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Results for “oncogenic mutations”

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PubMed1998

[Detection of K-ras oncogene mutations in human lung cancer by PCR-SSCP-DNA direct sequencing].

K-ras oncogene mutations were detected with PCR-SSCP-DNA direct sequencing technique in 40 cases of lung cancer. The result of PCR-SSCP silver staining indicated that the mutational rate was 30% (12/40), all mutations were observed in lung adenocarcinoma and its mutational rate was 44% (12/27). The result of DNA direct sequencing showed that 11 of the 12 positive samples screened by PCR-SSCP had mutation and 90% of K-ras mutations were in codon 12. The mutation was mainly G-->T transversion and G-->A transition. The study suggested that SSCP silver staining analysis is very useful in screening large amount of samples simultaneously and PCR-SSCP-DNA direct sequencing method is quite efficient for the detection of oncogene mutation.

Adenocarcinoma↗

PubMed1997

Genetic testing for familial cancer. Consequences of RET proto-oncogene mutation analysis in multiple endocrine neoplasia, type 2.

OBJECTIVE: To assess clinician use and acceptance of RET proto-oncogene mutation testing in multiple endocrine neoplasia, type 2 (MEN 2) family members. DESIGN: A retrospective survey of clinicians managing 26 MEN 2 families with documented RET mutations to assess the effect of genetic screening on subsequent investigation and management of family members. SETTING: Tertiary referral center for RET mutation testing. MAIN OUTCOME MEASURES: The screening procedures used by clinicians and the altered incidence of C-cell hyperplasia vs medullary thyroid carcinoma in genetically as opposed to biochemically identified affected family members. RESULTS: Among RET mutation-positive patients, thyroidectomy performed for clinical or biochemical indication disclosed medullary thyroid carcinoma in 44 (98%) of 45 patients and precursor C-cell hyperplasia in only 1 (2%) patient. When prophylactic thyroidectomy was performed based on a positive genetic result, medullary thyroid carcinoma occurred in 3 (43%) of 7 patients and C-cell hyperplasia in 4 (57%) of 7 patients (P < .001). RET mutation-negative patients were not subjected to further biochemical testing, but 4 had already undergone thyroidectomy based on abnormal results of pentagastrin stimulation tests, including 2 patients who were known to be RET mutation-negative at the time of surgery. RET mutation testing was well accepted and resulted in additional family members consenting to screening in more than 85% of families. CONCLUSIONS: Genetic screening for RET proto-oncogene mutations in MEN 2 is a powerful diagnostic tool that enables prophylactic thyroidectomy to be performed in RET mutation-positive patients at an earlier stage of the disease process than does traditional biochemical screening.

Adolescent↗

PubMed2025

Structural and thermodynamic impact of oncogenic mutations on the nucleosome core particle.

The nucleosome core particle is essential for chromatin structure and function, serving as the fundamental unit of eukaryotic chromatin. Oncogenic mutations in core histones disrupt chromatin dynamics, altering DNA repair and transcription processes. Here, we investigate the molecular consequences of two mutations-H2BE76K and H4R92T-using 36 μs of all-atom molecular dynamics simulations and experimental biophysical assays. These mutations destabilize the H2B-H4 interface by disrupting critical salt bridges and hydrogen bonds, reducing binding free energy at this interface. Principal-component analysis reveals altered helix conformations and increased interhelical distances in mutant systems. Thermal stability assays and differential scanning calorimetry confirm that these mutations lower the dimer dissociation temperature and reduce enthalpy compared with the wild-type. Taken together, our results elucidate how these mutations compromise nucleosome stability and propose mechanisms through which they could modulate chromatin accessibility and gene dysregulation in cancer.

Nucleosomes↗

PubMed2004

Oncogenic mutations in B-Raf: some losses yield gains.

A study by Wan et al. in this issue of Cell demonstrates that the majority of oncogenic mutations in the B-Raf protein kinase result in increased catalytic activity, through disruption of the autoinhibited state of the kinase domain. Surprisingly, several mutations lead to impaired B-Raf kinase activity, yet these mutants are nevertheless capable of stimulating downstream signaling through transactivation of C-Raf.

Animals↗

PubMed1993

[Detection of Ki-ras oncogene mutations in normal mucosa, adenoma and adenocarcinoma of the colon].

Paraffin embedded tissues, including 41 surgically resected colonic specimens in which separable normal mucosa, adenoma and adenocarcinoma were available, and 10 endoscopically excised colonic adenomas were studied for Ki-ras mutations by RFLP, SSCP and S1 nuclease protection methods. Mutations of Ki-ras codon 12 or 61 were found in 9/41 and 21/41 surgically resected adenomas and adenocarcinomas respectively. One of the ten endoscopically excised adenomas had Ki-ras codon 12 mutation. No mutations of Ki-ras 12 or 61 were detected in normal mucosa. All adenomas with Ki-ras oncogene mutation were over 1cm in diameter and had moderate or severe atypical hyperplasia. Our results indicate that RFLP is the most sensitive method of the three used for detecting oncogene mutations.

Adenocarcinoma↗

PubMed1998

K-ras oncogene mutations indicate malignancy in cystic tumors of the pancreas.

OBJECTIVE: To evaluate clinical parameters, presurgical diagnostic tests, histologic findings, and the presence of K-ras oncogene mutations in cystic tumors of the pancreas to determine which best predict malignancy. SUMMARY BACKGROUND DATA: Because presurgical, intraoperative, and final pathologic differentiation is difficult in cystic tumors of the pancreas, it would be a major benefit to identify markers that accurately predict malignancy in these rare tumors. The role of K-ras oncogene mutations as an indicator of malignancy has not been determined in these tumors. METHODS: Nineteen patients with cystic tumors of the pancreas were evaluated, including K-ras mutation analysis based on polymerase chain reaction and restriction digestion assays and direct DNA sequencing, to screen for parameters that accurately predict malignancy. RESULTS: All malignant cystic pancreatic tumors (five cystadenocarcinomas and three mucin-producing adenocarcinomas) harbored K-ras mutations at codon 12 or 13. K-ras mutations were also detected in the percutaneous fine-needle aspirates of two of these patients. In contrast, none of nine benign cystadenomas or the solid-papillary neoplasm had K-ras mutations. None of the patients with a benign tumor carrying K-ras wild-type sequences developed recurrent disease after a mean follow-up of 50 months. Seven of the 8 malignant cystic pancreatic tumors, but none of the 11 benign tumors, showed dilatation of the main pancreatic duct on computed tomography or endoscopic retrograde cholangiopancreatography. CONCLUSIONS: K-ras mutation analysis seems to be a powerful tool to determine the malignant potential of cystic pancreatic tumors before and after surgery. Dilatation of the main pancreatic duct on computed tomography or endoscopic retrograde cholangiopancreatography is highly suggestive for malignancy in these rare tumors.

Adult↗

PubMed1995

Oncogenic mutations of alpha-Gi2 protein are not determinant for human adrenocortical tumourigenesis.

Activating mutations of G proteins, which are membrane signal transducers, have been associated recently with the development of various endocrine neoplasms. Mutations of two highly conserved codons, Arg201 and Gln227, in the alpha-subunit of the Gs protein, the adenylyl cyclase-stimulating protein, were first described in growth hormone-producing pituitary tumours. They resulted in constitutive activation of the alpha s-subunit by decreasing intrinsic GTPase activity. A similar mutation, affecting codon Arg179 (exon 5) in the alpha-subunit of the Gi2 protein, the adenylyl cyclase-inhibiting protein, has been described by a single group in ovarian and adrenocortical tumours. We evaluated the frequency of activating mutations in the alpha-subunit of the Gi2 protein in 18 human adrenocortical tumours. We screened exons 5 (codon Arg179) and 6 (codon gln205) for mutations by denaturing gradient gel electrophoresis analysis of leucocyte and tumoural DNA. No abnormal migration pattern was found in either exon. The absence of mutation in exon 5, which includes the Arg179 codon, was confirmed in all tumoural DNA by direct sequencing. In conclusion, we did not find any oncogenic mutations in the GTPase domain of the alpha-subunit of the Gi2 protein in adrenocortical tumours. Thus, the previously oncogenic gip2 mutations do not appear to be determinant for adrenocortical tumourigenesis.

Adolescent↗

PubMed2000

Unilateral surgery supported by germline RET oncogene mutation analysis in patients with sporadic medullary thyroid carcinoma.

Compared to hereditary medullary thyroid carcinoma (MTC), sporadic MTC tends to be unicentric and confined to one lobe. Patients with sporadic MTC usually undergo total thyroidectomy because of a possible hereditary or bilateral process. We evaluated the usefulness of germline RET oncogene mutation analysis in surgery for apparently sporadic MTC and performed unilateral surgery on patients without detectable mutation. In 36 patients with a preoperative diagnosis of apparently sporadic MTC, we performed germline RET oncogene mutation analyses: before surgery in 8 recent patients and after surgery in 28 who had been treated before 1996. Of the latter, 5 had bilateral MTC. DNA samples were extracted from their peripheral blood, and the polymerase chain reaction products of the RET proto-oncogene were analyzed using single-strand conformation polymorphism analysis and the direct sequencing methods. Before 1996 we often performed total thyroidectomy but changed to hemithyroidectomy thereafter, except in one patient with associated Graves' ophthalmopathy. Our minimal standard practice included systematic central and ipsilateral neck dissection. The outcome was assessed in terms of gastrin- and calcium-stimulated plasma calcitonin levels. Germline RET mutations were found in six patients. Five of these patients had bilateral MTC, whereas all 30 patients without mutation had unilateral disease. Hemithyroidectomy in seven of our recent patients resulted in normalization of plasma calcitonin levels in all, although four were found to have microscopic lymph node involvement. In conclusion, hemithyroidectomy with systematic central and ipsilateral neck dissection is an appropriate procedure for patients with sporadic MTC without detectable germline RET mutations.

Adult↗

PubMed2026

Oncogenic Mutations and Tumor Microenvironment Alterations in Diffuse Large B-Cell Lymphoma With Bulky Disease.

BACKGROUND: Bulky disease represents a clinically aggressive subset of diffuse large B-cell lymphoma (DLBCL) associated with adverse clinical outcomes. The aim of this study was to investigate the influence of oncogenic mutations and tumor microenvironment alterations on bulky disease in DLBCL. METHODS: We analyzed a cohort of 939 patients with newly diagnosed DLBCL. Using DNA (n = 934) and RNA (n = 524) sequencing, we compared oncogenic mutations and tumor microenvironment (TME) alterations based on tumor diameter, with cutoff values at 5.0 cm and 10.0 cm. Further stratification by mutations in key genes (CD58, STAT6, EBF1) correlated with tumor diameter revealed distinct transcriptomic and immunologic profiles. Subsequent single-cell RNA sequencing, guided by these mutational signatures, resolved the cellular heterogeneity within the TME. RESULTS: Integrative analysis revealed that tumor diameter correlated with increased incidence of mutations in CD58, STAT6, and EBF1; adverse genetic subtypes such as EZB-like MYC+ and TP53Mut; activation of oncogenic pathways (JAK/STAT, BCR, PI3K, and MYC); and an immunosuppressive tumor microenvironment. Notably, immune checkpoint molecules varied across the bulky stages, with CTLA-4, TIGIT, ICOS, and CD28 expression inversely correlated with tumor diameter, while CD70 and 4-1BBL expression positively correlated. Single-cell RNA sequencing further revealed mutation-specific tumor microenvironment insights. CD58-mutated tumor exhibited a profoundly immune-deserted microenvironment dominated by malignant B cells with minimal immune infiltration, whereas STAT6-mutated tumor was associated with increased fibroblasts and CD4 + T cells, particularly regulatory T cells (Treg) and Th1-like cells; EBF1-mutated tumor was characterized by increased proportions of malignant B cells. CONCLUSIONS: Collectively, our findings highlight the biological complexity of bulky disease, identifying candidate molecular targets and providing a biological framework for future therapeutic hypothesis generation in this clinically aggressive subset of DLBCL.

Humans↗

PubMed2006

New RB1 oncogenic mutations and intronic polymorphisms in Serbian retinoblastoma patients: genetic counseling implications.

The purpose of this work was to identify germ line RB1 mutations in 16 Serbian retinoblastoma patients for genetic counselling. Mutation analysis was carried out by PCR directed sequencing of the 27 exons. Loss of heterozygosity for two RB1 intragenic markers was also analyzed in 14 tumour samples. Five new RB1 oncogenic mutations (g.2078 del C, g.77047_48 del GC, g.78117_8 del TT, g.160797 del T, and g.64439+2 T>C) and two recurrences (R445X and Q383X) have been found in this study. In addition, four intronic variants were observed germ line in some unilateral patients. Two of these variants (g.44668-15T/G, and g.166204-8T/A) are discussed as potential oncogenic mutation candidates. The results show the relevance of studies aimed to investigate the role of intronic variants in exon splicing regulation. Such studies will help to disclose hidden retinoblastoma susceptibilities, important for accurate genetic counselling.

DNA Mutational Analysis↗

PubMedDate not supplied

RET oncogene mutations in medullary thyroid carcinoma in Mexican families.

BACKGROUND: Different RET oncogene mutations have been found to be associated with inherited medullary thyroid carcinoma (MTC) in the context of three different syndromes including multiple endocrine neoplasia types 2A (MEN 2A) and 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC). These mutations have been recorded in different populations, but to date there is no corresponding study in Mexican families. Our purpose was identification of RET mutations in Mexican families with inherited or sporadic MTC (SMTC) and search for RET protein expression as prognostic marker in MTC tumors. METHODS: Nine unrelated families with MTC corresponding either to two MEN 2A, three MEN 2B, or four SMTC were studied. Screening of exons 10, 11, and 13-16 of RET oncogene in DNA from circulating lymphocytes and tumor samples were analyzed. Immuno- staining for RET was performed in the corresponding tumor. RESULTS: Germline 918 ATG-->ACG RET mutation was present in three unrelated MEN 2B individuals and corresponding somatic mutation in one individual with SMTC; 634 TGC-->TTC RET mutation was detected in two related patients in an MEN 2A family and the 634 TGC-->TAC RET mutation was detected in 12 related individuals from a second MEN 2A family. RET protein expression was detected in all MTC tumors showing different staining intensity. CONCLUSIONS: RET mutations found in Mexican patients with MTC are similar to those previously reported in several MTC families worldwide. This indicates that RET mutations are highly conserved and that MTC etiology does not depend to a great extent on environmental factors or ethnic differences. Detection of RET protein in MTC tissue sections is not useful as prognostic marker.

Adolescent↗

PubMed2004

Why does the Ras switch "break" by oncogenic mutations?

The elucidation of the structure of the RasGAP complex provides what is perhaps the most detailed link between protein structure and cancer causing mutations. In particular, it is known that mutations of Gln 61 destroy the GTPase activity of the complex, locks the cell in its ON state and thus, can cause cancer. It is entirely unclear however, why this specific mutation is so important. The present work uncovers the elusive role of Gln 61 by computer simulation of the GTPase reaction in Ras, RasGAP and of their mutants. Simulations of the effects of mutations of Gln 61 reproduce the corresponding observed changes in activation energies and allow us to analyze the energy contributions to these effects. It is found that Gln 61 does not operate in a direct chemical way nor by a direct electrostatic or steric interaction with the transition state (TS). Instead, oncogenic mutations of Gln 61 lead to the destruction of the exquisitely preorganized catalytic configuration of the active site of the RasGAP complex. This "allosteric" effect causes a major reduction in the electrostatic stabilization of the TS. Our findings have general relevance to other proteins that control signal transduction processes.

Allosteric Site↗

PubMed1997

Analysis of K-ras oncogene mutations in chronic pancreatitis with ductal hyperplasia.

BACKGROUND: K-ras oncogene mutations have been identified in up to 95% of pancreatic cancers, implying their critical role in their molecular pathogenesis. However, the earliest stage in which K-ras mutations can be detected in potential precursor lesions of pancreatic cancer remains unclear. This study evaluates pancreatic ductal hyperplasia in the setting of chronic pancreatitis, which predisposes to pancreatic cancer development, for K-ras codon 12 and 13 mutations. METHODS: Paraffin-embedded surgical specimens from 42 patients with chronic pancreatitis were examined microscopically for the presence of ductal hyperplasia. Both hyperplastic and nonhyperplastic ducts were microdissected from the specimens that contained hyperplasia (11 of 42). Four of the remaining specimens without hyperplasia served as controls. Genomic DNA was extracted, and polymerase chain reaction and amplification of the K-ras oncogene was performed. Polymerase chain reaction products were evaluated by means of hybridization to mutant specific oligonucleotide probes and by means of automated DNA sequencing. RESULTS: K-ras codon 12 mutations representing glycine to valine substitutions were present in 2 of (18%) 11 patients with ductal hyperplasia. No mutations were found in the controls without ductal hyperplasia. CONCLUSIONS: Our study supports the premise that K-ras mutations develop in a subset of chronic pancreatitis associated hyperplasia and provides a genetic basis for the potential progression of chronic pancreatitis to pancreatic cancer.

Adult↗

PubMed2025

Unscheduled polyploidy synergizes with oncogenic mutations to enhance genome instability and tumorigenesis.

Polyploid Giant Cancer Cells (PGCCs) occur across multiple cancer types and are associated with therapy resistance, genome instability, disease progression, and metastasis. PGCCs can grow through endocycles, a variant cell cycle of alternating Growth (G) and DNA Synthesis (S) phases without cell division. Unlike programmed endocycles that occur during normal tissue development, PGCCs switch from mitotic cycles to unscheduled endocycles in response to stress. PGCCs can subsequently return to error-prone divisions which generate aneuploid daughter cells that contribute to disease progression. However, the regulation of PGCC cell cycles and contributions to cancer are still being defined. Filling this knowledge gap will lead to the development of improved cancer therapies. In this study, we used a molecular-genetic system in the model organism Drosophila melanogaster to examine how oncogenes interact with unscheduled endocycles in vivo. We found that several oncogenes promote bypass of an endocycle arrest, resulting in increased polyploid cell size and DNA content. The extent of this increased growth was dependent on the type of oncogenic mutation. When these polyploid cells returned to division, RasG12V promoted continued divisions of polyploid daughter cells with elevated genome instability. RasG12V expression during transient endocycles and subsequent divisions also induced expression of a matrix metalloprotease and a Wnt pathway ligand. Importantly, RasG12V with transient endocycles enhanced the growth of large, neoplastic tumors. These findings indicate that oncogenic mutations can synergize with transient, unscheduled endocycles to promote tumorigenesis with important broader implications for cancer prognosis and therapies.

Animals↗

PubMed2000

The origin of oncogenic mutations: where is the primary damage?

Cancer is generally believed to arise from a single cell which has become 'initiated' by mutation of a few crucial genes, caused by random 'hits' in its DNA, a 'hit' being an error in DNA replication or a reaction of the DNA with free radicals or other chemical species of exogenous or endogenous origin. It is not obvious how the epidemiological data on cancer incidence can be interpreted within the framework of this paradigm. For example, it cannot account quantitatively for the age dependence of cancer incidence, or for the fact that the incidence of cancer in people with hereditary mutations in tumour suppressor genes is much lower than expected, or for the observation that while in some types of cancer, like colon and pancreas, certain highly oncogenic mutations, such as that of TP53, are prevalent, there is no significant increase in the incidence of these cancers in people who carry the mutations by heredity. It is argued here that although mutations in such genes appear to be of crucial importance in carcinogenesis they may not be the rate limiting events in common cancer. The epidemiological data are consistent with the hypothesis that the rate limiting processes involve large numbers of cells. Conceivably, the mutations directly underlying neoplastic transformation may be the result of a local collapse in the system of intercellular processes on which the stability of the normal genotype and phenotype depends, and thereby trigger a cascade of mutations, among them the highly oncogenic ones. This local collapse may be due to mutations of many different genes in many cells as well as to other factors affecting the integrity of tissue.

Animals↗

PubMed1995

RET proto-oncogene mutations in multiple endocrine neoplasia type 2 and medullary thyroid carcinoma.

The identification of RET proto-oncogene mutations in patients with MEN2 2 years ago was a watershed event in the management of this genetic cancer syndrome. The identification of a finite number of mutations that together causes more than 95% of hereditary and 15-25% of sporadic MTC has made it possible to develop simple and definitive tests to screen individuals at risk for this tumour syndrome. The impact of this technology is enormous. It is now possible to reassure 50% of family members at risk that they, and their children, do not have to worry about developing MTC. In the other 50% who are gene carriers, it is now possible to approach clinical management with greater certainty and plot strategies that are likely to result in a greater percentage of curative therapy. It seems likely that this technology will also have an impact on the management of sporadic MTC, although it is still too early to define a specific role for mutational analysis in these patients, except to exclude hereditary disease. The identification of specific mutations causative for MTC makes it possible to conceive future strategies for the treatment or prevention of MTC and to further extend the impact of these exciting findings.

Carcinoma, Medullary↗

PubMed1999

A codon 891 exon 15 RET proto-oncogene mutation in familial medullary thyroid carcinoma: a detection strategy.

A ser891ala RET proto-oncogene mutation has been previously discovered in a single kindred with familial medullary thyroid carcinoma (FMTC). An additional two probands with this mutation and with medullary thyroid carcinoma (MTC) without any other manifestations of MEN 2 have been identified. In one of thse families, two other individuals also had the mutant sequence and FMTC. Analysis of both cases showed cosegregation of the mutation and MTC. To facilitate detection of this mutation, a primer was engineered which creates a Hha I recognition site in the presence of the mutant sequence. As a result, this codon 891 exon 15 mutation can be identified with a restriction enzyme digestion.

Amino Acid Substitution↗

PubMed1997

KRAS oncogene mutations suggest a common histogenetic origin for pleomorphic giant cell tumor of the pancreas, osteoclastoma of the pancreas, and pancreatic duct adenocarcinoma.

Giant cell neoplasms of the pancreas are rare tumors of uncertain histogenesis. Mutation of the KRAS oncogene is common in typical pancreatic duct adenocarcinoma. We have analyzed DNA from five pancreatic tumors with giant cells for mutations in the KRAS oncogene and found alterations of the second position of codon 12 in each case (four G > A transitions and one G > C transversion). The common mutation pattern in tumors with giant cells and duct adenocarcinoma suggests a common route to malignant transformation and may indicate a shared histogenesis. We also tested 11 cases of malignant fibrous histiocytoma, a histological mimic of pleomorphic giant cell tumor, for mutations in the KRAS oncogene. The absence of KAS mutations in each of the malignant fibrous histiocytomas (MFHs) and in other histologically similar tumors may provide assistance in the differential diagnosis of pleomorphic pancreatic tumors.

Adenocarcinoma↗