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At least 1,621 records · Page 90Linked to original sources
PubMed2002

p53 as a mutagen test in breast cancer.

The p53 gene is mutated in about half of all tumors. The p53 gene can be used as a "mutagen test," that is, the relative frequencies of the different types of mutation can be used as an epidemiological tool to explore the contribution of exogenous mutagens vs. endogenous processes in particular cancers. p53 has been used as a mutagen test in breast cancer. Surprisingly, the pattern of p53 mutations differs among 15 geographically and ethnically diverse populations. In contrast, mutation patterns in the human factor IX gene are similar in geographically and ethnically diverse populations. Diverse p53 mutation patterns in breast cancer are consistent with a significant contribution by a diversity of exogenous mutagens. Breast tissue may be uniquely sensitive to lipophilic mutagens because of its unique architecture, characterized by tiny islands of cancer-prone mammary epithelial cells surrounded by a sea of adipocytes. Mammary epithelial cells may be differentially susceptible to released lipophilic mutagens preferentially concentrated in adjacent adipocytes and originating in the diet. To test this hypothesis, we developed a method for measuring mutation load from ethanol-fixed, paraffin-embedded human tissues immunohistochemically stained with anti-p53 antibodies. Single cells staining positively for p53 overabundance are microdissected and the gene is sequenced. It is possible to identify individuals with a high mutation load in normal breast tissue and who are presumably at increased risk for breast cancer. In addition, analysis of the p53 gene with appropriate mutation detection methodology markedly improves the prediction of early recurrence, treatment failure, and death in breast cancer patients. Mutagen tests and mutation load measurements are useful tools to identify the role of mutagens in breast cancer.

Breast Neoplasms↗
PubMed1992

Mutation pattern of the p53 gene as a diagnostic marker for multiple hepatocellular carcinoma.

Hepatocellular carcinoma, sometimes shows multiple tumor nodules, therefore poses a problem of differential diagnosis between cancers of multifocal and those of metastatic origin. Conventionally, pathological criteria have been used for this purpose, but these are largely subjective. In order to facilitate more objective differential diagnosis of multiple hepatocellular carcinoma, we used the pattern of mutation of the p53 gene as a marker for each tumor nodule. We studied 58 nodules from 26 cases of multiple hepatocellular carcinoma using polymerase chain reaction-single strand conformation polymorphism analysis, a simple method for detecting mutations. p53 gene mutations were detected in 65% (17 of 26) of cases. The internodule mutation patterns were heterogeneous in 11 cases and homogeneous in 6, enabling a multifocal origin to be diagnosed in the former and a metastatic origin in the latter at the genetic level. Moreover, the origin of recurrent tumors was determined from the mutation pattern. It is concluded that analysis of p53 mutations seems to be useful for differentiating the origin of multiple cancers, since the information it yields is essentially objective.

Base Sequence↗
PubMed2005

Atypical absences and recurrent absence status in an adult with Angelman syndrome due to the UBE3A mutation.

Angelman syndrome is a neurogenetic disorder resulting in refractory epilepsy and profound psychomotor retardation in its most prevalent form, caused by deletion of maternal chromosome 15q11-13. We report the case of a 29-year-old, mentally retarded man with unusual electroencephalographic changes during periods of atypical absence status epilepticus, a previously unreported manifestation of the usually milder, drug-responsive epilepsy associated with Angelman syndrome due to the UBE3A mutation.[Published with video sequences].

Adult↗
PubMed2001

Evidence of a founder mutation of BRCA1 in a highly homogeneous population from southern Italy with breast/ovarian cancer.

Several genes have been involved in the pathogenesis of hereditary breast/ovarian cancer (BOC), but mutations in the BRCA1 gene are by far the most recurrent. In this study, we report the identification of a founder mutation in a geographically and historically homogeneous population from Calabria, a south Italian region. A screening performed on 24 patients from unrelated families highlighted the high prevalence of a 5083del19 alteration in the BRCA1 gene, which accounts for 33% of the overall gene mutations. The same mutation was also detected in 4 patients, all of Calabrian origin, referred to us by research centres from the north of Italy. Allelotype analysis, performed on probands and unaffected family members revealed the presence a common allele, therefore suggesting a founder effect due to a common ancestor. Our findings underscore the importance of ethnic background homogeneity in patients' selection and highlight the usefulness of founder mutations as a potential tool for optimisation of preclinical diagnosis in gene carriers and therapeutic approaches in affected individuals.

Adult↗
PubMed2005

[Determination of fitness components of flies bearing the recessive lethal l(2)M167(DTS) mutation with dominant heat sensitivity in artificial Drosophila melanogaster populations].

Elimination of the heat-sensitive l(2)M167(DTS) mutation from artificial Drosophila melanogaster populations at constant temperature 25 degrees C and various frequencies of the mutation in the parental generation was studied. Components of fitness of the l(2)M167(DTS) mutation were estimated in the artificial populations by means of the recurrent model of the dependence of the frequency of this mutation in a given generation on its frequency in the previous generation. The model was solved by a numerical method with limitations on the values of some fitness components obtained in test experiments. According to the limitations and frequencies of the l(2)M167(DTS) mutation, the leading role and limits of the variation in egg-to-adult viability and female fertility were determined. The previously suggested effect of the positive selection for viability of individuals heterozygous for l(2)M167(DTS) was confirmed.

Animals↗
PubMed2001

Loss of p53 function confers high-level multidrug resistance in neuroblastoma cell lines.

Neuroblastomas can acquire a sustained high-level drug resistance during chemotherapy and especially myeloablative chemoradiotherapy. p53 mutations are rare in primary neuroblastomas, but a loss of p53 function could play a role in multidrug resistance. We determined p53 function by measuring induction of p21 and/or MDM2 proteins in response to melphalan (L-PAM) in seven L-PAM-sensitive and 11 L-PAM-resistant neuroblastoma cell lines. p53 was functional in seven/seven drug-sensitive but in only 4/11 drug-resistant cell lines (P = 0.01). In four of the seven cell lines lacking p53 function, mutations of p53 were detected by the microarray GeneChip p53 Assay and automated sequencing, whereas six cell lines with functional p53 had no evidence of p53 mutations. All of the cell lines with wild-type (wt) p53 showed a strong transactivation of the p53-HBS/CAT reporter gene, whereas the four cell lines with mutant p53 failed to transactivate p53 HBS/CAT. Overexpression of MDM2 protein (relative to p53 functional lines) was seen in two p53-nonfunctional cell lines with wt p53; one showed genomic amplification of MDM2. Nonfunctional and mutated p53 was detected in a resistant cell line, whereas a sensitive cell line derived from the same patient before treatment had functional and wt p53. Loss of p53 function was selectively achieved by transduction of human papillomavirus 16 E6 (which degrades p53) into two drug-sensitive neuroblastoma cell lines with intact p53, causing high-level drug resistance to L-PAM, carboplatin, and etoposide. These data obtained with neuroblastoma cell lines suggest that the high-level drug resistance observed in some recurrent neuroblastomas is attributable to p53 mutations and/or a loss of p53 function acquired during chemotherapy. If confirmed in patient tumor samples, these data support development of p53-independent therapies for consolidation and/or salvage of recurrent neuroblastomas.

Antineoplastic Agents↗
PubMed2002

Cyclic neutropenia.

Cyclic neutropenia is a rare hematologic disorder, characterized by repetitive episodes of fever, mouth ulcers, and infections attributable to recurrent severe neutropenia. Fluctuations in blood cells are due to oscillatory production of cells by the bone marrow. Recent genetic, molecular, and cellular studies have shown that autosomal-dominant cyclic neutropenia and sporadic cases of this disease are due to a mutation in the gene for neutrophil elastase (ELA2), located at 19p13.3. This enzyme is synthesized in neutrophil precursors early in the process of primary granule formation. It is currently presumed that the mutant neutrophil elastase functions aberrantly within the cells to accelerate apoptosis of the precursors, resulting in effective and oscillatory production. Cyclic neutropenia is effectively treated with granulocyte colony-stimulating factor (G-CSF), usually at doses of 1 to 5 microg/kg/d (median dose, 2.5 microg/kg/d). Long-term, daily, or alternate-day administration reduces fever, mouth ulcers, and other inflammatory events associated with this disorder. Leukemic transformation is not a recognized risk for cyclic neutropenia, with or without treatment with G-CSF.

Granulocyte Colony-Stimulating Factor↗
PubMed2005

bcr/abl-negative, classic myeloproliferative disorders: diagnosis and treatment.

Essential thrombocythemia, polycythemia vera, and myelofibrosis with myeloid metaplasia constitute the "classic" bcr/abl-negative myeloproliferative disorders (MPDs). Each of these MPDs represents a stem cell-derived clonal myeloproliferation with the respective features of thrombocytosis, erythrocytosis, and bone marrow fibrosis. Unlike with cases of chronic myeloid leukemia, in which the bcr/abl mutation is invariably detected, current diagnosis of essential thrombocythemia, polycythemia vera, and myelofibrosis with myeloid metaplasia is based on a consensus-driven set of clinical and laboratory criteria that have undergone substantial modification in recent times. The recent discovery of a recurrent activating Janus tyrosine kinase (JAK2) mutation (JAK2VG17F) in all 3 classic MPDs offers another opportunity for refining current diagnoses and disease classifications. In this article, we outline contemporary diagnostic algorithms for each of these disorders and provide an evidence-based approach to management.

Erythropoietin↗
PubMed2001

Mitochondrial dysfunction associated with a mutation in the Notch3 gene in a CADASIL family.

BACKGROUND: Cerebral autosomal arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by recurrent subcortical ischemic strokes and dementia caused by mutations in the Notch3 gene. In Drosophila melanogaster, Notch signaling has a pleiotropic effect, affecting most tissues of the organism during development. OBJECTIVE: To characterize a potential mitochondrial dysfunction associated with mutations in the Notch3 gene. METHODS: Biochemical, histochemical, molecular, and genetic analyses were performed on muscle biopsy specimens and fibroblasts obtained from patients of a Spanish family with CADASIL. Additional biochemical and molecular analyses of the N(55e11) mutant of D. melanogaster were performed. RESULTS: In muscle biopsy specimens, a significant decrease was found in the activity of complex I (NADH [reduced form of nicotinamide adenine dinucleotide] dehydrogenase), and in one patient, histochemical analysis showed the presence of ragged-red fibers with abnormal cytochrome c oxidase staining. Reduced fibroblast activity of complex V (ATP synthase) was found. Supporting data on patients with CADASIL, it was found that the mutation N(55e11) in Drosophila decreases the activity of mitochondrial respiratory complexes I and V. CONCLUSIONS: Mitochondrial respiratory chain activity responds, directly or indirectly, to the Notch signaling pathway. Mitochondrial dysfunction in patients with CADASIL may be an epiphenomenon, but results of this study suggest that the pathophysiology of the disease could include a defect in oxidative phosphorylation.

Adult↗
PubMed1994

Leigh syndrome and hypertrophic cardiomyopathy in an infant with a mitochondrial DNA point mutation (T8993G).

Mutation of mitochondrial (mt) DNA at nucleotide (nt) 8993 has been reported to cause neurogenic weakness, ataxia, retinitis pigmentosa (NARP), or Leigh syndrome (LS). We report a family in whom the mutation was expressed clinically as LS and hypertrophic cardiomyopathy (CMP) in a boy who presented with a history of developmental delay and hypotonia, and who had recurrent lactic acidosis. The mother's first pregnancy resulted in the birth of a stillborn female; an apparently healthy older brother had died suddenly (SIDS) at age 2 months. MtDNA analysis identified the presence of the T8993G point mutation, which was found to be heteroplasmic in the patient's skeletal muscle (90%) and fibroblasts (90%). The identical mutation was present in leukocytes (38%) isolated from the mother, but not from the father or maternal grandmother. Our findings expand the clinical phenotype of the nt 8993 mtDNA mutation to include hypertrophic cardiomyopathy and confirm its cause of LS.

Acidosis, Lactic↗
PubMed1995

p53 immunohistochemistry of odontogenic keratocysts in relation to recurrence, basal-cell budding and basal-cell naevus syndrome.

Mutation of the p53 tumour suppressor gene can produce a more stable protein that does not inhibit mitosis, accumulates in the nucleus and can then be detected immunohistochemically in many human tumours using antibody CM-1. The protein has also been detected in odontogenic keratocysts. Routinely processed material from 30 odontogenic keratocysts was immunostained with antibody CM-1. Ten were recurrences and five were associated with the basal-cell naevus syndrome (Gorlin-Goltz syndrome). p53 protein was found in 50% (15/30) of the odontogenic keratocysts, in 53.3% (8/15) of non-recurrent cysts, in 40% (4/10) of recurrent cysts and in 60% (3/5) of those associated with the basal-cell naevus syndrome. Staining was weak and speckled and limited to occasional basal and suprabasal cells. There was no statistically significant difference in staining between these groups and no correlation between expression and the presence of satellite cysts, basal-cell budding or islands of odontogenic epithelium. The low levels of expression may represent physiological expression of wild-type p53 protein rather than mutant or complexed p53 protein.

Antibodies↗
PubMed2004

Variability of familial hemiplegic migraine with novel A1A2 Na+/K+-ATPase variants.

A1A2 Na+/K+-ATPase mutations cause familial hemiplegic migraine type 2 (FHM2). The authors identified three putative A1A2 mutations (D718N, R763H, P979L) and three that await validation (P796R, E902K, X1021R). Ten to 20% of FHM cases may be FHM2. A1A2 mutations have a penetrance of about 87%. D718N causes frequent, long-lasting HM, and P979L may cause recurrent coma. D718N and P979L may predispose to seizures and mental retardation. A1A2 does not play a major role in sporadic HM; only one variant, R383H, occurred in 1 of 24 cases.

Adolescent↗
PubMed1996

Mutation detection by highly sensitive methods indicates that p53 gene mutations in breast cancer can have important prognostic value.

Human cancer cells with a mutated p53 tumor-suppressor gene have a selective growth advantage and may exhibit resistance to ionizing radiation and certain chemotherapeutic agents. To examine the prognostic value of mutations in the p53 gene, a cohort of 90 Midwestern Caucasian breast cancer patients were analyzed with methodology that detects virtually 100% of all mutations. The presence of a p53 gene mutation was by far the single most predictive indicator for recurrence and death (relative risks of 4.7 and 23.2, respectively). Direct detection of p53 mutations had substantially greater prognostic value than immunohistochemical detection of p53 overexpression. Analysis of p53 gene mutations may permit identification of a subset of breast cancer patients who, despite lack of conventional indicators of poor prognosis, are at high risk of early recurrence and death.

Alternative Splicing↗
PubMed2005

Thrombophilias and recurrent pregnancy loss: a critical appraisal of the literature.

Thrombophilias are suggested to play a role in recurrent miscarriage. The aim of this study was to evaluate the literature of the past 10 years regarding the association between thrombophilias and recurrent miscarriage. We concluded that there is a large variety in applied study methodology. Therefore, we defined criteria for an adequate study on the relationship of thrombophilias on recurrent pregnancy loss: (i) no exclusion criteria for patients or at least the same criteria for patients and controls; (ii) a clear definition of the gestational age at previous losses; (iii) a well-described control group; (iv) clear description of the test methods and moment of testing; and (v) a clear description of the (non) significant differences or odds ratio between cases and controls. Eleven out of 69 studies fulfilled these criteria. Their results show significant higher serum homocysteine levels among women with a history of recurrent miscarriage. No relation was found between recurrent miscarriage and the methylenetetrahydrofolate reductase C667T mutation. No relation was observed for the levels of antithrombin, protein C and protein S. Seven studies on the association of factor V Leiden (FVL) and/or pathologic activated protein C ratio (pAPCR) showed that FVL may play a role in second trimester losses, as do antiphospholipid antibodies. Studies on the prothrombin gene mutation yielded conflicting results. Consequently, large prospective studies according to the aforementioned criteria are needed to establish if there is a relationship between thrombophilias and recurrent miscarriage at all. At present, there is only justification for testing for homocysteine levels, antiphospholipid antibodies and FVL in women with a history of recurrent miscarriage.

Abortion, Habitual↗
PubMed2003

Identification and characterization of 13 new mutations in mucopolysaccharidosis type I patients.

In this study we have investigated a group of 29 Brazilian patients, who had been diagnosed with the lysosomal storage disorder, Mucopolysaccharidosis type I (MPS-I). MPS I is caused by a deficiency in the lysosomal hydrolase, alpha-L-iduronidase. Ninety percent of the MPS I patients in this study were genotyped and revealed 10 recurrent and thirteen novel IDUA gene mutations. Eight of these new mutations and three common mutations W402X, P533R, and R383H were individually expressed in CHO-K1 cells and analyzed for alpha-L-iduronidase protein and enzyme activity. A correlation was observed between the MPS I patient clinical phenotype and the associated mutant alpha-L-iduronidase protein/enzyme activity expressed in CHO-K1 cells. This was the first time that Brazilian MPS I patients had been thoroughly analyzed and highlighted the difficulties of mutation screening and clinical phenotype assessment in populations with high numbers of unique mutations.

Animals↗
PubMed2026

Multiomic study of cutaneous T-cell lymphoma reveals single-cell clonal evolution in progression and therapy resistance.

Cutaneous T-cell lymphoma (CTCL) remains a challenging disease due to its significant heterogeneity, therapy resistance, and relentless progression. Multiomics technologies offer the potential to provide uniquely precise views of disease progression and response to therapy. Here, we present a comprehensive multiomics view of CTCL clonal evolution, incorporating exome, whole-genome, epigenome, bulk, single-cell T-cell receptor, and single-cell RNA sequencing of 99 clinically annotated serial skin, peripheral blood, and lymph node samples from 34 patients with CTCL. We leveraged this extensive data set to define the molecular underpinnings of CTCL progression in individual patients at single-cell resolution with the goal of identifying clinically useful biomarkers and therapeutic targets. Our studies identified recurrent progression-associated clonal genomic alterations; we highlight mutation of CCR4, phosphoinositide 3-kinase inhibitor signaling, and programmed cell death protein 1 (PD-1) checkpoint pathways as evasion tactics deployed by malignant T cells. We identified a gain-of-function mutation in STAT3 (D661Y) and demonstrated, using cleavage under targets and release using nuclease (CUT&RUN) and RNA sequencing, that it enhances binding to and transcription of genes in Rho GTPase pathways. With our previous work implicating this pathway in histone deacetylase inhibitor-resistant CTCL, these data provide further support for a previously unrecognized role for Rho GTPase pathway dysregulation in CTCL progression. Recurrent progression-associated mutations were common in the epigenetic modifier EZH2, suggesting that EZH2 inhibition may benefit patients with CTCL. Our findings support an approach in which genomic analysis is widely used for improved disease monitoring, biomarker-informed clinical trial design, and genome-guided therapeutic decision-making. Moreover, these molecular changes present new opportunities for therapeutic targeting in this challenging and incurable cancer.

Multiomics↗
PubMed2000

Effect of radiotherapy after breast-conserving treatment in women with breast cancer and germline BRCA1/2 mutations.

PURPOSE: Recent laboratory data suggest a role for BRCA1/2 in the cellular response to DNA damage. There is a paucity of clinical data, however, examining the effect of radiotherapy (RT), which causes double-strand breaks, on breast tissue from BRCA1/2 mutation carriers. Thus the goals of this study were to compare rates of radiation-associated complications, in-breast tumor recurrence, and distant relapse in women with BRCA1/2 mutations treated with breast-conserving therapy (BCT) using RT with rates observed in sporadic disease. PATIENTS AND METHODS: Seventy-one women with a BRCA1/2 mutation and stage I or II breast cancer treated with BCT were matched 1:3 with 213 women with sporadic breast cancer. Conditional logistic regression models were used to compare matched cohorts for rates of complications and recurrence. RESULTS: Tumors from women in the genetic cohort were associated with high histologic (P =.0004) and nuclear (P =.009) grade and negative estrogen (P=.0001) and progesterone (P=.002) receptors compared with tumors from the sporadic cohort. Using Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicity scoring, there were no significant differences in acute or chronic morbidity in skin, subcutaneous tissue, lung, or bone. The 5-year actuarial overall survival, relapse-free survival, and rates of tumor control in the treated breast for the patients in the genetic cohort were 86%, 78%, and 98%, respectively, compared with 91%, 80%, and 96%, respectively, for the sporadic cohort (P = not significant). CONCLUSION: There was no evidence of increased radiation sensitivity or sequelae in breast tissue heterozygous for a BRCA1/2 germline mutation compared with controls, and rates of tumor control in the breast and survival were comparable between BRCA1/2 carriers and controls at 5 years. Although additional follow-up is needed, these data may help in discussing treatment options in the management of early-stage hereditary breast cancer and should provide reassurance regarding the safety of administering RT to carriers of a germline BRCA1/2 mutation.

Adult↗
PubMed2006

Activating mutations of the stimulatory g protein in juvenile ovarian granulosa cell tumors: a new prognostic factor?

CONTEXT: Conflicting data have been reported regarding the presence of a constitutive activation of Galphas in ovarian granulosa cell tumors (OGCTs). Although the precise role of this mutation in the transformation of ovarian cells into malignant cells remains debatable, it has been demonstrated in other tissues that the rate of cell proliferation and invasiveness can be influenced by the gsp oncogene. OBJECTIVE: The objective of this study was to determine whether activating mutations of Galphas or Galphai are present in juvenile OGCTs and, if so, whether these mutations are significant prognostic factors. DESIGN AND SETTING: This was a multicentric nationwide study. PATIENTS AND METHODS: Thirty children with juvenile OGCT were included from the malignant germinal tumor protocol of the French Society for Childhood Cancer. Genetic studies of the tumoral DNA used nested PCR, laser microdissection, and direct sequencing. RESULTS: Galphas-activating mutations in hot spot position 201 were found in nine patients (30%). Laser microdissection confirmed that mutations R201C and R201H were exclusively localized in the tumoral granulosa cells and were absent in the ovarian stroma. Patients with a hyperactivated Galphas exhibited a significantly more advanced tumor (P < 0.05) because seven of them (77.7%) were staged as Ic or had had a recurrence. Galphai did not exhibit any mutation. CONCLUSIONS: Activating mutations of Galphas are present in 30% of juvenile OGCTs. The gsp oncogene, which is known to be implicated in cell proliferation and tumoral invasiveness, can be considered as a new prognostic factor of these tumors.

Cell Proliferation↗