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Initiation of human astrocytoma by clonal evolution of cells with progressive loss of p53 functions in a patient with a 283H TP53 germ-line mutation: evidence for a precursor lesion.
Little is known about the genetic and molecular events leading to the early stages of human astrocytoma formation. To examine this issue, we analyzed the significance of sequential accumulation of two somatic point mutations (R267W and E258D) in the TP53 gene during the initiation of astrocytoma in a patient born with a single germ-line p53 point mutation (R283H). We adapted a p53 transcriptional assay in yeast to establish the temporal occurrence and allelic distribution of the p53 mutations present in the patient and characterized these mutations through functional assays and structural modeling. Our results show that the first somatic mutation occurred at codon 267 on the p53 allele harboring the germ-line mutation R283H, whereas the second somatic mutation occurred in the remaining wild-type (wt) allele at codon 258. These two mutations induced the formation of tumor cells with the genotype p53(267W+283H/258D), which comprised 70% of the cells in the primary WHO grade II astrocytoma. Another 8% of cells within the tumor had the partially mutated genotype p53(267W+283H/WT) and represented the remnants of a clinically undetectable intermediate stage of astrocytic neoplastic transformation. The remaining 22% of cells had the constitutive p53(283H/WT) genotype and likely consisted of nontumor cells. Functional analysis of the p53 alleles present in the patient's tumor indicated that the germ-line p53(R283H) could transactivate the CDKN1A((p21, WAF1, cip1, SDI1)) but not the BAX gene and retained the ability to induce growth arrest of human glioblastoma cells. The p53(R267W+R283H) and p53(E258D) were incapable of transactivating either promoter or inducing growth arrest. Modeling of p53 interaction with DNA suggests that R283H mutation may weaken the sequence-specific interaction of p53 lysine 120 with the BAX gene but not the CDKN1A p53-responsive elements. Taken together, these results have characterized, for the first time, the genetic events defining a clinically undetectable precursor lesion leading to a grade II astrocytoma. They also suggest that astrocytoma initiation in this patient resulted from monoclonal evolution driven by a sequential loss of proapoptotic and growth arrest functions of p53.
Loss of DCC gene expression is of prognostic importance in acute myelogenous leukemia.
PURPOSE: Expression of the deleted in colorectal carcinoma (DCC) gene has been found to be lost in some patients with acute myelogenous leukemia (AML). Although this finding is critical to leukemogenesis, its prognostic significance remains uncertain. To evaluate this, loss of DCC gene expression in AML patients and their prognostic significance were investigated. EXPERIMENTAL DESIGN: A group of 170 patients with AML was analyzed. DCC gene expression in AML cells was determined by a semiquantitative reverse transcriptase-PCR. Simultaneous mutation analyses of the p53, N-ras, and FLT3 genes were performed in all of the AML cells by single-strand conformation polymorphism and sequencing subsequent to PCR. The importance of loss of DCC expression was evaluated by Cox proportional analysis and the Kaplan-Meier method. RESULTS: Loss of DCC expression was detected in 47 patients (27.6%). The p53, N-ras, and FLT3 mutations were detected in 20 (11.7%), 42 (24.7%), and 26 (15.2%) patients, respectively. The durations of overall survival (OS) and complete remission (CR) of the 47 DCC-negative AML patients were significantly shorter than that of the 123 DCC-positive patients (P < 0.0045 and <0.0060, respectively). Univariate and multivariate analyses showed that loss of DCC expression was an unfavorable prognostic factor for both OS (P < 0.0053 and <0.0084, respectively) and CR duration (P < 0.0146 and <0.0371, respectively). The 64 DCC-positive patients with wild p53, N-ras, and FLT3 had statistically better CR attainment compared with the other 106 patients (P < 0.0001). CONCLUSIONS: Loss of DCC gene expression was shown to be an independent prognostic factor in AML patients. Thus, loss of DCC gene expression might serve as an important molecular marker for predicting the CR duration and OS of patients with AML.
Impact of prothrombotic mutations and family history on the occurrence of intra-uterine fetal deaths.
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[Clinico-pathological investigation of radiation therapy for brain tumors].
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[Mutations of oncogenes and tumor suppressor genes in prostate neoplasms].
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[Role of DNA diagnosis in modern oncology].
DNA-diagnosis became to be a mandatory element of the modern oncological care. The molecular-genetic approaches aimed at identifying the high-risk categories in oncology are mostly-renowned. They comprise the diagnosis of the so-called familial cancerous syndromes, the identification of unfavorable normal genome variations (gene polymorphisms) and the detection of a number of oncoviral infections. Laboratory procedures facilitating the individualization of treatment schemes and the monitoring of oncology patients have been widely introduced into clinical practice. The turn between the 20th and 21st centuries was marked by the emergence of principally new DNA-analysis methods designed for a comprehensive and integral genome evaluation. The application of such radically novel techniques in the molecular diagnostics essentially promoted the detection and treatment of neoplasms.
[Severe toxicity after treatment with capecitabine and fluorouracil due to partial dihydropyrimidine dehydrogenase deficiency].
Two female patients, aged 48 and 52 years, developed severe bone marrow suppression and (gastrointestinal) mucositis following administration of capecitabine. Analysis of the dihydropyrimidine dehydrogenase (DPD) activity in peripheral blood mononuclear cells revealed the presence of DPD deficiency. Both patients recovered in 3-4 weeks, and both had a (partial) remission of their tumours. Capecitabine is metabolised to 5-fluorouracil (5-FU) in the body. DPD-deficiency leads to impaired breakdown of 5-FU and hence to severe cytotoxicity following treatment with capecitabine or 5-FU. The most common mutation, IVS14 + 1G > A, is found in approximately 2% of the Dutch population. In case of unexpected severe toxicity during 5-FU or capecitabine treatment, DPD deficiency should be considered. Screening could be considered in view of the widespread use of capecitabine and 5-FU, the severe toxicity that may develop in patients with low DPD activity and the prevalence of the mutation.
Genetic alteration of p53, but not overexpression of intratumoral p53 protein, or serum p53 antibody is a prognostic factor in sporadic colorectal adenocarcinoma.
Mutation of p53 is a common event in colorectal cancer and can result in cellular accumulation of p53 protein and induction of p53 antibodies. We investigated the association of colorectal cancer with alterations in p53 DNA, protein and serum antibody levels to determine their prognostic value in colorectal cancer. Colorectal cancer patients (n=167) who underwent surgery in Taipei Veterans General Hospital from January 1999 to December 2000 were enrolled [age 62.91+/-12.61 years (range: 22-85); 111 (66.5%) males]. Of these, 20 were stage I (12%), 54 stage II (32.3%), 58 stage III (34.7%), and 35 stage IV (21%). Median follow-up was 36.3 months (range: 4-58). p53 alteration was detected by DNA sequencing from exon 5 to 9 and loss of heterozygosity (LOH) at two microsatellite markers near p53; and demonstrating intratumoral accumulation of p53 protein and detection of serum p53 antibodies using ELISA. p53 mutation frequency was 41.9% (70/167). Of 127 informative cases for LOH analysis, 73 (57.5%) tumors that had LOH had at least one microsatellite marker. Genetic p53 alterations were found for 56.3% of cases when LOH and DNA sequencing methods were combined. Genetic p53 alterations were associated with advanced tumor stage and tumor differentiation. Overexpression of intratumoral p53 and anti-p53 antibody positivity were 44.9% and 28.1%. The presence of p53-Ab was associated with p53 mutations (chi2 test, 42.9% vs. 17.5%, p=0.001), but not with overexpression of intratumoral p53 protein. The mutations at exon 6 (57.1%) and 7 (53.3%) were associated with presence of serum p53-Ab. Of 132 potentially cured patients, 3-year disease-free survival (DFS) was affected by: advanced TNM stage (I, II, III: 90%, 84%, and 41%), genetic p53 alteration (89% vs. 43%), intratumoral p53 accumulation (71% vs. 56%), and preoperative CEA level >5 ng/ml (74% vs. 58%). In multivariate analysis, genetic alteration of p53 was the most significant independent prognostic factor [hazard ratio (HR) = 6.09; 95% confidence interval (CI): 2.45-15.11], followed by advanced tumor stage (HR = 3.93; 95% CI: 2.14-7.23), and preoperative CEA >5 ng/ml (HR = 1.98; 95% CI: 1.12-3.17). Genetic alterations in p53 but not intratumoral p53 protein accumulation or p53-Ab appear to play a significant role in the progression of colorectal cancer.
p16 gene alterations in locally advanced squamous cell carcinoma of the head and neck.
We previously documented the presence of mutations/deletions in the tumor suppressor gene p16 in squamous cell carcinoma of the head and neck (SCCHN). However, the association of these p16 alterations with clinical outcome is unknown. In this study, RNA was isolated from 19 frozen SCCHN from 19 patients who were previously enrolled in the OSU intensification regimen 2. Quantitative real-time RT-PCR and direct sequencing analysis was then performed on the specimens to detect p16 gene alterations. Clinical outcome for each patient was updated and correlated with the p16 alterations found. Five tumor specimens were found to have no or very low expression of p16 when compared with normal tissue. The remaining 14 tumor samples demonstrated overexpression of p16 relative to the level of expression in normal tissue. Sequence analysis of the p16 RT-PCR product from these specimens allowed identification of mutational changes in the coding sequence of p16 in four of the SCCHN specimens. Subsequent analysis of clinical outcome associated with locoregional/distant failure demonstrated no correlation with either altered expression of p16 or mutational status of p16. Results from this study indicate that p16 alterations are frequently found in this cohort of SCCHN. However, p16 alterations alone do not appear to be associated with clinical outcome.
[Pregnancy and tumor diseases--new perspectives of the modern reproduction medicine].
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FGF signaling network in the gastrointestinal tract (review).
Fibroblast growth factor (FGF) signals are transduced through FGF receptors (FGFRs) and FRS2/FRS3- SHP2 (PTPN11)-GRB2 docking protein complex to SOS-RAS-RAF-MAPKK-MAPK signaling cascade and GAB1/GAB2-PI3K-PDK-AKT/aPKC signaling cascade. The RAS approximately MAPK signaling cascade is implicated in cell growth and differentiation, the PI3K approximately AKT signaling cascade in cell survival and cell fate determination, and the PI3K approximately aPKC signaling cascade in cell polarity control. FGF18, FGF20 and SPRY4 are potent targets of the canonical WNT signaling pathway in the gastrointestinal tract. SPRY4 is the FGF signaling inhibitor functioning as negative feedback apparatus for the WNT/FGF-dependent epithelial proliferation. Recombinant FGF7 and FGF20 proteins are applicable for treatment of chemotherapy/radiation-induced mucosal injury, while recombinant FGF2 protein and FGF4 expression vector are applicable for therapeutic angiogenesis. Helicobacter pylori, a causative pathogen for peptic ulcer diseases, chronic atrophic gastritis and gastric cancer, injects bacterial proteins into gastric epithelial cells by using Type IV secretion system, which leads to FGF signaling activation through FGF2 upregulation as well as CagA-dependent SHP2 activation. FGFR2 gene is preferentially amplified and overexpressed in diffuse-type gastric cancer. PD173074 is a small-molecule inhibitor for FGFR, while RO4396686 and SU6668 are small-molecule inhibitors for FGFR and other tyrosine kinases. Cocktail therapy using multiple protein kinase inhibitors could enhance the therapeutic effects for gastrointestinal cancer through the reduction of recurrence associated with somatic mutations of drug-target genes. Single nucleotide polymorphism (SNP) and copy number polymorphism (CNP) of genes encoding FGF signaling molecules will be identified as novel risk factors of gastrointestinal cancer. Personalized prevention and personalized medicine based on the combination of genetic screening and novel therapeutic agents could dramatically improve the prognosis of cancer patients.
Staging of head and neck cancer.
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Localization of aberrant messenger RNA of epidermal growth factor receptor (EGFR) in malignant glioma.
Human gliomas occasionally show rearrangements with deletions (exons II to VII) in the epidermal growth factor receptor (EGFR) gene, resulting in the expression of aberrant EGFR mRNA. This abnormality of EGFR gene expression is closely related to the malignancy of glioma. However, this EGFR gene abnormality has not been demonstrated directly in the glioma cells themselves, as gliomas consist of heterogeneous tissue components. In this study, we used in situ hybridization (ISH) to detect aberrant EGFR mRNA in the tumor cells in 26 human gliomas and 19 human glioma xenografts. We used digoxigenin (DIG)-labeled antisense oligonucleotide probes for ISH, which demonstrated aberrant EGFR mRNA in 2 of the 26 gliomas and in 3 of the 19 human glioma xenografts. ISH with an aberrant EGFR-specific probe (oligo-PA) revealed that EGFR mRNA was absent from multinucleated giant cells and from proliferating endothelial cells, but this transcript was present in small glioma cells. Identical aberrant EGFR mRNA was confirmed in these glioma and human glioma xenografts by Southern blotting. Northern blotting, and by reverse transcription-polymerase chain reaction (RT-PCR). These findings suggest that small tumor cells specifically express the aberrant EGFR mRNA in certain high grade gliomas.
[Clinical importance of p53 gene mutation and PCNA expression in ureteral and renal pelvic cancers].
In order to know the clinical importance of p53 gene mutation and PCNA expression in ureteral and renal pelvic cancers, research was carried out with immunohistochemistry S-P method in 45 cases. Mutant p53 nuclear staining was positive in 24 cases (53.3%) and correlated with PCNA expression, being higher in clinical stages T3 and T4 than in T1 + T2. They also correlated with the grade of cell differentiation, being higher in G3 than in G1 + G2.
Commonly occurring loss and mutation of the MXI1 gene in prostate cancer.
One of the most common chromosomal abnormalities in prostate cancer involves loss of 10q22-qter. Rarely, a smaller deletion, involving 10q24-q25, has been observed, suggesting the presence of a tumor suppressor gene at this site. We previously demonstrated that the MXI1 gene maps to 10q24-q25 and is mutated in some tumors with cytogenetically detectable deletions of this locus. MXI1 encodes a basic-helix-loop-helix protein that suppresses the transcriptional activity of the MYC oncoprotein by competing for the common dimerization partner, MAX, and binding to identical DNA sites. Because more than 90% of prostate tumors contain no cytogenetic abnormality of 10q, the relevance of MXI1 loss and/or mutation to the vast majority of cases remains unclear. We prospectively evaluated prostate tumors for loss of MXI1 by fluorescence in situ hybridization (FISH) and cytogenetic techniques. Twenty-one of 40 tumors (53%) demonstrated loss of a single MXI1 allele as determined by FISH. Ten cases with cytogenetically normal 10qs, but with FISH-documented deletion of MXI1, were examined at the molecular level, and eight mutations were identified, albeit at low frequency. Five of the mutant proteins were unable to bind DNA in association with MAX. We conclude that MXI1 gene loss in prostate cancer is common and most frequently involves a cytogenetically undetectable deletion.
Endogenous TNF inducibility and prognosis of colorectal cancer.
BACKGROUND: We have demonstrated that the inducibility of endogenous TNF (en-TNF) by colorectal tumor cells is a factor in predicting a patient prognosis. The prognoses of colorectal tumor patients with the K-ras gene mutations in their tumors were poorer to those of patients with the wild type gene. Therefore, we analyzed the possible relationship between the inducibility of en-TNF by colorectal tumor cells during the follow-up of patients with K-ras mutations. MATERIALS AND PATIENTS: In 62 of 154 Dukes Stage C patients who received curative operation from June 1988 to June 1997, the prognoses in terms of the tumor-free rate and survival rate were compared with the inducibility of en-TNF by colorectal tumor cells, which were classified into three groups: grade 1: > or = 500 pg/ml, grade 2: 100-500 pg/ml, and grade 3: < 100 pg/ml. Regardless of the Dukes Stage of the patients, the K-ras gene was analyzed in 21 whose colorectal tumor cells were classified as grade 1: 8, grade 2: 4, and grade 3: 9. RESULTS: The tumor-free rate of the patients with grade 1 was significantly higher than that of the patients with grade 3, and the survival period of the patients with grades 1 and 2 was significantly longer than that of the patients with grade 3. Possible mutations disorder of K-ras were observed in 37.5% (grade 1), 50.0% (grade 2), and 88.9% (grade 3) of cases, respectively. CONCLUSION: The prognostic value of the inducibility of en-TNF by colorectal tumor cells from colorectal cancer patients who received curative operation at Dukes Stage C was confirmed. It is suggested that K-ras mutation may affect patient prognosis through modulation of the quality and/or quantity of cytokines such as TNF produced by tumor cells.
Biparental hydatidiform moles: a maternal effect mutation affecting imprinting in the offspring.
Highly recurrent hydatidiform moles (HMs) studied to date are not androgenetic but have biparental genomic contribution (BiHM). Affected women have an autosomal recessive mutation that causes their pregnancies to develop into HM. Although there is genetic heterogeneity, a major locus maps to chromosome 19q13.42, but a mutated gene has not yet been identified. Molecular studies have shown that maternal imprinting marks are deregulated in the BiHM trophoblast. The mutations that cause this condition are, therefore, hypothesized to occur in genes that encode transacting factors required for the establishment of imprinting marks in the maternal germline or for their maintenance in the embryo. Although only DNA methylation marks at imprinted loci have been studied in the BiHM, the mutation may affect genes that are essential for other forms of chromatin remodelling at imprinted loci and necessary for correct maternal allele-specific DNA methylation and imprinted gene expression. Normal pregnancies interspersed with BiHM have been reported in some of the pedigrees, but affected women repeatedly attempting pregnancy should be counselled about the risk for invasive trophoblastic disease with each subsequent BiHM.