Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Recurrent mutation”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

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

At least 1,387 records · Page 77Linked to original sources
PubMed2006

Pediatric paraganglioma: an early manifestation of an adult disease secondary to germline mutations.

BACKGROUND: Paraganglioma (PGL) and phaeochromocytoma (PCC) are chemotherapy and radiation-resistant neuroendocrine tumors that arise from sympathetic tissue, and rarely occur in children. PCC may be associated with predisposing (germline) conditions like the multiple endocrine neoplasia type 2 (MEN2; OMIM 164761), von Hippel-Lindau syndrome (VHL; OMIM 193300), and rarely neurofibromatosis type 1 syndrome (NF1; OMIM 162200) and multiple endocrine neoplasia type 1 (MEN1; OMIM 131100). PGL, on the other hand, may be related to predisposing germline conditions like the familial PGL syndrome and the NF1 syndrome. In adult studies, one of the highest predisposing factors for germline mutation among patients presenting apparently sporadic PCC/PGL was their age at presentation. The aim of this study was to determine the rate of germline mutations among the rare patients presenting with sporadic PGL during childhood. PROCEDURE: In this study, we report the genetic analysis for predisposing conditions for the only three PGL cases retrospectively identified at our pediatric institution in the last 20 years. RESULTS: None had NF1 clinical associated lesions. Mutation screening of genes associated to VHL (VHL), MEN (RET), and familial PGL (SDH-B, -C, and -D) showed that all cases had germline deletions in the SDHB gene. We report a novel mutation, c.778 del C. Importantly, several non-symptomatic relatives were found to be carriers, thus ensuring them a clinical follow-up. CONCLUSION: According to our findings, PGL presenting during childhood represents an early manifestation of an adult disease caused by predisposing germline mutations. These results underline the importance of genetic studies in pediatric PGLs.

Adolescent↗
PubMed2004

Quantifying and comparing the accuracy of binary biomarkers when predicting a failure time outcome.

The positive and negative predictive values are standard measures used to quantify the predictive accuracy of binary biomarkers when the outcome being predicted is also binary. When the biomarkers are instead being used to predict a failure time outcome, there is no standard way of quantifying predictive accuracy. We propose a natural extension of the traditional predictive values to accommodate censored survival data. We discuss not only quantifying predictive accuracy using these extended predictive values, but also rigorously comparing the accuracy of two biomarkers in terms of their predictive values. Using a marginal regression framework, we describe how to estimate differences in predictive accuracy and how to test whether the observed difference is statistically significant.

Biomarkers↗
PubMedDate not supplied

Genetics of transitional cell carcinoma.

Several models of genetic events which define the origin and progression of human tumors have been elucidated over the last several years. These models suggest that the study of tumors at the level of both the chromosome and the gene can be useful in elucidating molecular events in tumor progression and in determining the biologic behavior of individual tumors. The genetics of transitional cell carcinomas are reviewed with emphasis on potential mechanisms of tumorigenicity and the clinical utility of genetic markers.

Carcinoma, Transitional Cell↗
PubMed2004

Delayed hepatitis B virus reactivation after cessation of preemptive lamivudine in lymphoma patients treated with rituximab plus CHOP.

Preemptive lamivudine in lymphoma patients undergoing intensive chemotherapy can effectively prevent chemotherapy-related HBV reactivation. Nevertheless, the safety profile after withdrawal of lamivudine and the impact of rituximab-containing chemotherapy on HBV reactivation has not been defined. To illustrate the necessity of prolonged surveillance after cessation of preemptive lamivudine in lymphoma patients treated with rituximab and chemotherapy, four patients with B-cell NHL carrying HBV received rituximab plus CHOP. Preemptive lamivudine therapy was administered 1 week before chemotherapy until 4 weeks after completion of chemotherapy. Serial serum alanine aminotransferase (ALT), total bilirubin, and HBV-DNA levels were prospectively monitored in three patients. The fourth patient was closely monitored for ALT. The HBV DNA was checked after development of clinical overt hepatitis. The peripheral blood CD20+ B-lymphocyte counts were analyzed periodically in two patients. All of the three patients studied prospectively had virological relapses with surgence of HBV DNA 6-8 months after completion of rituximab-plus-CHOP (R+CHOP) therapy. Two of the three patients had biochemical relapses and one of them developed severe hepatitis. Sequencing for HBV polymerase gene in these patients failed to show evident emergence of lamivudine-resistant mutations. The fourth patient developed a hepatitis flare-up 6 months after completion of chemotherapy. The CD2+ lymphocytes were totally depleted when HBV DNA started to increase. Delayed HBV reactivation can occur in lymphoma patients receiving R+CHOP after withdrawal of preemptive lamivudine. More protracted lamivudine therapy may be an alternative to close monitoring following chemotherapy, and further studies are needed to define optimal duration of lamivudine therapy.

Adult↗
PubMed1998

Congenital hydrocephalus: nosology and guidelines for clinical approach and genetic counselling.

UNLABELLED: Congenital hydrocephalus is a serious condition that can arise from multiple causes. It comprises a diverse group of conditions which result in impaired circulation and absorption of cerebrospinal fluid. Congenital malformations of the central nervous system, infections, haemorrhage, trauma, teratogens and, occasionally, tumours can all give rise to hydrocephalus. In this paper we focus on the genetic aspects of hydrocephalus, excluding neural tube defects. The incidence is 0.4-0.8 per 1000 liveborns and stillbirths. X-linked hydrocephalus comprises approximately 5% of all cases. This condition is caused by mutations in the gene at Xq28 encoding for L1, a neural cell adhesion molecule. Carrier detection and prenatal diagnosis can be offered to affected families by means of chorionic villus biopsy and linkage analysis or L1 mutation analysis. In general, recurrence risk for congenital hydrocephalus excluding X-linked hydrocephalus, is low; empiric risk figures found in various studies range from <1% to 4%. Unfortunately, prenatal diagnosis based on an early ultrasound scan is not always reliable as ventriculomegaly usually starts after 20 weeks of gestation. We stress the importance of additional clinical investigations. Prognosis in the prenatally diagnosed patients depends on additional malformations but in general, is not very good. CONCLUSION: Congenital hydrocephalus may be non-syndromic and syndromic. Prognosis depends primarily on the underlying cause and/or associated malformations, which have to be delineated on the basis of clinical, cytogenetic and molecular analysis.

Female↗
PubMed1984

Line-of-descent and genealogical processes, and their applications in population genetics models.

A variety of results for genealogical and line-of-descent processes that arise in connection with the theory of some classical selectively neutral population genetics models are reviewed. While some new results and derivations are included, the principle aim is to demonstrate the central importance and simplicity of genealogical Markov chains in this theory. Considerable attention is given to "diffusion time scale" approximations of such genealogical processes. A wide variety of results pertinent to (diffusion approximations of) the classical multiallele single-locus Wright-Fisher model and its relatives are simplified and unified by this approach. Other examples where such genealogical processes play an explicit role, such as the infinite sites and infinite alleles models, are discussed.

Alleles↗
PubMed2005

[Genetic bases of the radiosensitivity of breast cancer].

Local-regional radiation therapy is one of the major therapeutic means in the management of breast cancer. Three questions however arise from the important advances achieved in this domain in the past years. The first question concerns the possibilities to identify and overcome the radioresistance of a subset of tumours. The second question is how to recognize women likely to benefit from adjuvant radiation therapy, and therefore to diminish treatment indications in other groups. Finally, the third question is how to identify subjects at high risk for long term injury following breast irradiation, in order to adapt techniques and indications in such populations. The major advances of breast cancer molecular genetics in the past years should provide clinicians with tools to answer these important questions. In this paper, we review the molecular germline (BRCA1, BRCA2, ATM, ...) and somatic (p53, tyrosine kinase receptors, as well as actors of cell cycle, signal transduction, apoptosis, DNA repair ...) main bases of breast cancer radiosensitivity. Recent methods of exploration of the genetic background of both the host and the tumours (gene and protein expression profiles) are also reviewed as major tools of breast cancer management in the next few years.

Apoptosis↗
PubMed2006

A case of hyperparathyroidism-jaw tumour syndrome found in the treatment of an ossifying fibroma in the maxillary bone.

Hyperparathyroidism-jaw tumour (HPT-JT) syndrome is characterized by parathyroid tumours as well as by ossifying fibromas of the mandible and maxilla, renal cysts, or Wilms' tumours. Recently, the gene responsible for HPT-JT syndrome has been identified as the HRPT2 tumour suppressor gene. In an 18-year-old male, a tumour in the maxilla was first diagnosed as an ossifying fibroma. During biochemical screening before surgery, the patient received a diagnosis of primary hyperparathyroidism. Neck computed tomography scanning showed a parathyroid tumour. Surgical excisions to remove the jaw tumour and parathyroid adenoma were performed. The postoperative course has been uneventful and a follow up at 2 years revealed no evidence of recurrence. The HRPT2 germline mutation of 39delC was detected in the proband, but not in his unaffected parents. These results suggested that the germline mutation occurred de novo.

Adenoma↗
PubMed2004

Evolution of FLT3-ITD and D835 activating point mutations in relapsing acute myeloid leukemia and response to salvage therapy.

Internal tandem duplications (ITDs) of the juxtamembrane region of the FLT3 tyrosine kinase receptor are the most frequent genetic alterations in acute myeloid leukemia (AML). The presence of this mutation has been recognized as an independent poor prognostic factor. In this study, we compared the FLT3 mutational status between diagnosis and subsequent relapses in 31 patients with AML. At diagnosis, seven patients were identified to contain FLT3-ITD mutations and one patient to harbor the D835 mutation. Five patients remained FLT3-ITD positive throughout the disease course (+/+). Three patients lost the FLT3 gene mutation at first (one FLT3-ITD, one D835 mutation), or second relapse (one FLT3-ITD) (+/-). One additional patient lost a small FLT3-ITD positive clone at relapse and at the same time gained an apparently unrelated FLT3-ITD positive clone. One patient without FLT3 mutation at diagnosis relapsed with an FLT3-ITD mutation (-/+). A shorter median duration of first remission (6 months versus 11.5 months) and a higher relapse rate after salvage therapy (e.g. allogeneic peripheral blood stem cell transplantation) resulted in a lower leukemia-free survival in the FLT3 mutated group (11% versus 31%). The loss of a clone with a mutation in the FLT3 gene at relapse did not improve the prognosis.

Acute Disease↗
PubMed2026

Acute Myeloid Leukemia With KMT2A Amplification: A TP53-Alteration-Enriched Subgroup Associated With Chromoanagenesis and Poor Prognosis.

KMT2A amplification (KMT2A-amp) is a rare but aggressive genomic abnormality in acute myeloid leukemia (AML), with limited characterization in prior studies. We retrospectively analyzed 96 patients with AML harboring KMT2A-amp, including 56 newly diagnosed (ND) and 40 relapsed/refractory (RR) cases, with a median age of 68 years. Approximately half of the cases had therapy-related or secondary AML. All cases demonstrated highly complex karyotypes, with frequent -5/del(5q), -7/del(7q), and -17/del(17p). TP53 alteration was present in 93% of patients, whereas other recurrent AML-associated mutations were uncommon, and no AML-defining gene fusions or mutations were identified. In cases evaluated by optical genome mapping, all showed chromoanagenesis involving chromosome 11q23 region. Clinical outcomes were poor, with a median overall survival of 5.5 months in ND and 2.3 months in RR patients. Intensive chemotherapy did not improve survival compared with lower-intensity therapy, whereas venetoclax-based regimens were associated with improved overall survival (7.1 vs 4.6 months; p = 0.04) and event-free survival (6.7 vs 0.17 months; p < 0.01). We conclude that KMT2A-amp AML represents an extremely high-risk subgroup occurring in the context of TP53-associated genomic instability and chromoanagenesis. Its refractoriness to conventional chemotherapy highlights the urgent need for more effective, targeted therapeutic strategies.

KMT2A amplification↗
PubMed2006

Tip60-dependent acetylation of p53 modulates the decision between cell-cycle arrest and apoptosis.

Upon DNA damage and other types of stress, p53 induces either cell-cycle arrest or apoptosis depending on the cellular context. However, the molecular mechanisms that govern the choice between cell-cycle arrest and apoptosis are not well understood. Here, we show that Tip60 is required for both cell growth arrest and apoptosis mediated by p53 and also induces its acetylation specifically at lysine 120 (K120) within the DNA-binding domain. Interestingly, this modification is crucial for p53-dependent apoptosis but is dispensable for its mediated growth arrest. K120 is a recurrent site for p53 mutation in human cancer, and the corresponding acetylation-defective tumor mutant (K120R) abrogates p53-mediated apoptosis, but not growth arrest. Thus, our study demonstrates that Tip60-dependent acetylation of p53 at K120 modulates the decision between cell-cycle arrest and apoptosis, and it reveals that the DNA-binding core domain is an important target for p53 regulation by posttranslational modifications.

Acetylation↗
PubMed2026

Integrated expression profiling of trophoblast cell-surface antigen 2 (TROP2), folate receptor alpha (FR&#x3b1;), and human epidermal growth factor receptor 2 (HER2) in endometrial Cancer across molecular classes, genomic alterations, and histologic subtypes.

OBJECTIVE: Antibody-drug conjugates (ADCs) are expanding treatment options in endometrial carcinoma, but the distribution of actionable surface targets across histologic, molecular, and genomic subgroups remains incompletely defined. METHODS: This single-institution retrospective tissue microarray (TMA) study included 312 endometrial carcinomas: 158 endometrioid and 154 serous tumors. Trophoblast cell-surface antigen 2 (TROP2) was quantified by histochemical score (H-score); human epidermal growth factor receptor 2 (HER2) was assessed using endometrial carcinoma-specific and gastric/DESTINY-PanTumor02 criteria; and folate receptor alpha (FR&#x3b1;) positivity was defined as &#x2265;75% viable tumor cells with &#x2265;2+ membranous staining. Molecular class was assigned using a hierarchical DNA polymerase epsilon (POLE)-mutant, microsatellite instability/mismatch repair-deficient (MSI/MMRd), p53-abnormal, and no specific molecular profile (NSMP) classifier. Tumor mutational burden (TMB) and recurrent genomic alterations were analyzed in relation to biomarker expression. RESULTS: TROP2 was broadly expressed, with median H-scores of 280 in endometrioid and 200 in serous carcinomas. HER2 gastric-score 2+/3+ expression and FR&#x3b1; positivity were enriched in serous versus endometrioid carcinoma (22.5% vs 8.9% and 20.1% vs 4.4%), restricted to FIGO grade 3 tumors, and concentrated in p53-abnormal disease. FR&#x3b1; positivity was absent in POLE-mutant and MSI/MMRd tumors. HER2 2+/3+ expression correlated with erb-b2 receptor tyrosine kinase 2 (ERBB2) alterations, whereas FR&#x3b1;-positive tumors were enriched for TP53 alterations and showed lower frequencies of ARID1A and PTEN alterations. Triple-negative TROP2/HER2/FR&#x3b1; tumors were uncommon (6/308, 1.9%). CONCLUSIONS: TROP2 is broadly expressed in endometrial carcinoma, whereas HER2 and FR&#x3b1; define a more restricted high-grade, serous/serous-like, p53-abnormal compartment, supporting biomarker-informed ADC development.

Humans↗
PubMed2001

Gain of 1q is associated with adverse outcome in favorable histology Wilms' tumors.

Although several genes/genetic loci involved in the etiology of Wilms' tumor have been identified, little is known of the molecular changes associated with relapse. We therefore undertook an analysis by comparative genomic hybridization (CGH) of 58 tumor samples of favorable histology Wilms' tumor taken at initial diagnosis and/or relapse. Tumors with anaplastic histology were excluded as this is known to be associated with p53 mutation and a poor prognosis. A control group of 21 Wilms' tumors that did not relapse was also analyzed. The overall frequency of gains or losses of genetic material detected by CGH was similar in both groups (77% in relapsing tumors and 70% in the nonrelapse group) as was the median number of changes per tumor (relapse group: n = 4, range, 1 to 19; nonrelapse group: n = 3, range, 1 to 8). However, gain of 1q was significantly more frequent in the relapse series [27 of 46 (59%) versus 5 of 21 (24%), P: = 0.019]. In 12 matched tumor pairs, the CGH profiles, including 1q gain, were similar at diagnosis and relapse, with little evidence for further copy number changes being involved in clonal evolution. The results suggest that 1q gain at diagnosis could be used to identify patients with favorable histology Wilms' tumor at increased risk of relapse who might benefit from early treatment intensification.

Chromosome Aberrations↗
PubMed1998

Identification of a genetic cause for isolated unilateral coronal synostosis: a unique mutation in the fibroblast growth factor receptor 3.

To determine whether the autosomal dominant fibroblast growth factor receptor 3 (FGFR3) Pro250Arg mutation causes anterior plagiocephaly, patients with either apparently sporadic unicoronal synostosis (N = 37) or other forms of anterior plagiocephaly (N = 10) were studied for this mutation. Of 37 patients with unicoronal synostosis, 4 tested positive for the Pro250Arg mutation in FGFR3, and 33 were negative for this mutation. In three mutation positive patients with full parental studies, a parent with an extremely mild phenotype was found to carry the same mutation. None of the 6 patients with nonsynostotic plagiocephaly and none of the 4 patients with additional suture synostosis had the FGFR3 mutation. Because it is impossible to predict the FGFR3 Pro250Arg mutation status based on clinical examination alone, all patients with unicoronal synostosis should be tested for it. To assess their recurrence risk, all parents of mutation positive patients should be tested regardless of their clinical findings, because the phenotype can be extremely variable and without craniosynostosis.

Craniosynostoses↗