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PubMed2003

Chromosomal anomalies in oligodendroglial tumors are correlated with clinical features.

BACKGROUND: Patients who have oligodendrogliomas (OD) that demonstrate loss of both 1p and 19q appear to have a better prognosis after they receive chemotherapy and radiotherapy compared with patients who have OD without these characteristics. It is unclear whether this improvement in outcome is due only to a better response to treatment. The authors investigated the correlation between genetic and clinical characteristics of OD in 33 patients who received chemotherapy with procarbazine, lomustine, and vincristine for recurrent disease after receiving radiotherapy. METHODS: The initial presentation, prior treatments, overall survival, and response to chemotherapy were assessed. The 1p and 19q status in OD lesions was determined with fluorescence in situ hybridization on paraffin embedded, archival material using locus specific probes. P53 mutations were assessed by polymerase chain reaction-single-strand conformation polymorphism analysis and immunohistochemistry for P53; the proliferation index was assessed with the MIB-1 antibody. RESULTS: Patients who had OD lesions with a combined loss of 1p and 19q typically presented with low-grade tumors that manifested with seizures of long-standing duration. In contrast, patients who had OD lesions without a combined loss of 1p and 19q usually presented with focal deficits that required immediate treatment. Both the response rate to chemotherapy and the time to disease progression after chemotherapy were significantly better in patients who had a combined loss of 1p and 19. Tumors with classic OD morphology more often had a combined loss of 1p and 19q, although the genotype was better at identifying patients with chemoresponsive tumors. P53 mutations were observed in three tumors, none of which had a combined loss of 1p and 19q. CONCLUSIONS: OD lesions with combined a loss of 1p and 19q have a more indolent nature compared with OD lesions that do not have these losses. Virtually all patients with these tumors present with low-grade tumors accompanied by seizures and remain stable for prolonged periods. Future trials must keep these tumor types apart.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Mutations within the cyclooxygenase-1 gene in aspirin non-responders with recurrence of stroke.

INTRODUCTION: Aspirin is a common antiplatelet drug used in the prevention of ischemic stroke due to its inhibitory effect on platelet cyclooxygenase-1 (Cox-1). Patients can be categorized as either aspirin 'responders' or 'non-responders' depending on whether they are protected against a secondary stroke event or not. In this study, we have searched for variants of the Cox-1 gene that could possibly result in an unblocked and thus, aspirin-resistant Cox-1 enzyme and phenotype. MATERIALS AND METHODS: The Cox-1 gene was sequenced in 68 patients with recurrent ischemic stroke despite taking aspirin. The genotype distribution of identified variants was determined and compared with healthy control subjects. Mutations that involved amino acid substitutions of the mature Cox-1 molecule were analysed by molecular modelling and functional analysis using whole blood aggregometry. RESULTS: Fourteen variants of the Cox-1 gene were identified. Seven of the variants involved amino acid substitutions of the Cox-1 molecule. None of the mutations were located near the catalytic site as judged from a three-dimensional model of the human Cox-1. Carriers and non-carriers of one of the mutations behaved similarly when aggregation and granule content release function were studied using collagen, ADP and arachidonic acid as agonists. CONCLUSION: The results do not support the hypothesis that common variants of the Cox-1 gene results in unblocked Cox-1 molecules in aspirin non-responders.

Aged↗
PubMed2006

[A Dutch family with the hereditary periodic fever or tumour necrosis factor receptor-associated periodic syndrome (TRAPS)].

A 9-month-old girl was referred to the paediatrician because of fever of unknown origin. Since the age of 4 years she had recurrent attacks of muscle, joint and abdominal pain, in addition to periodic fever. Her sister and her mother had similar symptoms. The tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) was suspected and confirmed by DNA analysis. Several members of the extended family were carriers of the same mutation. In patients with recurrent unexplained periods offever in combination with myalgia, arthralgia and abdominal pain, and in whom these symptoms also occur in members of the family, TRAPS should be considered as the cause. Glucocorticosteroids and etanercept, a TNF-receptor antagonist, may be effective in the treatment of attacks. Early recognition of this syndrome is important because of the risk of developing amyloidosis.

Adult↗
PubMed2003

Novel types of mutation in the choroideremia ( CHM) gene: a full-length L1 insertion and an intronic mutation activating a cryptic exon.

Choroideremia (CHM) is a progressive chorioretinal degeneration caused by mutations in the widely expressed CHM gene on chromosome Xq21. The product of this gene, Rab escort protein (REP)-1, is involved in the posttranslational lipid modification and subsequent membrane targeting of Rab proteins, small GTPases that play a key role in intracellular trafficking. We have searched for mutations of the CHM gene in patients with choroideremia by analysis of individual CHM exons and adjacent intronic sequences PCR-amplified from genomic DNA and by reverse transcription (RT)-PCR analysis of the coding region of the CHM mRNA. In 35 patients, at least 21 different causative CHM defects were identified. These included two partial CHM gene deletions and an insertion of a full-length L1 retrotransposon into the coding region of the CHM gene, a type of mutation that has not been previously reported as a cause of CHM. We also detected nine different nonsense mutations, five of which are recurrent, a small deletion, a small insertion, and at least five distinct splice site mutations, one of which has been described previously. Moreover, we report for the first time the identification of an intronic mutation remote from the exon-intron junctions that creates a strong acceptor splice site and leads to the inclusion of a cryptic exon into the CHM mRNA. Finally, in an affected male who did not have a mutation in any of the CHM exons or their splice sites, the deletion of a complete exon from the CHM mRNA was observed.

Adaptor Proteins, Signal Transducing↗
PubMed2026

Whole genome and exome sequencing of pancreatic neuroendocrine tumour to investigate PRRT response.

Patients with pancreatic neuroendocrine tumours (PNETs) often have similar baseline clinical characteristics, including grade and molecular imaging phenotype, yet have highly variable responses to peptide receptor radionuclide therapy (PRRT). To identify genomic alterations and mutational patterns associated with PRRT treatment response and acquired somatic changes following PRRT exposure, whole genome or exome sequencing was applied to 40 PNET samples from 32 patients, including eight paired pre- or post-PRRT samples. The genomic profile of tumours reflected the known mutational landscape of PNET with MEN1 (34%), ATRX/DAXX (47%) alterations and a recurrent pattern of aneuploidy (38%) detected. A recurrent PSIP1::TBL1X fusion of unknown function was also identified in four tumours. The disease control rate following PRRT using RECIST1.1 and molecular imaging criteria was 88% (28/32). No mutational features were found to be statistically associated with progression-free survival. There was no significant increase in tumour mutational burden in the post-PRRT tumours, nor recurrent emergent mutational changes in cancer driver genes to explain progression to higher-grade disease, when observed. However, a small indel signature (ID8) previously associated with DNA damage repair by non-homologous end joining (NHEJ) was higher in PRRT-exposed compared with PRRT-naive samples (23.8 vs 4.8%, respectively; P < 0.001). Thus, comprehensive DNA analysis of pancreatic NETs did not identify biomarkers predictive of PRRT response nor evidence for high-level PRRT-induced genomic instability or hypermutation, yet mutation signature analysis supports NHEJ as being important for DNA repair and survival of neuroendocrine cells following exposure to beta-particle radiation.

Humans↗
PubMed1997

Human papillomavirus and host variables as predictors of clinical course in patients with juvenile-onset recurrent respiratory papillomatosis.

This study provides the first systematic evaluation of papillomavirus type and viral mutation occurring during the course of juvenile-onset recurrent respiratory papillomatosis. One hundred ninety-nine consecutive papillomas excised from 47 children between 1981 and 1996 at The New Children's Hospital in Sydney, Australia, were tested for human papillomavirus (HPV) DNA by PCR. PCR products from the viral upstream regulatory region (URR) enhancer were sequenced, and variation was related to clinical variables. Forty-four of the 47 children had HPV-induced papillomas, with type 11 accounting for 24 (55%) and type 6 accounting for 19 (43%); one (2%) was positive for either type 6 or 11. Overall, 183 (98%) of the 186 samples with amplifiable DNA were HPV positive. There was no change in HPV type over time and no statistically significant association between HPV type and disease aggressiveness. One novel, large-scale URR duplication was identified in an HPV type 11 isolate in the last of a series of six papillomas examined and the first from the bronchus. However, the duplication was not found in HPV type 11 isolates from the associated pulmonary carcinoma and its metastases in other organs. Three of 14 URR point mutations coincided with transcription factor binding sites, but there were no obvious associations with clinical course. Chi-square and multiple linear regression analyses of clinicopathological variables revealed early age at diagnosis (less than 4 years) as an independent predictor of aggressive disease (P < 0.001). A bimodal distribution of the age at diagnosis was noted, with peaks at 2 and 11 years of age.

Adolescent↗
PubMed2001

The relation of mutant p53 accumulation in transitional cell carcinoma of bladder with pathological stage, grade, recurrence and survival.

In this study prognostic significance and clinical value of mutant p53 gene in bladder transitional cell tumors is investigated. In our clinic, between 1997-2000, transurethral resection was performed in 48 cases, 3 females (6%) and 45 males (94%) with the diagnosis of primary bladder tumor, age ranges between 30-81 years old (average 58.9 +/- 9.9). The patients whose pathology results were transitional cell carcinoma were gathered into two groups as p53 positive and p53 negative by immunohistochemical study. These cases who were followed 1-36 months were compared to each other for pathologic state, tumor grade, recurrence and survival. It's found out that mutant p53 accumulation is related to high grade and pathologic stage tumors. But it's concluded that p53 positivity doesn't effect recurrence and survival rates.

Adult↗
PubMed2002

Oncogenic beta-catenin and MMP-7 (matrilysin) cosegregate in late-stage clinical colon cancer.

BACKGROUND & AIMS: Recent in vitro studies showed that beta-catenin translocated into the tumor cell nucleus functions as an oncogene by transactivating oncogenes, including MMP-7. We conducted a large-scale analysis of beta-catenin and MMP-7 expression in human colon cancer to determine the potential clinical importance of these molecules. METHODS: In 202 colon cancer patients with known postoperative outcomes, we determined the expression of beta-catenin and MMP-7 in the tumors immunohistochemically and correlated the findings with the patients' clinicopathological characteristics and survival. RESULTS: We found 2 distinct patterns of beta-catenin nuclear accumulation (NA) in the colon cancers: diffuse NA (NAd) in 89 cases (44%) and selective NA at the invasion front (NAinv) in 18 cases (9%). The presence of the NAinv pattern was significantly correlated with advanced Dukes' stage (P = 0.0187) and tumor recurrence (P = 0.0005) as well as with MMP-7 expression in the tumor invasion front (P = 0.0025), resulting in extremely unfavorable clinical outcomes. A multivariate analysis determined that the NAinv expression pattern and Dukes' C stage were independent prognostic factors. CONCLUSIONS: Oncogenic activation of beta-catenin in the tumor invasion front, as represented by its NAinv pattern of expression, may be an independent and reliable indicator of membership in a subset of colon cancer patients who are highly susceptible to tumor recurrence and have a less favorable survival rate.

Adult↗
PubMed2000

Novel mutation (E113X) of antithrombin III gene (AT3) in a woman with gestational recurrent thrombosis.

A 35-year-old Japanese woman with a low level (42-54%) of blood antithrombin (AT) III, experienced two induced abortions due to deep venous thrombosis at 8 weeks of gestation (GW) and cerebral thrombosis at 10 GW. The present pregnancy was successfully managed with intravenous administration of AT III (6,000-8,000 U/wk). Analysis of polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) for exons 3A and 4 of the AT III gene (AT3) using her DNA revealed extra expansion bands with altered migration. The DNA sequencing demonstrated novel mutations in exon 3A of AT3: a G to T substitution at nucleotide position 5333 in codon GAG for Glu 113, causing a stop codon (E113X), and an A to T substitution at position 5338 in codon AAA for Lys 114, forming Asn (K114N). These novel mutations, especially E113X, in AT3 may be related to recurrent thrombosis in the pregnancy.

Abortion, Induced↗
PubMed2000

Integrated analysis of sequence evolution and population history using hypervariable compound haplotypes.

We have examined compound haplotypes from a highly informative region of human chromosome 16, in which information from the rapid evolution of a highly unstable minisatellite is integrated with data on the longer-term evolution of this segment from 10 flanking substitutional polymorphisms. Combined with sequence data from non-human primates, analysis of relationships between these compound haplotypes allows the reconstruction of a rooted network of the evolutionary pathways between them. Most relationships can be explained via simple substitutional mutations, although the origins of some haplotypes involve recurrent events at a hotspot for substitutional mutation and/or gene conversion. For compound haplotypes including the minisatellite array, the network found in a range of world-wide populations constitutes a highly informative data set for the analysis of population history (437 different compound haplotypes were discriminated among 658 studied). Since the mutation rates and processes of the minisatellite array are known from direct studies, ages for individual lineages have been estimated using associated minisatellite diversity. These analyses suggest that the higher information content and sampling depth of these compound haplotypes may allow more precise calibration of lineage ages than is possible using coalescent analysis of DNA sequence. Using this method we have dated the oldest Eurasian lineage as 52,000-66,000 years and the oldest European specific lineage as 37,600-56,200 years.

Africa↗
PubMed2025

Clinicopathologic, Immunohistochemical, and Molecular Analysis of Primary Ovarian Carcinoid Tumors With Correlation of Ki67 Proliferation Index With Patient Outcomes.

Primary ovarian carcinoid tumors (pOCTs) are a rare subset of ovarian neoplasms resembling well-differentiated neuroendocrine tumors (NETs) arising in the gastrointestinal tract. Unlike NETs at other anatomic sites, the use of proliferation markers, such as mitotic count and Ki67 proliferation index, is not well established in the classification of these tumors. In this study, we describe the clinicopathologic, immunohistochemical, and molecular characteristics of pOCTs and correlate mitotic count and Ki67 index with patient outcomes. In our series of 23 pOCTs, most cases were associated with at least 1 other ovarian neoplasm (19/23; 82.6%), most often a mature teratoma or struma ovarii (each 43.5%; 10/23). All 23 cases (100%) expressed synaptophysin, whereas 87.0% (20/23) expressed chromogranin. Frequent staining with TTF-1 and CDX2 (33.3% and 83.3%, respectively) was also observed. Targeted exome sequencing was performed in 14 cases, which identified no recurrent NET-associated mutations or novel mutations in pOCTs. Most pOCTs presented as stage IA disease (13/23; 56.5%), of which 6 had Ki67 indices >3% (46.2%; 6/13). There were 6 cases of stage IC disease (26.0%), which exhibited a variable Ki67 index (range: 1.2%-35.6%). Extraovarian spread was noted in 4 cases (17.4%), with 3 cases having Ki67 indices >3% (range: 1.0%-58.8%). Local recurrence occurred in 1 case (4.3%) with pelvic sidewall involvement at diagnosis and a Ki67 index of 58.8%. Follow-up, ranging from 3 to 153 months (median: 55.5 months), showed no disease-related deaths. We combined our findings with 16 previously published cases of pOCTs and found that cases with >20 mitoses per 2 mm2 had the highest rate of recurrence. Cases with Ki67 indices &#x2265; 7.5% were associated with worse overall and disease-free survival. Overall, our findings reaffirm the indolent nature of most pOCTs, although disease recurrence and aggressive behavior can occur, particularly in cases with elevated proliferation indices.

Humans↗
PubMed2005

Strategies for preimplantation genetic diagnosis of Angelman syndrome caused by mutations in the UBE3A gene.

Angelman syndrome (AS) is a neurodevelopmental disorder associated with the loss of maternal gene expression in chromosome region 15q11-q13. AS is caused by a wide variety of genetic mechanisms, including mutations in the UBE3A gene that have been identified in 10-15% of patients; when the mother is heterozygous for the causative mutation, the risk of recurrence in subsequent pregnancies is 50%. The present authors have developed a preimplantation genetic diagnosis (PGD) assay for a family displaying a 10 bp deletion in exon 9 of the UBE3A gene, which was shared by two affected children and their phenotypically normal mother. A duplex polymerase chain reaction protocol was established, allowing the efficient amplification of the mutation together with an informative microsatellite marker (D15S122) located in intron 1 of the UBE3A gene. As most of UBE3A mutations identified so far are unique to one family, the present authors have also developed an indirect single cell protocol based upon the co-amplification of two microsatellite markers located within (D15S122) and close to the UBE3A gene (D15S1506). This strategy may be applied to all informative families requesting PGD for Angelman syndrome associated with mutations in the UBE3A gene.

Alleles↗
PubMed2004

High alpha-fetoprotein level correlates with high stage, early recurrence and poor prognosis of hepatocellular carcinoma: significance of hepatitis virus infection, age, p53 and beta-catenin mutations.

alpha-Fetoprotein (AFP) is often elevated in hepatocellular carcinoma (HCC). This study was to elucidate the significance and related factors of AFP elevation in HCC in 781 unifocal HCCs receiving curative hepatectomy. We showed that high AFP (> 200 ng/ml), which was associated with AFP mRNA expression in HCC (p = 0.00001), correlated with major clinicopathologic factors. Younger age (< or = 55 years; p=0.00001), hepatitis B surface antigen (HBsAg) in serum (p=0.00001), p53 mutation (p=0.008), large tumor (p=0.00001), vascular invasion (p=0.00001) and early tumor recurrence (p=0.00001) were significant associates of high AFP, while anti-HCV in serum and beta-catenin mutation in HCC had less frequent high AFP (p=0.013 and < 0.0001, respectively). We also showed that HCC with high AFP had a lower 10-year survival (p < 0.0001), particularly in large HCC (p < 0.0001). At univariate analysis, high AFP (p < 0.0001), HBsAg positivity (p=0.05), p53 mutation (p=0.0004), liver cirrhosis (p=0.0094), large tumor (p=0.0003), vascular invasion (p < 0.0001) and early recurrence (p < 0.0001) were significant unfavorable prognostic factors. In Cox proportional hazards regression analysis, high AFP remained a borderline significance (OR=1.2; CI=1.0-1.4) after adjustment for the effect of tumor size and tumor stage (p=0.0821). Furthermore, the detection of AFP mRNA in the liver of AFP mRNA-positive HCC was associated with more frequent early recurrence (p=0.0026) and might be a useful marker of intrahepatic spread. We therefore conclude that AFP elevation, more than a coincidental epiphenomenon, appears to contribute to vascular invasion and HCC progression and help to identify subsets of HCC patients with increased risk for early recurrence and poor prognosis after hepatectomy.

Adolescent↗
PubMed2002

PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity.

Noonan syndrome (NS) is a developmental disorder characterized by facial dysmorphia, short stature, cardiac defects, and skeletal malformations. We recently demonstrated that mutations in PTPN11, the gene encoding the non-receptor-type protein tyrosine phosphatase SHP-2 (src homology region 2-domain phosphatase-2), cause NS, accounting for approximately 50% of cases of this genetically heterogeneous disorder in a small cohort. All mutations were missense changes and clustered at the interacting portions of the amino-terminal src-homology 2 (N-SH2) and protein tyrosine phosphatase (PTP) domains. A gain of function was postulated as a mechanism for the disease. Here, we report the spectrum and distribution of PTPN11 mutations in a large, well-characterized cohort with NS. Mutations were found in 54 of 119 (45%) unrelated individuals with sporadic or familial NS. There was a significantly higher prevalence of mutations among familial cases than among sporadic ones. All defects were missense, and several were recurrent. The vast majority of mutations altered amino acid residues located in or around the interacting surfaces of the N-SH2 and PTP domains, but defects also affected residues in the C-SH2 domain, as well as in the peptide linking the N-SH2 and C-SH2 domains. Genotype-phenotype analysis revealed that pulmonic stenosis was more prevalent among the group of subjects with NS who had PTPN11 mutations than it was in the group without them (70.6% vs. 46.2%; P<.01), whereas hypertrophic cardiomyopathy was less prevalent among those with PTPN11 mutations (5.9% vs. 26.2%; P<.005). The prevalence of other congenital heart malformations, short stature, pectus deformity, cryptorchidism, and developmental delay did not differ between the two groups. A PTPN11 mutation was identified in a family inheriting Noonan-like/multiple giant-cell lesion syndrome, extending the phenotypic range of disease associated with this gene.

Buffers↗
PubMed2000

[Recurrent Clostridium difficile enterocolitis].

Pseudomembranous enterocolitis generally occurs after antibiotic treatment. The standard treatment is oral metronidazol or vancomycin. Nevertheless, relapses of Clostridium difficile enterocolitis are observed in 10-25% of cases. Factors associated with recurrences include endogenous reinfection by spore formation, selective IgG1 or IgA deficiency or infection with mutated strains of Clostridium difficile. Recurrent Clostridium difficile enterocolitis may be treated with repeat oral vancomycin combined with Sacchoromyces boulardii, with intravenous immunoglobulin for severe colitis.

Aged↗
PubMed1994

Resistance to cytosine arabinoside in acute leukemia: the significance of mutations in CTP synthetase.

The molecular events which confer cellular resistance to cytotoxic drugs such as cytosine arabinoside (ara-C) are poorly understood. Nevertheless, in a proportion of patients with acute leukemia, such events will be responsible for the failure of therapy. Mutations which cause ara-C resistance in a chinese hamster ovary (CHO) cell model have been identified as regulatory base substitutions, occurring in specific sites of the gene coding for an enzyme critical in pyrimidine metabolism, CTP synthetase (CTPs). These cells have elevated dCTP pools, a feature common to biochemical studies of other ara-C resistant leukemic cells. A 94% homology exists between the hamster and human ctps genes. In this study, similar mutations were sought in samples taken from 36 patients, with recurrent or resistant acute leukemia. No mutations were identified in the regions indicated by the CHO model using techniques capable of detecting mutations only if present in more than 10% of the cells studied. Thus, mutations in these sites within the human ctps gene do not appear to be a major mechanism of resistance to ara-C in acute leukemia. Further studies should be directed towards developing more sensitive methods of detection, and these then applied both to CTPs and to other enzymes involved in pyrimidine metabolism.

Acute Disease↗
PubMed2004

Invariant p53 immunostaining in primary and recurrent breast cancer.

In animal models, acquired mutations of the p53 gene that result in increased p53 protein expression are associated with tumour recurrence following chemotherapy. The aim of this study was to test the hypothesis that breast cancer recurrences following adjuvant therapy exhibit aberrant p53 expression. We therefore evaluated p53 expression in paired primary and recurrent breast tumours: 48% of primary and 32% of recurrent tumours had abnormally increased p53 expression. Of the paired samples, 84% showed no change in p53 expression between the primary tumour and the metastasis. In fact, in no case was low (normal) p53 expression in the primary tumour followed by the development of high (aberrant) p53 expression in the recurrence. These results show that increased p53 expression is not selected for in the malignant cells emerging following adjuvant therapy, suggesting that p53 expression is unlikely to play a central role in breast cancer recurrences.

Adult↗