PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “mutational profiling”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 55 records · Page 3Linked to original sources
PubMed1996

Dose-dependent differences in the mutational profiles of (-)-(1R,2S,3S,4R)-3,4-dihydroxy-1, 2-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene and its less carcinogenic enantiomer.

Chinese hamster V-79 cells were treated with high cytotoxic or low noncytotoxic concentrations of the highly carcinogenic and mutagenic (-)-(1R,2S,3S,4R)-3,4-dihydroxy-1, 2-epoxy-1,2,3,4-tetrahydrobenzo[c]phenanthrene [(-)-B[c]PhDE; fjord-region diol epoxide] or its biologically less active (+)-(1S,2R,3R,4S) enantiomer [(+)-B[c]PhDE]. The benzylic 4-hydroxyl group and the epoxide oxygen are trans in both enantiomers. Independent 8-azaguanine-resistant clones were isolated. The coding region of the hypoxanthine (guanine) phosphoribosyltransferase gene was amplified by reverse transcription-PCR and sequenced. For (-)-B[c]PhDE, mutation frequencies were 10- or 356-fold above background for the low (0.01-0.1 microM; 97% cell survival) or high (1.0-1.25 microM; 26% cell survival) doses, respectively. For the high dose group, 20 of 64 base substitutions occurred at GC base pairs (31%) and 44 at AT base pairs (69%). For the low-dose group, 6 of 55 base substitutions were at GC base pairs (11%), and 49 were at AT base pairs (89%). For the less active (+)-B[c]PhDE, mutation frequencies were 17- or 372-fold above background for the low (0.12-0.5 microM; 95% cell survival) or high (2.0-3.0 microM; 31% cell survival) doses, respectively. In contrast to the results with the (-)-B[c]PhDE, both the high- and the low-dose groups for (+)-B[c]PhDE gave a 50:50 distribution of base substitution at GC versus AT base pairs. Our data indicate that: (a) transversions were the predominant base substitutions observed for both the (+)- and (-)-enantiomers of B[c]PhDE; (b) (-)-B[c]PhDE showed high selectivity for causing AT --> TA transversions, whereas considerably less selectivity was observed for (+)-B[c]PhDE; (c) (-)-B[c]PhDE had a different hot spot profile for base substitutions than did (+)-B[c]PhDE, but some common hot spots were observed for both compounds; and (d) decreasing the dose of (-)-B[c]PhDE increased the proportion of mutations at AT base pairs and decreased those at GC base pairs, but this was not observed for (+)-B[c]PhDE.

Animals↗
PubMed1998

Exhaustive screening of the acid beta-glucosidase gene, by fluorescence-assisted mismatch analysis using universal primers: mutation profile and genotype/phenotype correlations in Gaucher disease.

Gaucher disease (GD) is one of the most prevalent lysosomal storage disorders and one of the rare genetic diseases now accessible to therapy. Outside the Ashkenazi Jewish community, a high molecular diversity is observed, leaving approximately 30% of alleles undetected. Nevertheless, very few exhaustive methods have been developed for extensive gene screening of a large series of patients. Our approach for a complete search of mutations was the association of fluorescent chemical cleavage of mismatches with a universal strand-specific labeling system. The glucocerebrosidase (GBA) gene was scanned by use of a set of six amplicons, comprising 11 exons, all exon/intron boundaries, and the promoter region. By use of this screening strategy, the difficulties due to the existence of a highly homologous pseudogene were easily overcome, and both GD mutant alleles were identified in all 25 patients studied, thus attesting to a sensitivity that approaches 100%. A total of 18 different mutations and a new glucocerebrosidase haplotype were detected. The mutational spectrum included eight novel acid beta-glucosidase mutations: IVS2 G(+1)-->T, I119T, R170P, N188K, S237P, K303I, L324P, and A446P. These data further indicate the genetic heterogeneity of the lesions causing GD. Established genotype/phenotype correlations generally were confirmed, but notable disparities were disclosed in several cases, thus underlining the limitation in the prognostic value of genotyping. The observed influence of multifactorial control on this monogenic disease is discussed.

Adolescent↗
PubMed2025

Stochastic epigenetic mutation profiles as biomarkers of clinical activity in juvenile idiopathic arthritis: a multi-omic machine learning approach for gene prioritization.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is a rare autoimmune disease arising from a complex interplay between genetic and environmental factors. Epigenetic modifications such as DNA methylation (DNAm) have been described as potential mediators in gene-environment interactions, contributing to immune system dysregulation. Emerging evidence suggests that DNAm profiles also predict therapeutic responses in autoimmune diseases. This study aims to identify epigenetic biomarkers and epigenetic-driven gene expression changes associated with JIA clinical activity. METHODS: We reanalyzed a publicly available dataset of 44 JIA patients, with whole-genome DNAm and gene expression from CD4 + T cells measured at two points: at anti-TNF therapy withdrawal (T0) and eight months later (Tend). At Tend, 30 patients maintained inactive disease (ID) while 14 did not (NO ID). We investigated differences between ID and NO ID patients in the epigenetic mutation load and various epigenetic clocks through linear regression models, and prioritized genomic regions with significantly higher number of epimutations in NO ID patients through machine learning. RESULTS: We found a higher mutation load in NO ID than ID patients, both at T0 and at Tend, with the differences at Tend reaching statistical significance (p = 0.02). In contrast, we found no evidence of association between epigenetic clocks and JIA clinical activity. Using a multi-omic approach, we identified a List of candidate epigenetically-driven differentially expressed genes, 80 up-regulated and 77 down-regulated, in NO ID patients. Finally, comparing our candidate gene list with the Connectivity Map database, we identified new candidate potential therapeutic targets. Key findings were validated in independent datasets: DNAm profiles from CD4 + T cells (56 JIA patients, 57 controls) and transcriptomic data from PBMCs of JIA patients with active or inactive disease, confirming dysregulation of pathways such as TNF-α signaling via NF-kB and TGF-β signaling among others. CONCLUSIONS: We described a significant association of epigenetic mutations with JIA clinical activity, indicating that epigenetic changes might precede clinical symptoms and may serve as biomarkers for early disease monitoring. Further, our results shed light on biomolecular mechanisms of JIA, supporting the development of more effective treatments.

Humans↗
PubMed2006

Mutation profile of the GAA gene in 40 Italian patients with late onset glycogen storage disease type II.

Glycogen storage disease type II (GSDII) is a recessively inherited disorder due to the deficiency of acid alpha-glucosidase (GAA) that results in impaired glycogen degradation and its accumulation in the lysosomes. We report here the complete molecular analysis of the GAA gene performed on 40 Italian patients with late onset GSDII. Twelve novel alleles have been identified: missense mutations were functionally characterized by enzyme activity and protein processing in a human GAA-deficient cell line while splicing mutations were studied by RT-PCR and in silico analysis. A complex allele was also identified carrying three different alterations in cis. The c.-32-13T > G was the most frequent mutation, present as compound heterozygote in 85% of the patients (allele frequency 42.3%), as described in other late onset GSDII Caucasian populations. Interestingly, the c.-32-13T > G was associated with the c.2237G > A (p.W746X) in nine of the 40 patients. Genotype-phenotype correlations are discussed with particular emphasis on the subgroup carrying the c.-32-13T > G/c.2237G > A genotype.

Adolescent↗
PubMed2002

Germline mutation profile of MEN1 in multiple endocrine neoplasia type 1: search for correlation between phenotype and the functional domains of the MEN1 protein.

Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant disease characterized by endocrine tumors of the parathyroids, the pancreatic islets, and the anterior pituitary. The MEN1 gene encodes menin, a nuclear protein interacting with JunD/AP1, Smad3, NFkappaB, and other proteins involved in transcription and cell growth regulation. Here, by exhaustive sequence analysis of 170 probands/families collected through a French clinical network, we identified 165 mutations located in coding parts of the MEN1 gene, which represent 114 distinct MEN1 germline alterations. These mutations have been included in a MEN1-locus specific database available on the world wide web together with approximately 240 germline and somatic MEN1 mutations listed from international published data. Our mutation series included 56 frameshifts, 23 nonsense, 27 missense, and eight deletion or insertion in-frame mutations. Mutations were spread over the entire coding sequence. Taken together, most missense and in-frame MEN1 genomic alterations affect one or all domains of menin interacting with JunD [codons 1-40; 139-242; 323-428], Smad3 [distal to codon 478], and NFkappaB [codons 276-479], three major effectors in transcription and cell growth regulation. No correlation has been observed between genotype and MEN1 phenotype. We suggest that the knowledge of structure and location of a specific mutation has not been useful in clinical practice for the follow-up of affected patients and asymptomatic gene carriers. Our results provide the largest series of MEN1 mutations published to date. They will be a useful tool for further studies focusing on the functional effects of missense mutations and understanding which mechanisms or pathways related to multiple menin interactions might be involved in tumorigenesis of endocrine cells.

Binding Sites↗
PubMed2000

Circulating p53 antibodies, p53 gene mutational profile and product accumulation in esophageal squamous-cell carcinoma in India.

Esophageal cancer (EC) in the Indian population presents in advanced stages with poor prognosis and warrants the identification of a non-invasive marker for early detection and better prognostic assessment. We have previously reported high prevalence of p53 protein accumulation in esophageal squamous-cell carcinomas (ESCCs). The present study was designed to determine (i) if esophageal cancer patients elicit a humoral immune response to intra-tumoral p53 protein accumulation and (ii) their relationship with p53 gene mutations. The goal was to compare the cellular events, p53 protein accumulation and gene mutations with the presence of serum anti-p53 antibodies (p53-Abs) and to assess the utility of serological p53-Ab analysis as a surrogate marker for p53 alterations in esophageal cancer. A high prevalence of circulating p53-Abs was observed in 36 of 60 (60%) ESCC patients. In a subset of 44 ESCCs, exons 5-9 of the p53 gene were examined for mutations by PCR and direct sequencing of PCR products. Mutational data have been correlated with p53-Abs and p53 protein accumulation in ESCCs. Circulating p53-Abs in ESCC patients were significantly associated with intra-tumoral p53 protein accumulation (p=0.0005). A strong correlation observed between humoral immune response against p53 protein, missense gene mutations and protein accumulation warrants the application of serological p53-Abs as a non-invasive surrogate marker in screening high-risk populations for early detection of malignancy.

Adult↗
PubMed2005

p53 mutation profiling of multiple esophageal carcinoma using laser capture microdissection to demonstrate field carcinogenesis.

Inactivation of the p53 tumor suppressor gene is one of the most frequent genetic alterations observed in human esophageal carcinomas. In patients with esophageal carcinoma, one of the significant pathological features of the tumor is the presence of multiple lesions within the esophagus. However, the molecular mechanisms involved in the occurrence of multiple lesions have remained elusive. To characterize p53 alterations in multiple esophageal carcinomas and to study their roles in carcinogenesis, we performed p53 immunohistochemical and p53 mutation analyses using laser capture microdissection on surgically resected human esophageal carcinomas from 11 patients: 9 patients with multiple esophageal carcinomas, 1 with an intramural metastasis lesion within the esophagus and 1 with an intraepithelial carcinoma lesion contiguous to the main lesion. In each of the patients with multiple esophageal carcinomas, we examined samples from 1 main lesion and 1 representative concomitant lesion. Molecular analyses of samples from fresh-frozen normal tissues and tumor tissues of the main lesion (whole tumor) were also performed by the same method. p53 protein accumulation was observed in 16 (72.7%) of 22 lesions from the 11 cases. No p53 mutation was found in normal esophageal tissues. In the 9 cases of multiple esophageal carcinomas, point mutations were detected in the whole tumor in 1 (11.1%) case, in the microdissected tumor samples of main lesions in 3 (33.3%) cases and in the microdissected tumor samples of concomitant lesions in 3 (33.3%) cases. For the microdissected tumor samples, there was a 54.5% (12/22) concordance rate between the results of immunostaining and molecular analysis. In the 8 cases of whole tumors in which a p53 mutation was not observed, 2 cases revealed p53 mutation in the microdissected tumor samples of the main lesion. All 6 cases of multiple esophageal carcinomas that showed a p53 mutation in the microdissected tumor sample had a discordant p53 mutational status between the main and concomitant lesions. In contrast, both the intramural metastasis lesion and the intraepithelial carcinoma contiguous to the main lesion showed p53 mutational patterns identical to those of the main lesions. In conclusion, the analysis of microdissected DNA by laser capture microdissection is useful for characterizing the heterogeneity of the p53 gene mutation in multiple carcinoma lesions that cannot be accurately analyzed in whole esophageal tumor DNA. The finding of different p53 gene mutations among multiple esophageal carcinoma lesions suggest further evidence of multicentric or field carcinogenesis of the human esophagus.

Carcinoma in Situ↗
PubMedDate not supplied

Glucose-6-phosphate dehydrogenase deficiency in Portugal: biochemical and mutational profiles, heterogeneity, and haplotype association.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzymopathy. This deficiency in erythrocytes has a prevalence of 0.51 +/- 0.109 in the Caucasoid male population of Portugal. The frequency for deficiency-conferring genes is 0.39% in the Portuguese population. In the herein study populations males from areas of Portugal presenting with the highest prevalence of G6PD deficiency (Castelo Branco, Setúbal, Faro, and Lisbon) as well as similar subjects located in the border Center/North area of the country (Viseu) have been analyzed for biochemical parameters and screened for mutations and haplotype-associated mutations commensurate with G6PD deficiency. Six intragenic restriction fragment length polymorphisms (RFLPs) were studied: exon 5, nt 376 A -->G, FokI; intron 5, nt 611 C--> G, PvuII; intron 8, nt 163 C--> T, BspHI; exon 10, nt 116 G --> A, PstI; exon 11, nt 1311 C--> T, BclI; and intron 11, nt 93 T -->C, NlaIII. New haplotypes were constructed with the inclusion of intron 11, nt 93 T--> C, NlaIII, and only 5 of 64 possible haplotypes were found to show a marked linkage disequilibrium for several RFLPs and also for mutations and specific haplotypes. The control population (n = 168 males) presented the G6PD B variant and corresponded to haplotypes I (- - + + - -), Ia (- - + + - +), and VIIa (- - + + + +), in 91.8, 2.3, and 5.9%, respectively. The PCR and sequencing analysis of extracted DNAs from the deficient G6PD group showed 48.6% (16/33) of individuals with the G6PD A- mutation, corresponding to haplotype VIa (+ + - + - +); 9% (3/33) with the Betica mutation and 18% (6/33) with the Santa Maria mutation, both of them associated with haplotype IVa (+ - - + \- +); 6.1% (2/33) with the Mediterranean mutation associated with haplotype VIIa; 12.3% (4/33) with the Seattle mutation, 3.0% (1/33) with Gaohe mutation; and a new mutation, 3.0% (1/33), which we designated by G6PD Flores, all of them associated with haplotype I.

Adolescent↗
PubMed1993

TP53 gene mutation profile in esophageal squamous cell carcinomas.

Esophageal squamous cell carcinoma is a form of cancer occurring most commonly in males, particularly those living in some areas of Asia, Africa, and western Europe. In some of these tumors, a sequence alteration has been identified in the coding region of the TP53 gene which is known to inactivate the tumor suppressor function of its product. Using a GC clamp (i.e., a GC rich domain) denaturing gradient gel electrophoresis assay we have been able to identify sequence modifications in 27 of the 32 tumor samples analyzed (84%). Most of the mutations occur in exon 6, a region of the gene which has not previously been reported as being a hot spot for the mutations of other cancers. Twelve of the mutations reported here have not been described in other types of tumors and these consist mostly of frameshift or splice mutations. The distribution of mutations [transitions (45%), transversions (34%), and frameshift (21%)] suggests that the etiological contribution of genotoxic factors might be complex and might associate different exogenous and endogenous mutagen exposures.

Adult↗
PubMed1997

Mutation profile of all 49 exons of the human myosin VIIA gene, and haplotype analysis, in Usher 1B families from diverse origins.

Usher syndrome types I (USH1A-USH1E) are a group of autosomal recessive diseases characterized by profound congenital hearing loss, vestibular areflexia, and progressive visual loss due to retinitis pigmentosa. The human myosin VIIA gene, located on 11q14, has been shown to be responsible for Usher syndrome type 1B (USH1B). Haplotypes were constructed in 28 USH1 families by use of the following polymorphic markers spanning the USH1B locus: D11S787, D11S527, D11S1789, D11S906, D11S4186, and OMP. Affected individuals and members of their families from 12 different ethnic origins were screened for the presence of mutations in all 49 exons of the myosin VIIA gene. In 15 families myosin VIIA mutations were detected, verifying their classification as USH1B. All these mutations are novel, including three missense mutations, one premature stop codon, two splicing mutations, one frameshift, and one deletion of >2 kb comprising exons 47 and 48, a part of exon 49, and the introns between them. Three mutations were shared by more than one family, consistent with haplotype similarities. Altogether, 16 USH1B haplotypes were observed in the 15 families; most haplotypes were population specific. Several exonic and intronic polymorphisms were also detected. None of the 20 known USH1B mutations reported so far in other world populations were identified in our families.

Amino Acid Substitution↗
PubMed2003

Microscopic papillary thyroid carcinoma compared with clinical carcinomas by loss of heterozygosity mutational profile.

The clinical significance of microscopic papillary thyroid carcinoma (PTCa) is controversial. Many authors think that microscopic PTCa (<1 cm) have the same pathogenetic origin as clinically sized papillary carcinomas (>1 cm). Despite the fact that all clinical risk prognostication schemes have the size of the tumor as a primary category, small tumors do have malignant potential and can metastasize. There is growing evidence that small PTCa have the molecular translocations between the proto-oncogene RET and various activating partner genes that are characteristic of clinically sized PTCa. This study used a microdissection and genotyping assay to study the patterns of loss of heterozygosity of tumor suppressor genes in microscopic and clinically sized PTCa. Our results indicate that all PTCa harbor mutations with similar frequencies and distribution patterns, regardless of the size of the tumor. These data are further evidence that microscopic and clinically sized PTCa are pathogenetically related.

Carcinoma, Papillary↗
PubMed1996

Molecular characterization of mutation and comparison of mutation profiles in the hprt gene of Chinese hamster ovary cells treated with benzo[a]pyrene trans-7,8-diol-anti-9,10-epoxide, 1-nitrobenzo[a]pyrene trans-7,8-diol-anti-9,10-epoxide, and 3-nitrobenzo[a]pyrene trans-7,8- diol-anti-9,10-epoxide.

Both 1- and 3-nitrobenzo[a]pyrene (nitro-BaP) are environmental contaminants, potent mutagens in Salmonella, and moderate mutagens in Chinese hamster ovary (CHO) cells. The mutagenicity of their oxidized metabolites,trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-epoxy -7,8,9,10-tetrahydro-1-nitrobenzo[a]pyrene (1-nitro-BaP-DE) and trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydro-3-nitrobenzo[a]- pyrene (3-nitro-BaPDE), together with trans-7,8-dihydroxy-anti-9, 10-ep- oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BaP-DE), was determined in CHO-K1 cells, and the resulting mutations at the hprt locus were characterized by polymerase chain reaction (PCR) amplification of reverse-transcribed hprt mRNA, followed by DNA sequence analysis. The mutant frequencies, in mutants/10(6) clonable cells, at 30 and 100 ng/ml, were BaP-DE, 248 and 456; 1-nitro-BaP-DE, 68 and 260; 3-nitro-BaP-DE, 81 and 232, respectively. In general, the three diolepoxides exhibited similar mutational spectra: 1) 64% (23/36 sequenced mutants) of BaP-DE, 53% (19/36) of 1-nitro-BaP-DE, and 64% (23/36) of 3-nitro-BaP-DE mutants resulted from simple base pair substitution, with the predominant mutation being G-->T transversion; 2) 90%, 100%, and 100% of mutations at G:C had the mutated dG on the nontranscribed DNA strand; and 3) about one quarter of the mutants produced by each mutagen had one or more PCR products with partial or complete exon deletions. The mutagens induced few frameshifts or complex mutations. Among the differences in mutational specificity for the three diolepoxides, the proportion of substituted dGs with 3' purines was significant (P < 0.05) for BaP-DE (16/19, 84%) and 3-nitro-BaP-DE (17/20, 85%), but not significant for 1-nitro-BaP-DE-induced mutants (11/17, 65%, P > 0.05). Also, high proportions of BaP-DE and 3-nitro-BaP-DE base pair substitutions at G:C occurred in DNA sequence contexts of 5'-GG-3', 5'-GGA-3', and 5'-TGGA-3', while the proportions of 1-nitro-BaP-DE mutants in these contexts were often lower. The results indicate that nitro substitution at C1 or C3 of BaP-DE reduces mutational potency in CHO cells and appears to have only subtle effects upon the mutational pattern in the hprt gene.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed2006

Assessing resistance to the echinocandin antifungal drug caspofungin in Candida albicans by profiling mutations in FKS1.

Resistance of clinical isolates of Candida albicans to the echinocandin drug caspofungin is slowly emerging and is linked to mutations in short conserved regions in the FKS1 gene. The most prominent changes occurred at the serine 645 position in Fks1p with substitutions of proline, tyrosine, and phenylalanine. An allele-specific real-time PCR molecular-beacon assay was developed for rapid identification of drug resistance by targeting FKS1 mutations. Mutations altering serine 645 were reliably identified in both heterozygous and homozygous states. The molecular-beacon assay was used to evaluate two large collections of spontaneous mutants from separate strains of C. albicans with resistance (MICs, >16 microg/ml) to caspofungin with the goal of understanding the relationship between FKS1 mutations and echinocandin resistance. Of 85 resistant isolates recovered, all were identified with mutations in FKS1; 93% showed changes at Ser645, with 62% displaying a characteristic S645P substitution expressed as either a homozygous or a heterozygous mutation in FKS1. Two other prominent amino acid substitutions, S645Y and S645F, were found at frequencies of 22% and 8%, respectively. Three new mutations were also identified: T1922C, G1932T, and C1934G, encoding F641S, L644F, and S645C substitutions, respectively. One strain had the double amino acid substitution L644F and S645C. Allele-specific probes were combined in a multiplex assay for reliable screening of known FKS1 mutations. These data support the importance of FKS1p substitutions in echinocandin resistance and demonstrate the feasibility of applying molecular screening for routine resistance assessment.

Alleles↗
PubMed2006

Characterization of the breast cancer associated ATM 7271T>G (V2424G) mutation by gene expression profiling.

Mutations in ATM are responsible for the autosomal recessive disorder ataxia telangiectasia. Heterozygous mutations in ATM have been associated with an elevated risk of breast cancer. We previously reported one breast cancer family in which ATM 7271T>G (V2424G) segregated with disease, and apparently acted in a dominant negative manner. We now report the screening of 782 multiple-case breast cancer families that identified two additional index cases with ATM 7271T>G. Phylogenetic sequence analysis showed that V2424 is a highly conserved residue, and that the 2424G variant is likely to interfere with function. To elucidate the consequences of this mutation, we expression profiled wild-type, heterozygous, and homozygous lymphoblastoid cell lines (LCLs) from Scottish and Australian families using an oligonucleotide microarray. Cluster analysis revealed 77 genes that were differentially expressed in homozygous and heterozygous V2424G cells (compared to wild-type) and 11 genes differentially expressed in the homozygous cells. We also evaluated the profiles of LCLs after exposure to ionizing radiation (IR) and identified 77 genes that were differentially expressed in wild-type cells, but not in homozygous or heterozygous V2424G cells. We validated the expression differences by RT-PCR in additional heterozygous V2424G LCLs from another breast cancer family. We found no consistent cytotoxicity or abrogation of ATM kinase activity after IR in seven heterozygous V2424G LCLs, compared to wild-type LCLs, but did find an increase in the number of chromosomal aberrations. These data suggest that the V2424G missense mutation acts largely as a dominant negative in terms of the associated expression profiles.

Amino Acid Sequence↗
PubMed2000

Genetic profile of insertion mutations in mouse leukemias and lymphomas.

Murine leukemia retroviruses (MuLVs) cause leukemia and lymphoma in susceptible strains of mice as a result of insertional mutation of cellular proto-oncogenes or tumor suppressor genes. Using a novel approach to amplify and sequence viral insertion sites, we have sequenced >200 viral insertion sites from which we identify >35 genes altered by viral insertion in four AKXD mouse strains. The class of genes most frequently altered are transcription factors, however, insertions are found near genes involved in signal transduction, cell cycle control, DNA repair, cell division, hematopoietic differentiation, and near many ESTs and novel loci. Many of these mutations identify genes that have not been implicated in cancer. By isolating nearly all the somatic viral insertion mutations contributing to disease in these strains we show that each AKXD strain displays a unique mutation profile, suggesting strain-specific susceptibility to mutations in particular genetic pathways.

Animals↗
PubMed2006

Molecular characterization of early-stage bladder carcinomas by expression profiles, FGFR3 mutation status, and loss of 9q.

We used gene expression profiling, mutation analyses of FGFR3 and TP53, and LOH analyses of chromosome 9 and the TP53 region on chromosome arm 17p, to molecularly characterize 75 Ta and T1 bladder carcinomas. We identified four major cellular processes related to cell cycle, protein synthesis, immune response, and extra cellular components that contribute to the expressional heterogeneity of early-stage urothelial cell carcinoma (UCC). Activating FGFR3 mutations were found at the highest frequency in G1 tumors (80%), and showed a strong correlation with FGFR3 expression. In contrast, G3 tumors displayed mutations in less than 10% of the cases and a low level of FGFR3 expression. Even though LOH on chromosome 9 was not associated with any specific expression pattern, our data indicate that loss of chromosome 9 is associated with tumor development rather than initiation. The combined analyses suggest the existence of two types of UCC tumors, one which is characterized by FGFR3 mutation or expression, high expression of protein synthesis genes, and low expression of cell cycle genes. Furthermore, the presented data underscore FGFR3 receptor involvement in urothelial cell transformation as the presence of FGFR3 mutations has a major impact on the global gene expression profile of bladder carcinomas.

Chromosomes, Human, Pair 17↗
PubMed2006

NF1 mutation rather than individual genetic variability is the main determinant of the NF1-transcriptional profile of mutations affecting splicing.

A significant number of neurofibromatosis type 1 (NF1) mutations result in exon skipping. The majority of these mutations do not occur in the canonical splice sites and can produce different aberrant transcripts whose proportions have not been well studied. It has been hypothesized that differences in the mutation-determined NF1-transcriptional profile could partially explain disease variability among patients bearing the same NF1 splice defect. In order to gain insight into these aspects, we analyzed the proportion of the different transcripts generated by nine NF1-splicing mutations in 30 patients. We assessed the influence of the mutation in the NF1-related transcriptional profiles and investigated the existence of individual differences in a global manner. We analyzed potential differences in tissue-specific transcriptional profiles and evaluated the influence of sample processing and mRNA nonsense-mediated decay (NMD). Small transcriptional differences were found in neurofibromas and neurofibroma-derived Schwann cells (SC) compared to blood. We also detected a higher cell culture-dependent NMD. We observed that mutation per se explains 93.5% of the profile variability among mutations studied. However, despite the importance of mutation in determining the proportion of NF1 transcripts generated, we found certain variability among patients with the same mutation. From our results, it seems that genetic factors influencing RNA processing play a minor role in determining the NF1-transcriptional profile. Nevertheless neurofibromin studies would clarify whether these small differences translate into significant functional changes that could explain the great clinical expressivity observed in the disease or any of the disease-related traits.

Alleles↗