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At least 19 recordsLinked to original sources
PubMed2026

Landscape of genetic alterations affecting cancer genes in primary and advanced malignant phyllodes tumours.

BACKGROUND: Malignant phyllodes tumours (MPT) are aggressive breast fibroepithelial neoplasms. Their rarity has limited their genetic characterization, and associations with genetic ancestry and progression drivers remain poorly understood. Prior studies suggest two evolutionary pathways according to MED12 mutational status. We sought to determine the repertoire of somatic genetic alterations in cancer genes in primary versus metastatic/recurrent MPTs, and according to MED12 mutational status and genetic ancestry. MATERIALS AND METHODS: We analysed the paired tumour-normal targeting sequencing data (up to 505 cancer-related genes) of 31 MPTs (primary, n = 20; metastatic/recurrent, n = 11). RESULTS: Metastatic/recurrent MPTs harboured a numerically higher frequency of genetic alterations in CDKN2A/2B (55% vs. 25%). Moreover, analysis of an MPT case with paired primary and metastatic samples revealed a CDKN2A/2B homozygous deletion restricted to the metastatic sample, suggesting a role for CDKN2A/2B in progression. Compared with MED12-wild type MPTs, MED12-mutant MPTs had higher tumour mutation burden (P = 0.002), frequency of TERT promoter (82% vs. 35%; P = 0.02) and RB1 mutations (45% vs. 5%; P = 0.01). Genetic alterations in the PI3K pathway, including PIK3CA and PTEN, were only present in MED12-wild type MPTs, and absent in MED12-mutant cases (15% vs. 0%; P > 0.05). Furthermore, genetic alterations in EGFR were restricted to MPTs from patients of European genetic ancestry and absent in those of Asian ancestry (43% vs. 0%; P > 0.05). CONCLUSIONS: Taken together, the repertoire of genetic alterations in primary and metastatic/recurrent MPTs shows overlap, and CDKN2A/2B homozygous deletions may play a role in progression. Additionally, molecular profiles of MPTs may vary according to genetic ancestry and MED12 mutational status.

Humans↗
PubMed1976

Genetic alteration in the (Na+ + K+) ATPase transport system expressed in human lymphoblasts and their isolated plasma membranes.

A series of ouabain-resistant human lymphoblastoid lines were shown to be genetically altered in the (Na+ + K+) ATPase transport system. The sensitivity to ouabain of Rb+ uptake in intact cells and (Na+ + K+) dependent ATP hydrolysis in purified plasma membrane vesicles was compared with measurement of ouabain binding to intact cells. Preliminary evidence for at least two categories of ouabain resistance was obtained.

Adenosine Triphosphatases↗
PubMed1975

Energy transduction in Escherichia coli. Genetic alteration of a membrane polypeptide of the (Ca2+,Mg2+)-ATPase.

Recent genetic analyses of the membrane components involved in energy transduction in Escherichia coli have concentrated on the (Ca2+, Mg2+)-ATPase complex (EC 3.6.1.3). Many mutants have been described with altered biochemical properties and defects in energy-requiring processes such as oxidative phosphorylation, transhydrogenase activity, and active transport of several solutes. This report describes the isolation of a mutant strain of E. coli that is defective in several energy-requiring processes. The strain BG-31 was obtained by "localized mutagenesis" using phage P1c1. The mutation maps at approximately 73.5 min on the E. coli chromosome. Reversion and suppression analyses indicate that the defect is the result of a single amber mutation. This strain is unable to utilize succinate, D-lactate, or malate for growth. Mutant cells are unable to couple the energy derived from the hydrolysis of ATP to the active transport of proline, although coupling of energy derived from electron transport to solute transport appears normal when examined in both cells and isolated membrane vesicles. Isolated membranes of the mutant are unable to couple the energy derived from the hydrolysis of ATP to transhydrogenase activity while they can utilize the energy generated from electron transport to drive transhydrogenase activity. Extracts of strain BG-31 have normal levels of (Ca2+, Mg2+)-ATPase activity. The ATPase portion of the complex, bacterial F1 (BF1), is poorly attached to the membrane portion of the complex. In vitro reconstitution of transhydrogenase activity with stripped membrane fractions and crude preparations of BF1 localize the defect in strain BG-31 to the membrane portion of the complex. Analysis of membranes of the strain BG-31 by acrylamide gel electrophoresis in the presence of sodium dodecyl sulfate demonstrate the absence of a single polypeptide of molecular weight about 54,000 and the appearance of a new polypeptide of lower molecular weight, about 25,000. Analysis of a spontaneous revertant of BG-31 shows complete restoration of the parental phenotype including the gel patterns. The characterization of this mutant provides the first demonstration of the consequences of a structural gene mutation on a polypeptide in the membrane portion of the complex and represents the initial stages in what we hope will be the biochemical definition and functional characterization of this important energy-transducing system.

2,6-Dichloroindophenol↗
PubMed1978

Genetic alterations of Streptococcus mutans' virulence.

The use of mutants defective in caries-associated traits has enabled the genetic dissociation of agglutination from adhesion, the demonstration of serotype-specific contributions of IPS to virulence, the importance of glucanohydrolase to virulence to a greater degree than to plaque formation, and the apparent lack of importance of agglutination to virulence. We have also been able to demonstrate the ability of plaque formation-defective mutants and other variants both to infect and to emerge, yet not to cause disease. Additional mutants, currently under study in our laboratory include fructanase, invertase, and sucrose permease-defectives. Ultimately, the identification of key, probably surface-associated virulence factors will offer more potent and specific antigens for directed immune responses by the host.

Adhesiveness↗
PubMed1975

A mammalian spot test: induction of genetic alterations in pigment cells of mouse embryos with x-rays and chemical mutagens.

Embroys heterozygous for five recessive coat-color genes from the cross C 57 BL/6 J Han x T-stock were x-irradiated with 100/r o r treated in utero with 50 mg/3 kg methyl methanesulfonate (MMS) and ethyl methanesulfonate (EMS), respectively. Controls consisted of irradiated embryos of C 57 BL x C 57 BL matings homozygous wild-type for the genes under study, and non-treated offspring of both types of mating. The colors of the spots were observed in the adult fur were either due to expression of the recessive coat genes or were white. I. Irradiated and mutagen-treated offspring of C 57 BL x T-stock matings had almost exclusively nonwhite spots, distributed randomly over the mouse surface. 2. Irraidated offspring of C 57 BL x C 57 BL matings had only white spots which were always midventral. 3. In non-treated offspring of both types of mating no spot could be observed. After correcting for white midventral spots observed in the one type of control, the frequency of expression of one or the other of the recessive color genes is calculated to be about 11% for embryos irradiated with 100r or 101/2 days postconception, about 1% for embryos irradiated with 100r at 9 days postconception, about &% for embryos treated with 50 mg MMS/kg at 101/2 days postconception, and about 8% for embryos treated with 50 mg EMS/2 days postconception. It is discussed that the white midventral spots are preferentially the result of pigment cell killing, while the nonwhite spots are preferentially the result of gene mutations or recombinational processes like mitotic crossing over and mitotic gene conversion. Of numerical and structural chromosome aberrations only those come into question which are able to pass the filter of several mitoses. Therefore, the test system described is supposted to cover not only heitable DNA-alterations, but the whole spectrum of them.

Animals↗
PubMed2025

Spectrum of genetic alterations in patients with peroxisome biogenesis defects in the Iranian population: a case series study.

Peroxisomal disorders are a group of hereditary metabolic disorders that happen when peroxisomes are defective. Around 80% of individuals affected by peroxisomal disorders are classified within the spectrum of Zellweger syndromes with autosomal recessive inheritance pattern that results from mutations in one of the 13 PEX genes. Clinical exome sequencing plays a vital role in the diagnosis where the symptoms are atypical. In the current study, we used this technique to find the underlying genetic cause in 14 Iranian patients with peroxisomal disorders. PEX1 variants were detected in five patients. PEX2, PEX5, PEX6 and PEX7 variants were detected in three, one, one, and two cases, respectively. Finally, ACOX1 variants were identified in two cases. All cases except two cases were homozygote for the suspected variants in Zellweger syndrome-related genes. Two cases were compound heterozygote for variants in the PEX1 gene. In total, two novel variants were identified, including c.313 C > T (p.Gln105*) and c.961 A > T (p.Ile321Phe) in the PEX1 and ACOX1 genes, respectively. The present research expands the range of genetic variations observed in Iranian individuals diagnosed with various forms of Zellweger spectrum disorders.

Humans↗
PubMed1979

Dose and effect of methyl-2-benzimidazolylcarbamate in the "mammalian spot test", an in vivo method for the detection of genetic alterations in somatic cells of mice.

In the spot test, mouse embryos which are heterozygous for four different recessive coat-colour genes are treated in utero by injection of a mutagen into the peritoneal cavity of the mother or by other appropriate routes of administration. If this treatment leads in a pigment precursor cell to an alteration of the wild type allele of one of the genes under study or to its loss, a colour spot in the adult coat may be seen. Peroral application of 100-300 mg methyl-2-benzimidazolylcarbamate (MBC)/kg to the mother during the tenth day postconception led to an increase in the frequency of colour spots in the coats of offspring. The data are consistent with the hypothesis that MBC is a point mutagen.

Alleles↗
PubMed2026

Targeted sequencing reveals a distinct genetic alteration landscape in oral multiple primary squamous cell carcinomas.

OBJECTIVE: Oral multiple primary cancers (MPCs) are associated with poor clinical outcomes, yet their genomic characteristics remain insufficiently understood. DESIGN: Fifty-four formalin-fixed paraffin-embedded (FFPE) tumor samples from 30 patients with oral MPCs were analyzed using high-depth targeted sequencing of a customized 14-gene panel derived from prior whole-exome sequencing data. Detected alterations were analyzed after removal of synonymous mutations. RESULTS: Non-silent genomic alterations were identified in 59.3% (32/54) of samples, involving 19 patients. A total of 70 variant loci across 13 genes were detected. AKAP13 was the most frequently mutated gene at both the sample (22.2%, 12/54), with recurrent mutations observed across multiple patients. In contrast, TP53 mutations occurred at a substantially lower frequency (11.1%, 6/54). Marked inter- and intra-patient mutational heterogeneity was observed. CONCLUSIONS: FFPE-based targeted sequencing enabled an initial characterization of genomic alterations in oral MPCs. Recurrent alterations in AKAP13, GLI2, JMJD1C, and DNAH8, together with the relatively low frequency of TP53 alterations, identify candidate genomic features for further investigation and provide a basis for future studies of the molecular basis of oral MPCs.

Humans↗
PubMed1978

Genetic alterations in potassium transport in L cells.

Starting with mutagenized cultures of the mouse fibroblastic cell line LM(TK-), we have selected mutant clones by their ability to grow at 0.2 micrometer K+, a concentration unable to support the growth of the parent cell. The mutants fall into two classes on the basis of their potassium transport properties. Both classes maintain a high intracellular K+ concentration when growing in low-potassium medium, and both are unaltered in the ouabain-sensitive Na/K pump. One class shows an increased activity of a ouabain-resistant, furosemide-sensitive K+ transport system; the other class shows a decreased activity of a specific component of K+ efflux.

Biological Transport↗
PubMed2026

Somatic genetic alterations in pituitary neuroendocrine tumors.

The molecular characterization of pituitary neuroendocrine tumors (PitNETs) has progressed pronouncedly in recent years, unraveling the molecular pathways driving initiation and progression of different PitNET types and allowing a better understanding of their biology. The most frequent recurring somatic driver alterations were recognized in corticotroph PitNETs (USP8, USP48, BRAF) and somatotroph PitNETs (GNAS) and, much less frequently, in lactotroph PitNETs (SF3B1). Additional well-characterized somatic driver alterations, including TP53, ATRX, and DAXX, are enriched in aggressive corticotroph tumors. Identification of new molecular markers and delineation of their clinical phenotypes are enabling further subclassification of PitNETs based on tumor molecular profiles, with earlier recognition of more aggressive variants. These molecular markers also provide an opportunity for new targeted therapies. Beyond single-gene alterations, epigenetic modifications, such as DNA methylation, histone modifications, and noncoding RNA dysregulation, are emerging as important contributors to PitNET pathogenesis and potential therapeutic targets. Multi-omics approaches encompassing genomics, transcriptomics, epigenomics, and proteomics are transforming PitNET classification. In this review, we provide a comprehensive, data-driven update on somatic driver alterations, epigenetic alterations, converging signaling pathways, and the related emerging therapeutic targets in PitNETs, integrating pooled analyses from published cohorts.

Humans↗
PubMed1975

Nucleotide sequence studies of normal and genetically altered glycine transfer ribonucleic acids from Escherichia coli.

The total nucleotide sequence of tRNAGGA/G -Gly2 from Escherichia coli is pG-C-G-G-G-C-A-U-C-G-U-A-U-A-A-U-G-G-C-U-A-U-U-A-C-C-U-C-A-G-C-C-U-N-C-C-A-A-G-C-U-G-A-U-G-A-U-G-C-G-G-G-T-psi-C-G-A-U-U-C-C-C-G-C-U-G-C-C-C-G-C-U-C-C-AOH, where T- at position 53 is ribothymidylic acid, and psi- at position 54 is pseudouridylic acid; N- at position 36 is an unidentified derivative of uridylic acid, and is present in modified form in a portion of tRNAGGA/G -Gly 2 molecules isolated from E. coli cells. The missense suppressor mutation, glyTsuA36(HA), results in a C yields U base substitution at the 3' end of the anticodon of tRNAGGA/G -Gly 2 (nucleotide position 38). A secondary effect of this base substitution is the modification of the A residue directly adjacent to the 3' end of the anticodon of tRNAsuA36(HA), -Gly 2 suggesting that the enzymes responsible for this modification recognize the anticodon sequences of prospective tRNA substrates. The creation of a missense-suppressing tRNA, tRNAsuA36(HA), -Gly 2 by an alteration of the anticodon sequence of tRNAGGA/G -Gly 2 is analogous to mechanisms whereby other suppressor tRNAs have arisen. The high degree of nucleotide sequence homology between the amino acid acceptor stems and anticodon regions of four glycine isoaccepting tRNAs specified by E. coli and bacteriophage T4 suggests that these regions may be recognized by the glycyl-tRNA synthetase; the involvement of the anticodon region in the synthetase recognition process is supported by the greatly decreased rate of aminoacylation of tRNAsuA36(HA) -Gly 2.

Anticodon↗
PubMed1979

Evolution of human longevity: a critical overview.

Evolution of longevity of the ungulates, carnivores and primates is reviewed. Special emphasis is focused on recent evolutionary history of longevity along the hominid ancestral-descendant sequence leading to modern man. Maximum life span potential (MLP) or the change in MLP is predicted in extinct species by (1) a phylogenetic analysis of the MLP of present living species and (2) an empirical equation using brain and body weight estimates from fossils. Both of these methods indicate MLP generally increased during mammalian evolution and at an extremely fast rate during the appearance of the hominid species. These results suggest that relatively few genetic alterations were necessary during the recent evolutionary history of man to significantly extend his innate ability to maintain mental and physical health. Much evidence indicates these genetic alterations principally involve regulatory genes, which control a conserved set of structural genes. Evolution of longevity in man could therefore be a result of simple changes in temporal and quantitative expression. Whether these genetic alterations result from mutational changes and/or chromosomal rearrangement cannot yet be evaluated.

Aging↗
PubMed2026

Association between smoking, tumor genetics, and outcomes in men with metastatic prostate cancer.

PURPOSE: Smoking has been associated with increased metastatic prostate cancer mortality, but the mechanisms behind this are largely unknown. We hypothesized that smoking increases the risk of genetic alterations associated with aggressive disease and/or the transformation to neuroendocrine prostate cancer (NEPC). PATIENTS AND METHODS: We utilized the Prostate Cancer Precision Medicine Multi-institutional Collaborative Effort (PROMISE) clinical genomic database for this retrospective analysis. We associated patient characteristics and tumor genetic data with smoking exposure at diagnosis (current, former, never and pack years) and with clinical outcomes, including overall survival (OS) from diagnosis or time to developing metastatic disease and NEPC status. RESULTS: We identified 2353 men with prostate cancer and next generation somatic tumor sequencing evaluable for analysis in PROMISE, including 8% current, 39% former, and 52% never smokers. Current smokers were more likely to be younger and to have metastatic (M1 or N1) disease at diagnosis, and less likely to have prior local therapy (all p&#x2009;<&#x2009;0.001). Current smoking was associated with worse OS from diagnosis (99.9 mo vs 137.6 mo, HR 1.42, 95% CI 1.14-1.77), which remained significant after adjusting for disease characteristics. We found no difference in the percentage of NEPC at initial diagnosis or at any time between current, former, and never smokers (p&#x2009;=&#x2009;0.8). We found positive associations between smoking status and genetic alterations in SPOP (current: 15%, former 6.7%, never 3.8%; p&#x2009;=&#x2009;0.018), FGFR1 (current 10%, former 0.4%, never 1.1% p&#x2009;=&#x2009;0.001), and ARID1A (current 5.1%, former 2.2%, never 0.4%; p&#x2009;=&#x2009;0.035) in patients with&#xa0;metastatic androgen pathway modulator sensitive prostate cancer (APMS). CONCLUSION: Active smoking is associated with worse overall and prostate cancer specific survival as compared to never/former smoking and was associated with specific tumor genetic alterations but not small cell/NEPC transformation.

Journal Article↗
PubMed2025

Efficacy of MET-targeting CAR T cells against glioblastoma patient-derived xenograft models.

BACKGROUND: Genetic alteration of the MET receptor tyrosine kinase frequently occurs in glioblastoma (GBM). Clinically, bevacizumab treatment results in MET signaling activation, leading to GBM recurrence with a more malignant phenotype. While MET has been a promising therapeutic target, MET inhibitors have not been successful in treating GBM patients. MET-directed chimeric antigen receptor (CAR) T cells hold the promise of targeting MET-positive GBM regardless of genetic alterations or kinase activity. METHODS: GBM patient-derived xenografts (PDX) harboring MET amplification (METamp) or PTPRZ-MET fusion (ZM) were propagated in vivo followed by glioma stem cell (GSC) isolation. Cell-based assays were used for comparing GSC survival in response to MET inhibitors and CAR T cells. Multi-panel cytokine release was analyzed to profile MET-CAR T cell activation during co-culture with GBM. Orthotopic tumor growth and real-time imaging were performed to evaluate MET-CAR T cell therapeutic efficacy in vivo. RESULTS: Although GBM are heterogeneous tumors, neuro-sphere cells isolated from METamp or ZM fusion PDX tumors showed universal cognate genetic MET alteration along with GSC markers such as SOX2 and nestin. Both METamp and ZM fusion tumors showed MET overexpression but only the METamp cells presented activated MET signaling which was vulnerable to MET inhibitors. In contrast, MET-CAR T cells specifically inhibited all MET-positive tumor growth regardless of MET activation status. CONCLUSIONS: Whereas MET inhibitors are effective in MET-active tumors, MET-CAR T cells eradicate MET-positive GBM growth in an antigen-dependent manner, demonstrating a promising therapeutic approach for treating MET-positive GBM. MET overexpression, especially METamp and ZM fusion may be used to predefine the GBM patients for treating with MET-CAR T cell therapy.

Glioblastoma↗
PubMed2026

High tumor mutational burden and PIK3CA mutations correlate with poor Merkel cell carcinoma-specific survival.

Merkel cell carcinoma (MCC) is a neuroendocrine carcinoma of the skin characterized by poor prognosis. This study aimed to explore the relationship between genetic alterations, tumor mutational burden (TMB), and MCC-specific survival (MCC-SS) in patients who underwent genomic profiling of tumors with OncoPanel. Univariate and multivariable analysis were used to assess the impact of genetic alterations on MCC-SS. Of the 188 identified patients, 164 were included in the analysis. The cohort had a mean age of 72.4 years (SD = 11.03), including 61.6% male. The median TMB was 5.32 (IQR = 3.04-25.53). Kaplan-Meier curves by high versus low TMB were significantly different (log-rank test, P = 0.017). PIK3CA (adjusted P = 0.003), SETBP1 (adjusted P = 0.002), KDR (adjusted P = 0.028), and RET (adjusted P = 0.033) were selected for multivariable analysis. In the multivariable regressions, only PIK3CA (HR = 2.07 [95% CI, 1.10-3.88]; P = 0.024) remained significant. PIK3CA remained significant across prespecified sensitivity analyses. In this study, high TMB and PIK3CA alterations were associated with poor MCC-SS. Identifying a higher-risk subgroup may inform risk stratification and motivate further evaluation of PI3K pathway targeting in future studies.

Humans↗