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At least 109 records · Page 6Linked to original sources
PubMed2005

Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction.

Gene-expression profiling has identified 3 major subgroups of diffuse large B-cell lymphoma (DLBCL): germinal center B-cell-like (GCB), activated B-cell-like (ABC), and primary mediastinal DLBCL (PMBCL). Using comparative genomic hybridization (CGH), we investigated the genetic alterations of 224 cases of untreated DLBCL (87 GCB-DLBCL, 77 ABC-DLBCL, 19 PMBCL, and 41 unclassified DLBCL) previously characterized by gene-expression profiling. The DLBCL subgroups differed significantly in the frequency of particular chromosomal aberrations. ABC-DLBCL had frequent trisomy 3, gains of 3q and 18q21-q22, and losses of 6q21-q22, whereas GCB-DLBCL had frequent gains of 12q12, and PMBCL had gains of 9p21-pter and 2p14-p16. Parallel analysis of CGH alterations, locus-specific gene-expression profiles, and global gene-expression signatures revealed that DNA amplifications and gains had a substantial impact on the expression of genes in the involved chromosomal regions, and some genes were overexpressed in a DLBCL subgroup-specific fashion. Unexpectedly, specific chromosomal alterations were associated with significant changes in gene-expression signatures that reflect various aspects of lymphoma cell biology as well as the host response to the lymphoma. In addition, gains involving the chromosomal region 3p11-p12 provided prognostic information that was statistically independent of the previously defined gene-expression-based survival model, thereby improving its predictive power.

Chromosomes, Human↗
PubMed2025

Development and validation of blood-based diagnostic biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) using EpiSwitch® 3-dimensional genomic regulatory immuno-genetic profiling.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating, multifactorial disorder characterised by profound fatigue, post-exertional malaise, cognitive impairments, and autonomic dysfunction. Despite its significant impact on quality of life, ME/CFS lacks definitive diagnostic biomarkers, complicating diagnosis and management. Recent evidence highlights potential blood tests for ME/CFS biomarkers in immunological, genetic, metabolic, and bioenergetic domains. Chromosome conformations (CCs) are potent epigenetic regulators of gene expression and cross-tissue exosome signalling. We have previously developed an epigenetic assay, EpiSwitch®, that employs an algorithm-based CCs analysis. Using EpiSwitch® technology, we have shown the presence of disease-specific CCs in peripheral blood mononuclear cells (PBMCs) of patients with amyotrophic lateral sclerosis (ALS), rheumatoid arthritis (RA), prostate and colorectal cancers, diffuse Large B-cell lymphoma and severe COVID-19. In a recent paper, we have identified a profile of systemic chromosome conformations in cancer patients reflective of the predisposition to respond to immune checkpoint inhibitors, PD-1/PD-L1 antagonists, with 85% accuracy. In this Retrospective case/control study (EPI-ME, Epigenetic Profiling Investigation in Myalgic Encephalomyelitis), we used whole blood samples retrospectively collected from n = 47 patients with severe ME/CFS and n = 61 age-matched healthy control patients to perform whole-genome 3D DNA screening for CCs correlating to ME/CFS diagnosis. We identified a 200-marker model for ME/CFS diagnosis (Episwitch®CFS test). First testing on the retrospective independent validation cohort demonstrated a strong systemic ME/CFS signal with a sensitivity of 92% and a specificity of 98%.Pathways analysis revealed several likely contributors to the pathology of ME/CFS, including interleukins, TNFα, neuroinflammatory pathways, toll-like receptor signalling and JAK/STAT. Comparison with pathways involved in the action of Rituximab and glatiramer acetate (Copaxone) (therapies with potential in ME/CFS treatment) identified IL2 as a shared pathway with clear patient clustering, indicating a possibility of a potential responder group for targeted treatment.

Humans↗
PubMed1990

Genetic profile of cosmopolitan populations: effects of hidden subdivision.

Natural populations of many organisms exhibit excess of rare alleles in comparison with the predictions of the neutral mutation hypothesis. It has been shown before that either a population bottleneck or the presence of slightly deleterious mutations can explain this phenomenon. A third explanation is presented in this work, showing that hidden subdivision within a population can also lead to an excess of rare alleles in the total population when the expectations of the neutral model are based on the allele frequency profile of the entire population data. With two examples (mitochondrial DNA-morph distribution and isozyme allele frequency distributions), it is shown that most cosmopolitan human populations exhibit excess of rare as well as total allele counts, when these are compared with the expectations of the neutral mutation hypothesis. The mitochondrial data demonstrate that such excesses can be detected from genetic variation at a single locus as well, and this is not due to stochastic error of allele frequency distributions. Contrast of the present observations with the allele frequency profiles in agglomerated tribal populations from South and Central America shows that even when the neutral expectations hold for individual subpopulations, if all subpopulations are grouped into a single population, the pooled data exhibit an excess of total number of alleles that is mainly due to the excess of rare alleles. Therefore, a primary cause of the excess number of rare alleles could be the hidden subdivision, and the magnitude of the excess indicates the extent of substructuring. The two components of hidden subdivision are: 1) Number of subpopulations, and 2) the average genetic distance among them. The implications of this observation in estimating mutation rate are discussed indicating the difficulties of comparing mutation rates from different population surveys.

Alleles↗
PubMed2005

Clinicopathologic and genetic profile of intracranial marginal zone lymphoma: a primary low-grade CNS lymphoma that mimics meningioma.

PURPOSE: Although rare overall, marginal zone B-cell lymphoma (MZBCL) is the most common primary low-grade CNS lymphoma reported in the literature. The aim of this study is to elucidate the biology and genetic features of this unusual tumor. PATIENTS AND METHODS: Fifteen CNS MZBCLs were studied clinically, pathologically, and genetically, including fluorescent in situ hybridization analyses with commercially available MALT1 and IgH break-apart and centromere 3, 7, 12, and 18 probes. RESULTS: CNS MZBCLs preferentially affect middle-aged women (female-to-male ratio, 4:1), with 93% presenting as dural-based masses mimicking meningioma. Ten patients with 1 to 7.6 years of follow-up after diagnosis showed no evidence of disease after radiation and/or chemotherapy. Like MZBCLs outside of the CNS, they consisted of CD20+, CD3- small B lymphocytes with varying degrees of plasmacytic differentiation and predominantly kappa light-chain restriction (78%). Lymphoid follicles with follicular colonization were seen in three patients and deposition of amyloid was noted in samples from two patients, one of which was tumefactive. Neither Bcl-6 protein nor Epstein-Barr virus-encoded RNA was expressed. Trisomy 3 was detected in six of 12 patients, with no rearrangements of MALT1 or IgH and no trisomies of 7, 12, or 18 detected. CONCLUSION: Our data suggest that intracranial MZBCL is an indolent primary CNS lymphoma that typically presents as a meningioma-like dural-based mass. Trisomy 3, but not MALT1 or IgH translocation, is a common genetic abnormality that may contribute to the pathogenesis of this CNS lymphoma.

Adult↗
PubMed1999

Genetic profile of the giant cell glioblastoma.

Giant cell glioblastoma is a rare glioblastoma variant characterized by the presence of large, bizarre, multinucleated giant cells. This glioblastoma subtype develops clinically de novo after a short clinical history and contains a high frequency of p53 mutations. In this study, we screened a series of 18 giant cell glioblastomas for additional genetic alterations. PCR-SSCP followed by DNA sequencing revealed PTEN mutations in 5 of 15 tumors (33%). Of these, two mutations were located in exon 5, two mutations in exon 6, and one mutation each in exons 1 and 9. Four mutations were point mutations and two mutations were deletions. One neoplasm contained two PTEN mutations (exons 5 and 6). None of the giant cell glioblastomas showed a homozygous deletion of PTEN orp16, or amplification of MDM2. Immunohistochemically, MDM2 overexpression was either not observed or detected in only a minor fraction of tumor cells. Differential PCR revealed EGFR amplification in only one of 17 tumors (6%). These results indicate that giant cell glioblastomas occupy a hybrid position, sharing with primary (de novo) glioblastomas a short clinical history, the absence of a less malignant precursor lesion and a 30% frequency of PTEN mutations. With secondary glioblastomas that develop through progression from low-grade astrocytomas, they have in common a younger patient age at manifestation and a high frequency (>70%) of p53 mutations.

Adult↗
PubMed2006

Enzymatic and genetic profiles in environmental strains grown on polycyclic aromatic hydrocarbons.

The possible generation of oxidative stress induced by aromatic hydrocarbon degradation suggests that ancillary enzyme activities could facilitate the utilization of polycyclic aromatic hydrocarbons as sole carbon source. To investigate the metabolic profiles of low molecular weight polycyclic aromatic hydrocarbon-degrading strains of Sphingobium chlorophenolicum, Rhodococcus aetherovorans, Rhodococcus opacus and Mycobacterium smegmatis, the determination of the activity of putative detoxifying enzymes (rhodanese-like and glutathione S-transferase proteins) was combined with genetic analyses. All the studied strains were able to utilize phenanthrene or naphthalene. Glutathione S-transferase activity was found in S. chlorophenolicum strains grown on phenanthrene and it was related to the presence of the bphK gene, since modulation of glutathione S-transferase activity by phenanthrene paralleled the induction of glutathione S-transferase transcript in the S. chlorophenolicum strains. No glutathione S-transferase activity was detectable in R. aetherovorans, R. opacus and in M. smegmatis strains. All strains showed 3-mercaptopyruvate:cyanide sulfurtransferase activity. A rhodanese-like SseA protein was immunodetected in R. aetherovorans, R. opacus and in M. smegmatis strains, where increase of 3-mercaptopyruvate:cyanide sulfurtransferase activity was significantly induced by growth on phenanthrene.

Environmental Microbiology↗
PubMed2003

Genetic profile of the Ecuadorian Mestizo population (Ecuador-South America) by using the Power Plex 16 System Kit.

Allele frequency data for the 15 STR systems and Amelogenine were determined in a population sample of healthy Mestizo unrelated individuals. All loci met Hardy-Weinberg expectations and the high discrimination power of combined system showed the forensic efficiency of these genetic markers. There is a lack of information on Ecuadorian population from a genetic point of view and therefore no previous publications on the distribution of STRs on Mestizos is available. Mestizos are descendents of Spanish and Amerindian people, however, significant differences were found between the former and the populations from Spanish peninsula, that have been analyzed for these genetic markers.

Alleles↗
PubMed2003

Genetics and susceptibility to toxic chemicals: do you (or should you) know your genetic profile?

This review is based on a symposium/roundtable session, sponsored by the Division of Toxicology of the American Society for Pharmacology and Experimental Therapeutics, that was held at the 2002 Experimental Biology meeting in New Orleans, LA. The focus is on the role of pharmacogenomics in determining individual susceptibility to chemically induced toxicity. An individual's risk of disease from exposure to toxic chemicals is determined by a complex interplay between genetics, physiology, and concurrent or prior exposures to drugs and other chemicals. The first section of the review defines the basics of pharmacogenetics and pharmacogenomics and assesses the current state of the science. Selected applications to specific enzyme systems are summarized by way of example. New, state-of-the-art approaches to studying genetic determinants of susceptibility, including analytical methods and transgenic technology, are then discussed. Finally, ethical and legal concerns with the application of this knowledge and methodology to human health will be discussed.

Animals↗
PubMed2001

Genetic profile of 22 pancreatic carcinoma cell lines. Analysis of K-ras, p53, p16 and DPC4/Smad4.

The K-ras, p53, p16 and DPC4 genes are among those most frequently altered in pancreatic ductal carcinoma. We analyzed 22 cell lines for alterations in these genes by direct sequence analysis and methylation-specific polymerase chain reaction. These cell lines showed mutations in K-ras and p53 at frequencies of 91% and 95%, respectively. Alterations in p16INK4a were found in all cases and included nine homozygous deletions, seven mutations and promoter methylation in six cases. Eight cell lines (36%) had an alteration of DPC4, including one mutation and seven homozygous deletions. The most typical mutational profile involved K-ras, p53, and p16INK4a, concurrently aberrated in 20 cases (91%). Eight cell lines had alterations in all four genes. Inactivation of DPC4 was always accompanied by alteration of all of the other three genes. This comprehensive data regarding the cumulative genetic alterations in pancreatic carcinoma cell lines will be of great value for studies involving drug sensitivity or resistance that may be associated with inactivation of a particular gene or molecular pathway.

Carcinoma, Pancreatic Ductal↗
PubMedDate not supplied

[Prevalence and genetic profile of alpha-thalassemia in the newborn in Ivory Coast].

The authors report 525 cases of alpha-thalassemia tracked from samples of cord blood proceeded from 12,709 new-borns. With a frequency of 4.13% alpha-thalassemia was frequently in studied population. The lack of symptomatical shapes (Hemoglobin H disease and hydrops foetalis) agree the present theory about the genetic of Black African alpha-thalassemia.

Blood Protein Electrophoresis↗
PubMed1990

Genetic profile of alloxan-induced diabetes-susceptible mice (ALS) and-resistant mice (ALR).

Two inbred strains from a foundation stock derived from Crj: CD-1 (ICR) mice were established after more than 20 generations of full-sib mating, and by simultaneous selective breeding for developing and not developing diabetes after alloxan administration (45 mg/kg in males, 47 mg/kg in females). To elucidate the genetic background of the two inbred strains, i. e., alloxan-induced diabetes-susceptible (ALS) strain and alloxan-induced diabetes-resistant (ALR) strain, their biochemical genetic markers and immunogenetic markers were examined. 1) For both strains, investigation of biochemical genetic markers at 19 loci and immunogenetic markers at 11 loci revealed no variation in any gene within the same strain, showing to be homogeneous, thus indicating establishment of the inbred strains. 2) The two strains differed from each other at 2 loci of biochemical genetic markers and at 5 loci of immunogenetic markers. 3) The ALS and ALR strains can be regarded as new inbred strains derived from ICR mice. 4) The results show that the marker genes of the two strains are different at 7 loci, but it remains unclear whether or not these genes are involved in the difference between the two strains in susceptibility to alloxan.

Alloxan↗
PubMed2006

Profiling genetic variation along the androgen biosynthesis and metabolism pathways implicates several single nucleotide polymorphisms and their combinations as prostate cancer risk factors.

Several candidate genes along androgen pathway have been suggested to affect prostate cancer risk but no single gene seems to be overwhelmingly important for a large fraction of the patients. In this study, we first screened for variants in candidate genes and then chose to explore the association between 18 variants and prostate cancer risk by genotyping DNA samples from unselected (n = 847) and familial (n = 121) prostate cancer patients and population controls (n = 923). We identified a novel single nucleotide polymorphism (SNP) in the CYP19A1 gene, T201M, with a mild significant association with prostate cancer [odds ratio (OR), 2.04; 95% confidence interval (95% CI), 1.03-4.03; P = 0.04]. Stratified analysis revealed that this risk was most apparent in patients with organ-confined (T(1)-T(2)) and low-grade (WHO grade 1) tumors (OR, 5.42; 95% CI, 2.33-12.6; P < 0.0001). In contrast, CYP17A1 -34T>C alteration was associated with moderate to poorly differentiated (WHO grade 2-3) organ-confined disease (OR, 1.42; 95% CI, 1.09-1.83; P = 0.007). We also tested a multigenic model of prostate cancer risk by calculating the joint effect of CYP19A1 T201M with five other common SNPs. Individuals carrying both the CYP19A1 and KLK3 -252A>G variant alleles had a significantly increased risk for prostate cancer (OR, 2.87; 95% CI, 1.10-7.49; P = 0.03). In conclusion, our results suggest that several SNPs along the androgen pathway, especially in CYP19A1 and CYP17A1, may influence prostate cancer development and progression. These genes may have different contributions to distinct clinical subsets as well as combinatorial effects in others illustrating that profiling and joint analysis of several genes along each pathway may be needed to understand genetic contributions to prostate cancer etiology.

Aged↗