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PubMed2005

Lifelong left ventricular remodeling of hypertrophic cardiomyopathy caused by a founder frameshift deletion mutation in the cardiac Myosin-binding protein C gene among Japanese.

OBJECTIVES: We studied the longitudinal evolution of hypertrophic cardiomyopathy (HCM) caused by a founder frameshift mutation in the cardiac myosin-binding protein C (MyBPC) gene. BACKGROUND: Mutations in the MyBPC gene have been associated with delayed expression of HCM and a good prognosis. Few studies, however, demonstrated the phenotype-genotype correlations in the longitudinal study. METHODS: We studied long-term evolution of clinical features of 15 unrelated families who were found to have an identical frameshift mutation in the MyBPC gene: a one-base deletion of a thymidine at nucleotide 11645 (V592fs/8). RESULTS: Thirty-nine individuals in 15 families were genotype-positive. Thirty of the 39 individuals with the mutation were phenotype-positive. The disease penetrance was 100% in subjects > or =50 years and 65% in those <50 years. "End-stage" HCM (ejection fraction <50%) was observed in 7 (18%) of the 39 genotype-positive individuals (7 [23%] of the 30 phenotype-positive patients); 6 of them were 60 years or older. Seven patients were hospitalized for treatment of repeated congestive heart failure, and four patients died or had implantable cardioverter-defibrillator discharge (13%; incidence, 1.4%/year) during a mean follow-up period of 9.2 +/- 5.5 years. CONCLUSIONS: Elderly patients with a V592fs/8 mutation in the MyBPC gene may evolve into the "end-stage" HCM, characterized by left ventricular systolic dysfunction, cavity dilation, and irreversible heart failure. The clinical course in patients with this mutation is not benign in the long run, with progressive left ventricular remodeling with advancing age.

Adolescent↗
PubMed2005

Defective DNA mismatch repair and XRCC2 mutation in uterine carcinosarcomas.

OBJECTIVES: A frameshift mutation in the double-strand breakage repair gene XRCC2 was identified in a mismatch repair (MMR) deficient cell line derived from a uterine carcinosarcoma. The frameshift mutation occurred in a mononucleotide run (poly-T tract), a target for strand-slippage mutation in MMR deficient tumors. We sought to determine if XRCC2 mutation is important to uterine carcinosarcoma tumorigenesis and whether the XRCC2 poly-T tract is a target for mutation in cells lacking MMR. METHODS: MSI-typing was used to assess the MMR status of 30 primary carcinosarcomas. The entire XRCC2 coding region was sequenced in all tumors. Single strand conformational variant (SSCV) analysis was used to screen for poly-T tract mutation in 50 endometrioid adenocarcinomas with defective MMR. RESULTS: Seven of 30 (23.3%) primary carcinosarcomas had an MSI-H phenotype. No XRCC2 coding mutations were identified in the 30 carcinosarcomas, and only one of the fifty MSI-H endometrioid adenocarcinomas had an XRCC2 poly-T tract mutation. CONCLUSIONS: Despite the high frequency of mismatch repair deficiency in carcinosarcomas, no XRCC2 poly-T tract frameshift mutations were identified in these tumors. The fact that only one of 50 additional MSI-H tumors had a frameshift mutation suggests that the XRCC2 poly-T tract is not a frequent target for defective MMR. The absence of coding sequence mutations in primary carcinosarcomas suggests that XRCC2 defects are unlikely to play a significant role in carcinosarcoma tumorigenesis.

Base Pair Mismatch↗
PubMed2004

Somatic mutations of APC gene in carcinomas from hereditary non-polyposis colorectal cancer patients.

AIM: To investigate the mutational features of adenomatous polyposis coli (APC) gene and its possible arising mechanism in hereditary non-polyposis colorectal cancers (HNPCC). METHODS: PCR-based In Vitro Synthesized Protein Test (IVSP) assay and sequencing analysis were used to confirm somatic mutations of whole APC gene in 19 HNPCC cases. RESULTS: Eleven cases with 13 mutations were determined to harbor APC mutations. The prevalence of APC mutation was 58%(11/19). The mutations consisted of 9 frameshift and 4 nonsense ones, indicating that there were more frameshift mutations (69%). The frameshift mutations all exhibited deletion or insertion of 1-2 bp and most of them (7/9) happened at simple nucleotide repeat sequences, particularly within (A)n tracts (5/9). All point mutations presented C-to-T transitions at CpG sites. CONCLUSION: Mutations of APC gene were detected in more than half of HNPCC, indicating that its mutation was a common molecular event and might play an important role in the tumorigenesis of HNPCC. Locations of frameshift mutations at simple nucleotide repeat sequences and point mutations at CpG sites suggested that many mutations probably derived from endogenous processes including mismatch repair (MMR) deficiency. Defective MMR might affect the nature of APC mutations in HNPCC and likely occur earlier than APC mutational inactivation in some patients.

Carcinoma↗
PubMed1992

A umuDC-independent SOS pathway for frameshift mutagenesis.

The chemical carcinogen N-acetoxy-N-2-acetylaminofluorene induces mainly frameshift mutations, which occur within two types of sequences (mutation hot spots): -1 frameshift mutations within contiguous guanine sequences and -2 frameshift mutations within alternating GC sequences such as the NarI and BssHII restriction site sequences. We have investigated the genetic control of mutagenesis at these sequences by means of a reversion assay using plasmids pW17 and pX2, which contain specific targets for contiguous guanine and alternating GC sequences, respectively. Our results suggest that mutations at these hot spot sequences are generated by two different genetic pathways, both involving induction of SOS functions. The two pathways differ both in their LexA-controlled gene and RecA protein requirements. In the mutation pathway that acts at contiguous guanine sequences, the RecA protein participates together with the umuDC gene products. In contrast, RecA is not essential for mutagenesis at alternating GC sequences, except to cleave the LexA repressor. The LexA-regulated gene product(s), which participate in this latter mutational pathway, do not involve umuDC but another as yet uncharacterized inducible function. We also show that wild-type RecA and RecA430 proteins exert an antagonistic effect on mutagenesis at alternating GC sequences, which is not observed either in the presence of activated RecA (RecA*), RecA730 or RecA495 proteins, or in the complete absence of RecA as in recA99. It is concluded that the -1 mutation pathway presents the same genetic requirements as the pathway for UV light mutagenesis, while the -2 mutation pathway defines a distinct SOS pathway for frameshift mutagenesis.

Acetoxyacetylaminofluorene↗
PubMed2005

Towards the molecular elucidation of congenital myasthenic syndromes: identification of mutations in MuSK.

Congenital myasthenic syndromes (CMS) are rare genetic diseases affecting the neuromuscular junction (NMJ) and characterized by a dysfunction of the neurotransmission. They are heterogeneous at the pathophysiological level and can be classified in three categories according to their origin: presynaptic, synaptic or postsynaptic. The strategy for the diagnosis and characterization of CMS relies on the clinic, EMG, muscle biopsy, identification of mutations in genes known to be responsible for CMS and the demonstration that the gene mutations are the cause of the disease by using experimental approaches. As an example of such strategy, we report briefly here the characterization of the first case of a human neuromuscular transmission dysfunction due to mutations in the gene encoding a postsynaptic molecule, the muscle-specific receptor tyrosine kinase (MuSK). Gene analysis identified two heteroallelic mutations, a frameshift mutation (c.220insC) and a missense mutation (V790M). The muscle biopsy showed marked pre- and postsynaptic structural abnormalities of the neuromuscular junction as well as a severe decrease in acetylcholine receptor epsilon-subunit and MuSK expression. In vitro and in vivo expression experiments were performed using mutant MuSK reproducing the human mutations. The results obtained strongly suggested that the missense mutation, in the presence of a null mutation on the other allele, was responsible for the severe synaptic changes observed in the patient and, hence, is causing the disease. However the molecular origin of a large number of CMS is still unknown. There are hundreds of molecules known to be present at the NMJ and mutations in the genes coding for these synaptic molecules are likely to be responsible for a neuromuscular block.

DNA Mutational Analysis↗
PubMed1998

Genetic basis and molecular mechanism for idiopathic ventricular fibrillation.

Ventricular fibrillation causes more than 300,000 sudden deaths each year in the USA alone. In approximately 5-12% of these cases, there are no demonstrable cardiac or non-cardiac causes to account for the episode, which is therefore classified as idiopathic ventricular fibrillation (IVF). A distinct group of IVF patients has been found to present with a characteristic electrocardiographic pattern. Because of the small size of most pedigrees and the high incidence of sudden death, however, molecular genetic studies of IVF have not yet been done. Because IVF causes cardiac rhythm disturbance, we investigated whether malfunction of ion channels could cause the disorder by studying mutations in the cardiac sodium channel gene SCN5A. We have now identified a missense mutation, a splice-donor mutation, and a frameshift mutation in the coding region of SCN5A in three IVF families. We show that sodium channels with the missense mutation recover from inactivation more rapidly than normal and that the frameshift mutation causes the sodium channel to be non-functional. Our results indicate that mutations in cardiac ion-channel genes contribute to the risk of developing IVF.

Action Potentials↗
PubMed2006

Significance of somatic mutations and content alteration of mitochondrial DNA in esophageal cancer.

BACKGROUND: The roles of mitochondria in energy metabolism, the generation of ROS, aging, and the initiation of apoptosis have implicated their importance in tumorigenesis. In this study we aim to establish the mutation spectrum and to understand the role of somatic mtDNA mutations in esophageal cancer. METHODS: The entire mitochondrial genome was screened for somatic mutations in 20 pairs (18 esophageal squamous cell carcinomas, one adenosquamous carcinoma and one adenocarcinoma) of tumor/surrounding normal tissue of esophageal cancers, using temporal temperature gradient gel electrophoresis (TTGE), followed by direct DNA sequencing to identify the mutations. RESULTS: Fourteen somatic mtDNA mutations were identified in 55% (11/20) of tumors analyzed, including 2 novel missense mutations and a frameshift mutation in ND4L, ATP6 subunit, and ND4 genes respectively. Nine mutations (64%) were in the D-loop region. Numerous germline variations were found, at least 10 of them were novel and five were missense mutations, some of them occurred in evolutionarily conserved domains. Using real-time quantitative PCR analysis, the mtDNA content was found to increase in some tumors and decrease in others. Analysis of molecular and other clinicopathological findings does not reveal significant correlation between somatic mtDNA mutations and mtDNA content, or between mtDNA content and metastatic status. CONCLUSION: Our results demonstrate that somatic mtDNA mutations in esophageal cancers are frequent. Some missense and frameshift mutations may play an important role in the tumorigenesis of esophageal carcinoma. More extensive biochemical and molecular studies will be necessary to determine the pathological significance of these somatic mutations.

Adenocarcinoma↗
PubMed1989

Molecular analysis of beta zero-thalassemia intermedia in Sardinia.

In this study we have carried out alpha- and beta-globin gene analysis and defined the beta-globin gene polymorphisms in a group of patients with thalassemia intermedia of Sardinian descent. A group of patients (109) with thalassemia major of the same origin served as control. Characterization of the beta-thalassemia mutation showed either a frameshift mutation at codon 6 or a codon 39 nonsense mutation. We found that homozygotes for the frameshift mutation at codon 6 or compound heterozygotes for this mutation and for the codon 39 nonsense mutation develop thalassemia intermedia more frequently than thalassemia major. The frameshift mutation at codon 6 was associated with haplotype IX that contains the C-T change at position -158 5' to the G gamma globin gene implicated in high gamma chain production and thus the mild phenotype. In patients' homozygotes for codon 39 nonsense mutation, those with thalassemia intermedia more frequently had the two-gene deletion form of alpha-thalassemia, or functional loss of the alpha 2 gene as compared with those with thalassemia major. In a few siblings with thalassemia major and intermedia, the thalassemia intermedia syndrome correlated with the presence of the -alpha/-alpha genotype. No cause for the mild phenotype was detected in the majority of patients who had not inherited either haplotype IX or alpha-thalassemia.

Blotting, Southern↗
PubMed2004

Two novel mutations of Wiskott-Aldrich syndrome: the molecular prediction of interaction between the mutated WASP L101P with WASP-interacting protein by molecular modeling.

Wiskott-Aldrich syndrome (WAS) is an X-linked disorder characterized by eczema, thrombocytopenia and increased susceptibility of infections, with mutations of the WAS gene being responsible for WAS and X-linked thrombocytopenia. Herein, two novel mutations of WAS at T336C on exon 3, and at 1326-1329, a G deletion on exon 10, resulting in L101P missense mutation and frameshift mutation 444 stop, respectively, are reported. The affected patients with either mutation showed severe suppression of WAS protein (WASP) levels, T cell proliferation, and CFSE-labeled T cells division. Because WASP L101 have not shown direct nuclear Overhauser effect (NOE) contact with the WASP-interacting protein (WIP) in NMR spectroscopy, molecular modeling was performed to evaluate the molecular effect of WASP P101 to WIP peptide. It is presumed that P101 induced a conformational change in the Q99 residue of WASP and made the side chain of Q99 move away from the WIP peptide, resulting in disruption of the hydrogen bond between Q99 WASP and Y475 WIP. A possible model for the molecular pathogenesis of WAS has been proposed by analyzing the interactions of WASP and WIP using a molecular modeling study.

Amino Acid Sequence↗
PubMed2004

Adaptive amplification and point mutation are independent mechanisms: evidence for various stress-inducible mutation mechanisms.

"Adaptive mutation" denotes a collection of processes in which cells respond to growth-limiting environments by producing compensatory mutants that grow well, apparently violating fundamental principles of evolution. In a well-studied model, starvation of stationary-phase lac(-)Escherichia coli cells on lactose medium induces Lac(+)revertants at higher frequencies than predicted by usual mutation models. These revertants carry either a compensatory frameshift mutation or a greater than 20-fold amplification of the leaky lac allele. A crucial distinction between alternative hypotheses for the mechanisms of adaptive mutation hinges on whether these amplification and frameshift mutation events are distinct, or whether amplification is a molecular intermediate, producing an intermediate cell type, in colonies on a pathway to frameshift mutation. The latter model allows the evolutionarily conservative idea of increased mutations (per cell) without increased mutation rate (by virtue of extra gene copies per cell), whereas the former requires an increase in mutation rate, potentially accelerating evolution. To resolve these models, we probed early events leading to rare adaptive mutations and report several results that show that amplification is not the precursor to frameshift mutation but rather is an independent adaptive outcome. (i) Using new high-resolution selection methods and stringent analysis of all cells in very young (micro)colonies (500-10,000 cells), we find that most mutant colonies contain no detectable lac-amplified cells, in contrast with previous reports. (ii) Analysis of nascent colonies, as young as the two-cell stage, revealed mutant Lac(+)cells with no lac-amplified cells present. (iii) Stringent colony-fate experiments show that microcolonies of lac-amplified cells grow to form visible colonies of lac-amplified, not mutant, cells. (iv) Mutant cells do not overgrow lac-amplified cells in microcolonies fast enough to mask the lac-amplified cells. (v)lac-amplified cells are not SOS-induced, as was proposed to explain elevated mutation in a sequential model. (vi) Amplification, and not frameshift mutation, requires DNA polymerase I, demonstrating that mutation is separable from amplification, and also illuminating the amplification mechanism. We conclude that amplification and mutation are independent outcomes of adaptive genetic change. We suggest that the availability of alternative pathways for genetic/evolutionary adaptation and clonal expansion under stress may be exploited during processes ranging from the evolution of drug resistance to cancer progression.

Adaptation, Biological↗
PubMed2004

A previously undescribed frameshift deletion mutation of HFE (c.del277; G93fs) associated with hemochromatosis and iron overload in a C282Y heterozygote.

A 62-year-old white man with a hemochromatosis phenotype was found to be heterozygous for the C282Y mutation of the HFE gene. The H63D and S65C mutations of HFE were not present. As most C282Y heterozygotes do not develop a hemochromatosis phenotype, the coding region of the patient's HFE gene was sequenced and a previously undescribed frameshift mutation was identified in exon 2 (c.del277; G93fs) that resulted in a premature stop-codon. There were no coding region mutations of the ferroportin gene (FPN1). We performed human leukocyte antigen (HLA) typing of the patient and his brother who was heterozygous for the C282Y HFE mutation unassociated with a hemochromatosis phenotype. They shared only C282Y and the HLA haplotype A*03, B*14; hence, the c.del277 mutation was linked to the HLA haplotype A*02, B*44 and therefore not on the same chromosome as the C282Y mutation. Thus, the present patient's only intact HFE protein is C282Y, and this may explain his hemochromatosis phenotype.

Amino Acid Sequence↗
PubMed2006

Microarray-based mutation analysis of the ABCA4 gene in Spanish patients with Stargardt disease: evidence of a prevalent mutated allele.

PURPOSE: To evaluate, in a pool of affected families, the mutation spectrum in Stargardt patients from Spain, using the ABCR400 microarray that contains described sequence variants in the gene encoding for the photoreceptor specific ATP-binding cassette transporter (ABCA4). METHODS: We analyzed 76 Spanish patients with STGD1 for a population-specific survey on the sequence variations in the ABCA4 gene, using the ABCR400 microarray. RESULTS: Potential disease-associated alleles were identified in 91 of the 152 STGD1 chromosomes studied, resulting in a detection rate of 60%. The two mutant alleles were found in 33/76 patients (43%), whereas in 25/76 cases (33%) only one allele could be identified. In the remaining 18 patients no mutations were found. In total, we identified 40 sequence variations that could be related to the disease. The vast majority of these substitutions (35/40) were missense mutations. Three frameshift mutations and two splicing variants were also found. CONCLUSIONS: We identified a major disease-associated allele, R1129L, which accounted for 24% of the mutated alleles detected, and a high frequency (12%) of complex alleles.

ATP-Binding Cassette Transporters↗
PubMed2001

Clinical and hematologic features of beta0-thalassemia (frameshift 41/42 mutation) in Thai patients.

BACKGROUND AND OBJECTIVES: Frameshift 41/42 mutation is the most common mutation of beta0-thalassemia found in Thailand. We studied clinical and hematologic features in 84 patients and relatives with frameshift 41/42 to determine whether it is possible to predict phenotypic severity from genetic factors. DESIGN AND METHODS: The clinical phenotypes and hematologic data of Thai patients with frameshift 41/42 were studied. Alpha-thalassemia, Hb Constant Spring (HbCS) genes and the presence of Xmnl-Ggamma polymorphism were studied in patients who had mild symptoms. RESULTS: Homozygotes for frameshift 41/42 and compound heterozygotes for frameshift 41/42 and beta0-thalassemia produced severe symptoms and have a thalassemia major phenotype. Combination of frameshift 41/42 and beta0-thalassemia or Hb E produced mild to moderate symptoms with thalassemia intermedia phenotype and severe symptoms with thalassemia major phenotype. The co-inheritance of beta-thalassemia or HbCS gene or the presence of Xmnl-Ggamma polymorphism was not associated with mild disease in patients with frameshift 41/42 and HbE. INTERPRETATION AND CONCLUSIONS: The clinical phenotype of homozygotes for frameshift 41/42 and compound heterozygotes for frameshift 41/42 and beta0-thalassemia could be used to predict a severe phenotype with thalassemia major. However, the clinical phenotype of compound heterozygotes of frameshift 41/42 and beta0-thalassemia or Hb E were variable and could not be accurately predicted. Associations between concomitant alpha-thalassemia or HbCS of the presence of Xmnl-Ggamma polymorphism and a mild clinical phenotype are not apparent, indicating the involvement of other ameliorating determinants or genetic modifications.

Alleles↗
PubMed1988

Frameshift mutagenesis in Escherichia coli by reversible DNA intercalators: sequence specificity.

The mutagenic potency of the simple reversible intercalators isopropyl-OPC (iPr-OPC) and 9-aminoacridine (9-AA) is assessed in E. coli using reversion assays based on plasmids derived from pBR322 carrying various frameshift mutations within the tetracycline resistance gene in repetitive sequences: +/- 2 frameshift mutations within alternating GC sequences; +/- 1 frameshift mutation at runs of guanines. The results obtained show that iPr-OPC and 9-AA have a sequence specificity for mutagenesis: they revert +1 and -1 frameshift mutations within runs of monotonous G:C base pairs. The precise determination of the size of a small restriction fragment which contains the mutation allowed us to demonstrate that reversion occurred by -1 deletions for the +1 frameshift mutations and by +1 additions for the -1 frameshift mutations. The possible relations of this specific reversion with the base sequence specificity of the mutagenesis are briefly discussed.

Alkaloids↗
PubMed2000

p53 mutations in defined structural and functional domains are related to poor clinical outcome in non-small cell lung cancer patients.

The prognostic value of p53 status in non-small cell lung cancer has been investigated in 148 patients with clinical stage I-IIIB disease. Tumor tissues were examined for mutations in exons 4-9, with emphasis on defined structural and functional domains. Eighty-four mutations were detected in 83 (54%) of the patients. Eighty-eight percent of the mutations were within exons 5-8, and 12% of the mutations were within exons 4 and 9. Missense mutations occurred in 67% of the tumors, and 30% were null mutations (10% stop mutations, 15% frameshift mutations, and 5% splice site mutations). Patients with mutations in p53 had a significantly higher risk for lung cancer-related death and for death from all causes than those with wild-type p53 [hazard ratio (HR) = 2.09 and 95% confidence interval (CI) = 1.20-3.64 and HR = 1.69 and 95% CI = 1.06-2.70, respectively]. Mutations in p53 related to even still poorer lung cancer-related prognosis were found at the following locations: (a) exon 8 (HR = 3.5; 95% CI, 1.59-7.71)]; (b) the structural domains L2 + L3 (HR = 2.36; 95% CI, 1.18-4.74), and (c) codons involved in zinc binding (HR = 11.7; 95% CI, 3.56-38.69). Together, the biologically functional group of severe flexible mutants (codons 172, 173, 175, 176, 179, 181, 238, 245, and 267) and severe contact mutants (248, 282) were significantly related to shorter lung cancer-related survival (HR = 4.16; 95% CI, 1.93-8.97). Squamous cell carcinoma was the dominant histological type in tumors involved in poor prognosis in exon 8 (HR = 3.19; 95% CI, 1.07-9.45). These results indicate that mutations in defined structural and functional domains of p53 may be useful molecular biological markers for prognosis and treatment strategy in non-small cell lung cancer patients.

Carcinoma, Non-Small-Cell Lung↗
PubMed1997

Selection for genome instability by DNA damage in human cells: unstable microsatellites and their consequences for tumourigenesis.

The emergence of tumour cells resistant to chemotherapeutic treatment is a major confounding factor in anticancer treatment. Many chemotherapeutic drugs are DNA damaging agents. Resistance to DNA damage can be acquired via a plethora of different mechanisms, including, surprisingly, loss of DNA mismatch repair activity. The DNA mismatch repair system acts after DNA replication and corrects non-Watson-Crick base pairs and other replication errors. Human cells lacking mismatch repair activity have high spontaneous mutation rates. Frequent frameshift mutations in repetitive DNA sequences are characteristically associated with the defect. This hypermutability at repetitive sequences is termed microsatellite instability. DNA mismatch repair defects underlie a predisposition to cancer and are associated with a significant fraction of apparently sporadic cancer cases. In contrast to many other neoplasms, gross genetic aberrations are rare in cells from tumours with microsatellite instability. In these mismatch repair-defective tumours, certain genes that would normally hinder tumour development are frequently found to be inactivated by frameshift mutations in repetitive DNA tracts within their coding sequences. This implies that the small-scale genome alterations characteristic of mismatch repair defects can act as a driving force in tumour development.

Antineoplastic Agents↗
PubMed2000

A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C.

Usher syndrome type 1 (USH1) is an autosomal recessive sensory defect involving congenital profound sensorineural deafness, vestibular dysfunction and blindness (due to progressive retinitis pigmentosa)1. Six different USH1 loci have been reported. So far, only MYO7A (USH1B), encoding myosin VIIA, has been identified as a gene whose mutation causes the disease. Here, we report a gene underlying USH1C (MIM 276904), a USH1 subtype described in a population of Acadian descendants from Louisiana and in a Lebanese family. We identified this gene (USH1C), encoding a PDZ-domain-containing protein, harmonin, in a subtracted mouse cDNA library derived from inner ear sensory areas. In patients we found a splice-site mutation, a frameshift mutation and the expansion of an intronic variable number of tandem repeat (VNTR). We showed that, in the mouse inner ear, only the sensory hair cells express harmonin. The inner ear Ush1c transcripts predicted several harmonin isoforms, some containing an additional coiled-coil domain and a proline- and serine-rich region. As several of these transcripts were absent from the eye, we propose that USH1C also underlies the DFNB18 form of isolated deafness.

Adaptor Proteins, Signal Transducing↗
PubMed1998

[Frequency, distribution and prognostic relevance of p53 mutations in soft tissue sarcomas].

Soft tissue sarcomas although rarely occurring (about 1% of malignant tumors), are because of their histo-morphological diversity and often similar appearance to tumor-like lesions difficult to characterize and estimate in their tumor biological behaviour. Analysis of molecular characteristics as alterations in tumor-suppressor and oncogenes may allow insight in STS genesis. We have chosen the in carcinomas well, but in STS not comprehensively investigated tumor-suppressor gene p53 for mutational analysis. In 16 out of 146 STS patients we could identify p53-mutations. In a multivariate Cox-regression analysis prognosis was correlated with the p53-mutation type. However, only patients with non-frameshift mutations possessed a poorer prognosis (RR = 2.42; p = 0.014) in comparison to patients without mutations, but frameshift-mutations didn't seem to affect prognosis negatively. Compiling our results and those of the literature an overall frequency of 16.3% of p53-mutations in STS, with various frequencies in different entities is detectable. STS specific hotspots are not recognizable. Rather mutational hotspots in codons 175, 245, 248 and 273 well known from studies in carcinomas are also apparent in STS. Summarizing, we want to state that the occurrence of p53-mutations (non-frameshift mutations) is of prognostic importance in STS. Combination of histo-pathological, clinical and molecular characteristics may allow to distinguish in future different groups of patients for an individual treatment.

Codon↗