignant cells and to cells in general. In this model the expression and activity of gene products from multigene families are affected by a variety of genetic and epigenetic controlling mechanisms, and alterations in regulatory genes caused by recombination, methylation, mutation, or other changes could lead to differences in gene expression, resulting in widespread quantitative (and perhaps some qualitative) changes in particular gene products or their activities. As they proceed down different pathways of gene expression, each cell would be exposed to continual host selection pressures creating diverse, ever-changing malignant cell-populations.

Animals↗
PubMed2005

Ndj1p-dependent epigenetic resetting of telomere size in yeast meiosis.

Telomeres are essential for the protection of chromosomes against nucleases and recombinases and for the addition of G+T-rich simple sequence by the ribonucleoprotein reverse transcriptase telomerase . Telomere size instability and loss of telomerase activity in somatic cells is strongly associated with both oncogenesis and aging . Yet, an understanding of the mechanisms that maintain telomere size and structure during meiosis is still in its infancy . We have investigated the stability of single elongated telomeres during yeast meiosis. We find that elongated telomeres undergo high rates of precise deletion to wild-type telomere size via an intrachromatid pathway that shares properties with mitotic telomere rapid deletion (TRD). Loss of Ndj1p, a telomeric protein necessary for meiotic bouquet structure formation , confers a severe reduction in deletion rates. Return-to-growth (RTG) experiments suggest that deletion occurs at or near the period of meiotic recombination in NDJ1/NDJ1, but not in ndj1Delta/ndj1Delta diploids . We propose that Ndj1p facilitates deletion by promoting telomeric interactions during meiosis, resulting in an effective increase in the concentration of limiting factors for deletion.

Base Sequence↗
PubMed2006

Fen1 does not control somatic hypermutability of the (CTG)(n)*(CAG)(n) repeat in a knock-in mouse model for DM1.

The mechanism of trinucleotide repeat expansion, an important cause of neuromuscular and neurodegenerative diseases, is poorly understood. We report here on the study of the role of flap endonuclease 1 (Fen1), a structure-specific nuclease with both 5' flap endonuclease and 5'-3' exonuclease activity, in the somatic hypermutability of the (CTG)(n)*(CAG)(n) repeat of the DMPK gene in a mouse model for myotonic dystrophy type 1 (DM1). By intercrossing mice with Fen1 deficiency with transgenics with a DM1 (CTG)(n)*(CAG)(n) repeat (where 104n110), we demonstrate that Fen1 is not essential for faithful maintenance of this repeat in early embryonic cleavage divisions until the blastocyst stage. Additionally, we found that the frequency of somatic DM1 (CTG)(n)*(CAG)(n) repeat instability was essentially unaltered in mice with Fen1 haploinsufficiency up to 1.5 years of age. Based on these findings, we propose that Fen1, despite its role in DNA repair and replication, is not primarily involved in maintaining stability at the DM1 locus.

Aging↗
PubMed2005

[Telomere and cancer: what's more at the end?].

Telomeres are nucleoprotein complexes that cap the end of eukaryotic chromosomes. They are essential for the functions and the stability of the genomes. There is now compelling evidences that telomerase, the enzyme that adds telomeric DNA repeats to chromosome end, is an important player in oncogenesis. The absence of telomerase in somatic tissues is thought to promote genome instability at initial stages of oncogenesis, favoring the emergence of cancer-associated chromosomal abnormalities \; restablishment of telomerase activity is expected afterwards if long term cell cycling is to occur. In addition to telomerase, various factors control the structure and function of telomeres, suggesting that additional telomeric components play important roles during oncogenesis.

Chromosomes↗
PubMed2004

Irregular telomeres impair meiotic synapsis and recombination in mice.

Telomere shortening can lead to chromosome instability, replicative senescence, and apoptosis in both somatic and male germ cells. To study roles for mammalian telomeres in homologous pairing and recombination, we characterized effects of telomere shortening on spermatogenesis and oogenesis in late-generation telomerase-deficient mice. We show that shortened telomeres of late-generation telomerase-deficient mice impair meiotic synapsis and decrease recombination, in particular, in females. In response to telomere shortening, male germ cells mostly undergo apoptosis, whereas female germ cells preferentially arrest in early meiosis, suggesting sexually dimorphic surveillance mechanisms for telomere dysfunction during meiosis in mice. Further, meiocytes of late-generation telomerase-deficient females with shortened telomeres, bred with early-generation males harboring relatively long telomeres, exhibit severely impaired chromosome pairing and synapsis and reduced meiotic recombination. These findings imply that functional telomeres are important in mammalian meiotic synapsis and recombination.

Animals↗
PubMed2001

BRCA1 and BRCA2 and the genetics of breast and ovarian cancer.

Germline mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose individuals to breast and ovarian cancers. Progress in determining the function of BRCA1 and BRCA2 suggests that they are involved in two fundamental cellular processes: DNA damage repair and transcriptional regulation. We evaluate current knowledge of BRCA1 and BRCA2 functions to explain why mutations in BRCA1 and BRCA2 lead specifically to breast and ovarian cancer. The BRCA1 and BRCA2 genes contain unusually high densities of repetitive elements. These features of the BRCAs genomic regions contribute to chromosomal instability of these genes. We propose that somatic alterations of BRCA1 and BRCA2 are common and driven by rearrangements between repetitive elements. Inherited and somatic mutations occur in BRCA1 and BRCA2; virtually all somatic mutations are the result of large genomic rearrangements. What are the consequences of such large somatic mutations of BRCA1 and BRCA2 in women with or without inherited mutations? The breast and ovary are estrogen-responsive tissues. Beginning in puberty, the breast epithelium proliferates rapidly in response to fluctuating levels of estrogen. We present a genetic model outlining how BRCA-deficient cells may gain uncontrolled proliferation leading to tumor formation. Central to this model of BRCA-mediated tumorigenesis are estrogen-mediated proliferation of breast and ovarian epithelium and the distinctive genomic context of the BRCA genes.

BRCA2 Protein↗
PubMed2001

Immunohistochemistry for MSH2 and MHL1: a method for identifying mismatch repair deficient colorectal cancer.

Colorectal cancers with DNA mismatch repair (MMR) gene mutations characteristically display a high rate of replication errors in simple repetitive sequences detectable as microsatellite instability (MSI). Most are the result of somatic MMR dysfunction; however, a subset are caused by germline mutations. The availability of commercial antibodies for MSH2 and MLH1 [corrected] offers an alternative strategy to molecular methods for identifying MMR deficient cancers. To evaluate immunohistochemistry, MLH1 and MSH2 expression was studied using monoclonal antibodies in formalin fixed, paraffin wax embedded cancers. The immunohistochemical staining patterns of 23 cancers displaying MSI, including four cases with germline mutations, were compared with 23 microsatellite stable (MSS) cancers. All MSS cancers exhibited staining with both antibodies. Twenty two of the MSI cases showed absent MMR expression with either anti-MSH2 or anti-MLH1 [corrected]. The high sensitivity and predictive value of immunohistochemistry in detecting MMR deficiency offers a method of discriminating between MSI and MSS cancers caused by MSH2 and MLH1 [corrected] dysfunction. The application and suitability of immunohistochemistry for the detection of MSI and as a strategy for prioritising the mutational analysis of MMR genes in routine clinical practice is discussed.

Adaptor Proteins, Signal Transducing↗
PubMed2026

Biomarkers of metastatic disease in pheochromocytoma and paraganglioma.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors with variable metastatic potential. While metastatic disease occurs in approximately 10-20% of cases, its prediction remains a major clinical challenge, as no histological system has been universally validated to reliably identify aggressive tumors at diagnosis. This review aims to provide a comprehensive and updated overview of current and emerging biomarkers of metastatic risk in PPGL, encompassing histopathological scoring systems, genetic and molecular markers, biochemical phenotyping, liquid biopsy approaches, and imaging-based biomarkers. Among established markers, germline SDHB mutation status, loss of SDHB expression by immunohistochemistry, elevated plasma 3-methoxytyramine, and histopathological scoring systems, such as GAPP and COPPS, represent the most clinically validated tools for risk stratification. Emerging biomarkers - including somatic alterations in ATRX and TERT, genomic instability indices, tumor immune microenvironment characterization, circulating tumor DNA, and oncometabolite quantification - show promise in refining prognostic assessment but require prospective validation before routine clinical implementation. Accurate risk stratification in PPGL demands a multiparametric and dynamic approach, integrating clinical, genetic, biochemical, and molecular parameters. Future progress will depend on large prospective international cohorts, standardized biomarker platforms, and biomarker-driven clinical trial designs to translate emerging molecular knowledge into improved patient outcomes.

SDHB↗
PubMed2004

Using bradykinin-potentiating peptide structures to develop new antihypertensive drugs.

Angiotensin I-converting enzyme (ACE) is a dipeptidyl-carboxypeptidase expressed in endothelial, epithelial and neuroepithelial cells. It is composed of two domains, known as N- and C-domains, and it is primarily involved in blood pressure regulation. Although the physiological functions of ACE are not limited to its cardiovascular role, it has been an attractive target for drug design due to its critical role in cardiovascular and renal disease. We examined natural structures based on bradykinin-potentiating peptides (BPPs) extracted from Bothrops jararaca venom for ACE inhibition. Modeling, docking and molecular dynamics were used to study the conserved residues in the S2', S1' and S1 positions that allow enzyme-substrate/inhibitor contacts. These positions are conserved in other oligopeptidases, and they form tight and non-specific contacts with lisinopril, enalapril and BPP9a inhibitors. The only specific inhibitor for human somatic ACE (sACE) was BPP9a, which is instable in the N-sACE-BPP9a complex due to repulsive electrostatic interactions between Arg P4-Arg 412 residues. Specificity for the C-terminal domain in human sACE inhibition was confirmed by electrostatic interaction with the Asp 1008 residue. Peptide-like BPP structures, naturally developed by snakes across millions of years of evolution, appear to be good candidates for the development of domain-selective ACE inhibitors with high stability and improved pharmacological profiles.

Angiotensin-Converting Enzyme Inhibitors↗