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PubMed2001

Clinical management of women with genomic BRCA1 and BRCA2 mutations.

PURPOSE: There is increasing evidence that BRCA1 and BRCA2 associated tumors may differ from sporadic cancers. The purpose of this report is to review the current state of knowledge of BRCA1 and BRCA2, the biology of associated tumors, and possible risk reduction strategies in women with these deleterious mutations. DESIGN AND METHODS: We conducted an extensive literature search of all published articles (including Medline) on preclinical data on the function of BRCA1 and BRCA2, associated tumor pathology, and the clinical management for both unaffected carriers and affected patients. RESULTS: BRCA1 and BRCA2 are likely to act as tumor suppressor genes, and together with RAD51 operate in a common DNA damage response pathway implicated in double-strand repair. Breast cancers associated with BRCA1 are frequently of a higher grade, steroid hormone receptor negative, and appear to have a higher proportion of atypical or typical medullary subtype. Conversely, BRCA2 associated breast cancers do not differ significantly from sporadic cancers. No special tumor phenotype has been ascribed to BRCA1 or BRCA2 associated ovarian cancers. Guidelines for risk reduction strategies for the high risk unaffected carrier have been recommended by expert panels in the USA and Europe. Lifestyle changes, multi-modality screening, chemoprevention, and prophylactic oophorectomy and mastectomy, with their possible benefits and attendant risks are described. Finally, locoregional and systemic treatment in breast and ovarian cancers associated with these mutations, and differences between these and sporadic cancers are discussed. CONCLUSIONS: Although the incidence of breast or ovarian cancers that can be attributed to BRCAI or BRCA2 mutations account for less than 5% of all cancers, these cancers may differ from sporadic cases in terms of tumor biology and phenotype. These differences may impact directly on clinical management of breast and ovarian cancer patients, and their relatives. Further recommendations of these patients are constantly changing as new information emerges on the clinical behavior of these cancers.

Adult↗
PubMed1999

Rapid identification of essential and nonessential herpesvirus genes by direct transposon mutagenesis.

Herpesviruses are important pathogens in animals and humans. The large DNA genomes of several herpesviruses have been sequenced, but the function of the majority of putative genes is elusive. Determining which genes are essential for their replication is important for identifying potential chemotherapy targets, designing herpesvirus vectors, and generating attenuated vaccines. For this purpose, we recently reported that herpesvirus genomes can be maintained as infectious bacterial artificial chromosomes (BAC) in Escherichia coli. Here we describe a one-step procedure for random-insertion mutagenesis of a herpesvirus BAC using a Tn1721-based transposon system. Transposon insertion sites were determined by direct sequencing, and infectious virus was recovered by transfecting cultured cells with the mutant genomes. Lethal mutations were rescued by cotransfecting cells containing noninfectious genomes with the corresponding wild-type subgenomic fragments. We also constructed revertant genomes by allelic exchange in bacteria. These methods, which are generally applicable to any cloned herpesvirus genome, will facilitate analysis of gene function for this virus family.

Base Sequence↗
PubMed1999

Prevalence of Ras mutations in thyroid neoplasia.

OBJECTIVE: Mutations at codons 12, 13 or 61 of ras which result in constitutive activation occur frequently in human malignancies. There have been varied reports on their prevalence and hence their likely significance in the pathogenesis of primary thyroid neoplasia. To address this, we have examined a large series of benign and malignant thyroid tumours for ras mutations. DESIGN: Genomic DNA was analysed for the presence of mutations at codons 12, 13 and 61 of H-ras, K-ras and N-ras by allele-specific oligonucleotide hybridization. Direct DNA sequencing was used to confirm the mutations. PATIENTS: A total of 90 samples with benign (66) and malignant (24) thyroid disease were investigated. RESULTS: A total of 14/90 (15.5%) samples had a ras mutation. All mutations were at codon 61 of either N-ras or K-ras. The positive cases were 1/25 (4%) nodular goitre, 7/38 (18%) follicular adenoma, 4/9 (44%) follicular carcinoma, 1/1 anaplastic carcinoma, 1/1 follicular variant of papillary carcinoma, and 1 metastatic follicular carcinoma in which the primary tumour had the same mutation. CONCLUSIONS: Our data demonstrate a relatively low overall prevalence of ras mutations in thyroid neoplasia, with a predominance in follicular neoplasms. Their presence in follicular adenomas suggests that they may have an early aetiological role in the development of thyroid neoplasia.

Adenocarcinoma, Follicular↗
PubMed2006

The SH3 binding motif of HCV [corrected] NS5A protein interacts with Bin1 and is important for apoptosis and infectivity.

BACKGROUND & AIMS: HCV nonstructural protein 5A (NS5A) has been implicated in regulating cell growth and interferon response. The NS5A protein contains proline-rich regions that are highly conserved among HCV genotypes and match Src homology 3 (SH3)-binding motifs (PxxP) found in various cellular signaling molecules. METHODS: We screened for HCV NS5A interacting proteins by using the yeast 2-hybrid system and studied the functional consequence of this interaction. RESULTS: Several independent clones containing SH3 domains were isolated along with Bin1, a tumor suppressor with pro-apoptotic properties, being the most frequently identified clone. The protein-protein interaction between NS5A and Bin1 was confirmed by in vitro binding, in vivo co-immunoprecipitation, and confocal microscopy. Deletion and mutation analyses indicated that the SH3 binding motif of HCV NS5A and SH3 domain of Bin1 are essential for interaction. Human hepatoma (HepG2) cells lacking expression of Bin1 undergo apoptosis upon infection with adeno-Bin1. Bin1-induced apoptosis was inhibited in HepG2 cells expressing wild-type NS5A but not NS5A mutant with mutations in the SH3 binding motif. Infectious HCV genome containing mutations in the SH3 binding motif was not infectious in chimpanzees. CONCLUSIONS: Our results indicate that this interaction is implicated in productive HCV infection and may contribute to the pathogenesis of hepatocellular carcinoma. In addition, the NS5A PxxP motif may represent a novel target for antiviral development.

Adaptor Proteins, Signal Transducing↗
PubMed1993

Functional complementation of an Escherichia coli ribonuclease H mutation by a cloned genomic fragment from the trypanosomatid Crithidia fasciculata.

A gene designated Cfa RNH1 has been cloned by complementation of an RNase H deficiency in an Escherichia coli rnhA mutant by using a genomic DNA library from the trypanosomatid Crithidia fasciculata. The encoded RNase H is predicted to have 494 amino acid residues and a molecular mass of 53.7 kDa. The carboxyl half of the protein is homologous to the 155-residue E. coli RNase HI (41% identity) and the 166-residue Saccharomyces cerevisiae RNase HI (33% identity). The recombinant protein has been purified as a six-histidine-tagged fusion protein by metal chelate chromatography and was shown to have RNase H activity. Antibodies against the recombinant protein recognize proteins of approximately 65 kDa and 56 kDa on Western blots of C. fasciculata extracts. These results demonstrate the feasibility of cloning trypanosome genes by complementation of appropriate E. coli mutants with genomic DNA libraries.

Amino Acid Sequence↗
PubMed2004

General stress response regulator RpoS in adaptive mutation and amplification in Escherichia coli.

Microbial cells under growth-limiting stress can generate mutations by mechanisms distinct from those in rapidly growing cells. These mechanisms might be specific stress responses that increase mutation rates, potentially altering rates of evolution, or might reflect non-stress-specific processes in rare growing cells. In an Escherichia coli model system, both frameshift reversion mutations and gene amplifications occur as apparent starvation-induced mutations. Whereas frameshift reversion ("point mutation") requires recombination proteins, the SOS response, and error-prone DNA polymerase IV (DinB), amplification requires neither SOS nor pol IV. We report that both point mutation and amplification require the stationary-phase and general stress response transcription factor RpoS (sigmaS). Growth-dependent mutation does not. Alternative interpretations are excluded. The results imply, first, that point mutation and amplification are stress responses that occur in differentiated stationary-phase (not rare growing) cells and, second, that transient genetic instability, producing both point mutation and genome rearrangement, may be a previously unrecognized component of the RpoS-dependent general stress response.

Adaptation, Biological↗
PubMed1985

Studies of heterogeneous mitochondrial populations in a mouse cell line: the effects of selection for or against mitochondrial genomes that confer chloramphenicol resistance.

A single nucleotide substitution in a highly conserved region of the mitochondrial genome of a mouse cell line confers both chloramphenicol resistance and an alteration to the recognition site for the endonuclease Eco RV. This has enabled a detailed study on the effects of selection on a mitochondrial population comprising initially both chloramphenicol-resistant and chloramphenicol-sensitive mitochondrial genomes. The mutation confers advantage to cells grown in the presence of chloramphenicol, but is apparently deleterious in its absence. Selection at the cellular level is sufficient to explain the results observed. Fixation, which results in cells having mitochondria of only a single type, is slow. It is probable, therefore, that mammalian oocyte mitochondria are derived from only a small number of progenitors. This would allow fixation of new mutations and explain the observed uniformity in mitochondrial genomes of the individual in the presence of extensive variation between different members of the population.

Animals↗
PubMed2005

Mutations in Turnip mosaic virus genomes that have adapted to Raphanus sativus.

The genetic basis for virulence in potyviruses is largely unknown. Earlier studies showed that there are two host types of Turnip mosaic virus (TuMV); the Brassica/Raphanus (BR)-host type infects both Brassica and Raphanus systemically, whereas the Brassica (B)-host type infects Brassica fully and systemically, but not Raphanus. The genetic basis of this difference has been explored by using the progeny of an infectious clone, p35Tunos; this clone is derived from the UK1 isolate, which is of the B-host type, but rarely infects Raphanus systemically and then only asymptomatically. Two inocula from one such infection were adapted to Raphanus by passaging, during which the infectivity and concentration of the virions of successive infections increased. The variant genomes in the samples, 16 in total, were sequenced fully. Four of the 39 nucleotide substitutions that were detected among the Raphanus sativus-adapted variant genomes were probably crucial for adaptation, as they were found in several variants with independent passage histories. These four were found in the protein 1 (P1), protein 3 (P3), cylindrical inclusion protein (CI) and genome-liked viral protein (VPg) genes. One of four 'parallel evolution' substitutions, 3430G-->A, resulted in a 1100Met-->Ile amino acid change in the C terminus of P3. It seems likely that this site is important in the initial stages of adaptation to R. sativus. Other independent substitutions were mostly found in the P3, CI and VPg genes.

Adaptation, Physiological↗
PubMed2025

Colorectal cancer-associated PCBP1 mutations disrupt protein stability in a dominant negative manner.

Mutations in RNA-binding proteins are increasingly identified in cancers through tumor sequencing and are correlated with disease progression, therapy response, and overall patient outcomes, underscoring the need to study them. Here, we focus on the RNA-binding protein Poly-C binding protein 1 (PCBP1), which binds target RNAs through K-homology (KH) domains to regulate RNA fate. PCBP1 is a tumor suppressor gene and hotspot missense mutations at leucine residues 100 and 102 are observed in colorectal cancer (CRC). PCBP1 mutations have been recurrently reported in CRC genome-wide mutation studies and are associated with poor clinical outcomes; however, their effects on PCBP1 expression and function remain largely unexplored. We show that cancer-associated mutations substituting leucine 100 and 102 with glutamine, proline, or arginine destabilize PCBP1, leading to increased protein turnover. The L100/L102 residues occur at the interface of the RNA-binding KH1 and KH2 domains, and our molecular dynamics simulations show that mutations at these residues disrupt the secondary structure of PCBP1. Additionally, these mutants display increased cytoplasmic localization. Importantly, mutant PCBP1 physically interacts with wild type PCBP1 and suppresses its expression through a dominant-negative mechanism. Together, our data demonstrate that CRC-associated PCBP1 mutations destabilize the protein and act as dominant-negative variants, revealing a novel mechanism of tumor suppressor inactivation in colorectal cancer.

Journal Article↗
PubMed1999

Resistance of human cytomegalovirus to antiviral drugs.

Resistance of cytomegalovirus (CMV) to antiviral agents is a well-recognized phenomenon that has been observed in the laboratory and in the clinical setting. Infections caused by antiviral-resistant CMV have been found exclusively among immunocompromised individuals, including patients with AIDS, bone marrow and solid-organ transplant recipients, and patients with hematologic malignancies, and in individuals with primary immunodeficiencies. The majority of these infections have been described to occur in patients with AIDS receiving prolonged antiviral therapy for CMV end-organ disease. Antiviral agents currently licensed for the treatment of CMV infections include ganciclovir, foscarnet, and cidofovir. Resistance of CMV to ganciclovir is related to mutations in the UL97 region of the viral genome and/or mutations in the viral DNA polymerase. Resistance to foscarnet and cidofovir is associated with mutations in the viral DNA polymerase. Antiviral susceptibility of CMV strains containing DNA polymerase mutations is dependent on the region of the DNA polymerase where the mutations are located. Some DNA polymerase mutant viruses are cross-resistant to ganciclovir, foscarnet, and cidofovir. The recognition that specific UL97 and UL54 mutations are associated with resistance to antiviral agents has led to the development of molecular methods for detection of mutant viruses. This article reviews the mechanisms of resistance of CMV to antiviral agents, the laboratory methods for detection of resistant CMV, and the clinical aspects of infections caused by antiviral-resistant CMV.

Antiviral Agents↗
PubMed1995

Genetics of hereditary colon cancer.

A new mechanism leading to cancer has been delineated in the last two years when genes whose mutations cause susceptibility to hereditary nonpolyposis colorectal cancer, HNPCC, have been mapped, cloned, and characterized. The genes involved belong to a family of DNA mismatch repair genes, and the homozygous effects of their mutations lead to a so-called mutator or replication error phenotype characterized by genome-wide mutations most readily detectable as lengthening or shortening of microsatellite repeats in tumor tissue as compared to normal tissue from the same individual. Germline mutations are inherited in a dominant Mendelian fashion causing the multiorgan cancer susceptibility syndrome misnamed HNPCC. Clinically, the molecular characterization of these mutations in affected individuals now allows genotype-phenotype correlations, and a new view of the natural history of the disease may arise. In at risk individuals, it allows predictive testing for cancer susceptibility, enhanced clinical surveillance with the aim of early cancer detection and cure, and preventive measures.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed2002

BCL10 mutation does not represent an important pathogenic mechanism in gastric MALT-type lymphoma, and the presence of the API2-MLT fusion is associated with aberrant nuclear BCL10 expression.

Two recurrent translocations have been associated with mucosa-associated lymphoid tissue (MALT)-type lymphoma, t(11;18)(q21;q21) and t(1;14)(p22;q32). The first, t(11;18)(q21;q21), results in the fusion protein API2-MLT (API2-MALT1). Through t(1;14)(p22;q32), the BCL10 gene is entirely transferred to the IgH gene, resulting in its overexpression. Wild-type BCL10 is implicated in apoptosis, and it has been suggested that mutated forms gain oncogenic activity. The occurrence of genomic BCL10 mutations in 35 gastric MALT-type lymphomas with or without t(11;18)(q21;q21) (10 and 25 cases, respectively) was investigated. DNA extracted from either whole tissue sections or microdissected clusters of tumor cells was used. Five polymerase chain reactions amplifying the coding exons were performed and were followed by direct sequencing of the products. Twenty differences with the published BCL10 sequence, all single nucleotide substitutions, were detected in 16 cases. Of these, 12 represented known polymorphisms, either at codon 8, 213, or 5. Of the remaining 8 substitutions, 2 were silent and 6 resulted in amino acid substitutions. Mutation analysis results were correlated with the BCL10 expression pattern. Aberrant nuclear BCL10 expression was detected in 14 cases. No association could be demonstrated between the latter and the presence of BCL10 mutations. In contrast, all 10 cases carrying t(11;18)(q21;q21) showed nuclear expression, whereas this staining pattern was absent in 21 of 25 cases without t(11;18)(q21;q21). These results demonstrate that BCL10 mutations are rare in gastric MALT-type lymphoma and are not related to the aberrant nuclear expression of BCL10. In contrast, they indicate that the presence of the API2-MLT fusion protein is associated with aberrant nuclear BCL10 expression.

Adaptor Proteins, Signal Transducing↗
PubMed2026

Comprehensive Genomic Profiling Reveals the Mutational Spectrum and Clinical Significance of BRCA1/2 and Other Cancer-Susceptibility Genes in Breast Cancer Patients from Southern Tunisia.

BACKGROUND/OBJECTIVES: This study aims to investigate the mutational spectrum of BRCA1 and BRCA2 genes in a cohort of breast cancer (BC) patients from southern Tunisia, and to evaluate their clinical and prognostic significance. Additionally, this study explores the contribution of other cancer predisposition genes and the prevalence of variants of uncertain significance (VUS). RESULTS: Among the 165 patients included, pathogenic or likely pathogenic variants (P/LPVs) in BRCA1/BRCA2 were identified in 19 cases (11.51%), including 8 in BRCA1 and 11 in BRCA2. The presence of BRCA P/LPVs associated with young patients (p = 0.006) and those with TNBC (p = 0.036). Beyond BRCA1/2, PV/LPVs were detected in other cancer-related genes, including TP53 (n = 3), CHEK2, RAD50 (n = 2 cases each), and MUTYH, BARD1, and BRIP1 (one case each). Furthermore, 56 VUS were identified; among them, 7 were prioritized based on in silico predictive analyses, suggesting a potential deleterious effect. However, these VUS should not be used for clinical decision-making without additional evidence from functional and familial segregation studies. CONCLUSIONS: Our findings provide novel insights into the genetic landscape of breast cancer in southern Tunisia, highlighting the clinical relevance of BRCA1/2 mutations and the contribution of other susceptibility genes. These results support the personalized management of breast cancer patients and the implementation of expanded multigene panel testing in routine clinical practice to improve genetic counseling.

BRCA1↗
PubMed1999

Analysis of the p53 tumor suppressor gene in rheumatoid arthritis synovial fibroblasts.

OBJECTIVE: To determine whether mutations in the tumor suppressor gene p53 may contribute to the transformed-appearing phenotype of rheumatoid arthritis (RA) synovial fibroblasts. METHODS: We performed p53 gene mutation analysis using different molecular approaches. Synovial fibroblasts of 10 patients with RA were cultured and RNA and DNA were harvested after 3-5 passages in cell culture. Sequence analysis of all exons of the p53 gene was performed using 3 different techniques: 1) single-strand conformational polymorphism, 2) nonisotopic RNase cleavage assay, and 3) base excision sequence scanning T-scan, followed by sequence analysis of specific gene segments. RESULTS: Although p53 antigen could be detected by immunocytochemistry in numerous cultured fibroblasts, gel electrophoresis analysis of products obtained using all 3 methods and subsequent sequence analysis showed no specific mutation pattern in the genome of the synovial fibroblasts from patients in Germany, including the known "hot spots" within the p53 genome. However, p53 mutations were identified in different clones of 3 additional RA synovial fibroblast populations from the United States. Sequence analysis of the p53 promoter did not reveal mutational base changes. CONCLUSION: The findings of the study support the hypothesis that the majority of the mutations of the p53 gene observed in RA synovium are not derived from the genome of RA synovial fibroblasts, and that the variability of the mutation pattern reflects, in part, the heterogeneity of the disease.

Arthritis, Rheumatoid↗
PubMed2004

Mutation accumulation and the effect of copia insertions in Drosophila melanogaster.

Repeated efforts to estimate the genomic deleterious mutation rate per generation (U) in Drosophila melanogaster have yielded inconsistent estimates ranging from 0.01 to nearly 1. We carried out a mutation-accumulation experiment with a cryopreserved control population in hopes of resolving some of the uncertainties raised by these estimates. Mutation accumulation (MA) was carried out by brother sister mating of 150 sublines derived from two inbred lines. Fitness was measured under conditions chosen to mimic the ancestral laboratory environment of these genotypes. We monitored the insertions of a transposable element, copia, that proved to accumulate at the unusually high rate of 0.24 per genome per generation in one of our MA lines. Mutational variance in fitness increased at a rate consistent with previous studies, yielding a mutational coefficient of variation greater than 3%. The performance of the cryopreserved control relative to the MA lines was inconsistent, so estimates of mutation rate by the Bateman-Mukai method are suspect. Taken at face value, these data suggest a modest decline in fitness of about 0.3% per generation. The element number of copia was a significant predictor of fitness within generations; on average, insertions caused a 0.76% loss in fitness, although the confidence limits on this estimate are wide.

Animals↗