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At least 829 records · Page 46Linked to original sources
PubMed2005

Somatic mutations in human cancer: applications in molecular epidemiology.

The tumour suppressor protein p53 mediates cell-cycle arrest, DNA repair and apoptosis after activation by multiple forms of cellular stresses. When activated, this "master protein" modulates its response depending on the type and intensity of the stress. The TP53 gene with its nearly 20,000 described mutations is the most mutated gene in cancer. Most mutations are missense and occur at over 200 codons within the central portion of the gene. In several cancers, the distribution of mutation types and sites follow a specific pattern reflecting the effects of environmental mutagens. An example for such a "mutagen fingerprint" is TP53 mutation at codon 249 in hepatocellular carcinoma in regions of the world characterised by high levels of the mutagen aflatoxin B1 and endemic HBV infection. Recently, TP53 mutations have been detected in surrogate sources of genetic material such as free circulating DNA isolated from plasma. Plasma TP53 mutations can be detected in the blood of pre-cancer and cancer patients, with potential application for early cancer detection. Thus, TP53 mutations have multiple applications as markers of mutagenic exposures, or as intermediate end-points in assessment of cancer occurrence and progression.

Aflatoxin B1↗
PubMed1994

Somatic mutation. From the dark zone to the light.

The affinity maturation of antibodies that occurs during immune responses to protein antigens involves site-directed hypermutation of immunoglobulin variable-region genes that is activated in germinal centres.

Animals↗
PubMed2003

Multicentric occurrence of hepatocellular carcinoma in patients with a somatic mutation of mitochondorial DNA and hepatitis C virus.

The relationship between the multicentric occurrence of hepatocellular carcinoma (HCC) and the frequency of mutation of mitochondrial DNA (mtDNA) in the noncancerous hepatic tissue in patients infected with hepatitis C virus was investigated. Of the 48 patients, multicentric occurrence of HCC was found in ten of 33 patients with three or more mutations in the mtDNA, whereas no patients had multicentric HCCs in 15 patients with two or fewer mutations in the mtDNA (P=0.0201). A high rate of mtDNA mutation in noncancerous hepatic tissue may be related to multicentric hepatocarcinogenesis and the hypercarcinogenic state in such patients.

Journal Article↗
PubMed1988

Somatic mutations in B lymphocytes: new perspectives in tolerance research?

This paper extends the concept of clonal anergy developed in the author's laboratory. It has been shown that the primary population of B lymphocytes induced into clonal expansion and IgM antibody formation by mitogens contains many cells capable of autoantibody synthesis, but the affinity of binding to the self constituents, or indeed to foreign antigens, is low. The creation of high affinity antibody, which will still register strongly in an ELISA as an IgG molecule, demands not only the addition of lymphokines to cause isotype switching, but also intentional immunization of the donor mice to permit mutations in V region genes and selection of higher affinity B memory cells. This process appears to begin about 6 days after in vivo immunization. It is postulated that these mutational events occur primarily in germinal centres, and that there must be mechanisms to prevent escape of cells which, by chance, mutate not to higher affinity against an immunogen, but to higher affinity against a self constituent. If such mutants were allowed to enter the long-lived, recirculating pool of B lymphocytes, they might pose a graver threat of autoimmune disease than the low-affinity anti-self cells of the primary repertoire. Therefore, it is suggested that recently mutated germinal centre B cells represent a pool of 'pre-memory' cells, which are immature in the sense of displaying the same kind of sensitivity to negative signalling by antigen that immature B cells from newborn spleen or adult bone marrow display. If so, then the earliest phases of memory generation represent a second window of opportunity for tolerance induction within the B lymphocyte compartment.

Animals↗
PubMed1997

Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas.

Hereditary papillary renal carcinoma (HPRC) is a recently recognized form of inherited kidney cancer characterized by a predisposition to develop multiple, bilateral papillary renal tumours. The pattern of inheritance of HPRC is consistent with autosomal dominant transmission with reduced penetrance. HPRC is histologically and genetically distinct from two other causes of inherited renal carcinoma, von Hippel-Lindau disease (VHL) and the chromosome translocation (3;8). Malignant papillary renal carcinomas are characterized by trisomy of chromosomes 7, 16 and 17, and in men, by loss of the Y chromosome. Inherited and sporadic clear cell renal carcinomas are characterized by inactivation of both copies of the VHL gene by mutation, and/or by hypermethylation. We found that the HPRC gene was located at chromosome 7q31.1-34 in a 27-centimorgan (cM) interval between D7S496 and D7S1837. We identified missense mutations located in the tyrosine kinase domain of the MET gene in the germline of affected members of HPRC families and in a subset of sporadic papillary renal carcinomas. Three mutations in the MET gene are located in codons that are homologous to those in c-kit and RET, proto-oncogenes that are targets of naturally-occurring mutations. The results suggest that missense mutations located in the MET proto-oncogene lead to constitutive activation of the MET protein and papillary renal carcinomas.

Adult↗
PubMed1994

Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma.

The MTS1 gene on chromosome 9p21 encodes the p16 inhibitor of cyclinD/Cdk-4 complexes, and is deleted or mutated in a variety of tumour types. We found allelic deletions of 9p21-p22 in 85% of pancreatic adenocarcinomas. Analysis of MTS1 in pancreatic carcinomas (27 xenografts and 10 cell lines) showed homozygous deletions in 15 (41%) and sequence changes in 14 (38%). These included eight point mutations (four nonsense, two missense and two splice site mutations) and six deletions/insertions, all accompanied by loss of the wild-type allele. Sequencing of MTS1 from primary tumours confirmed the mutations. Coexistent inactivations of both MTS1 and p53 was common and suggests that abnormal regulation of cyclin-dependent kinases may play an important role in the biology of pancreatic carcinoma.

Adenocarcinoma↗
PubMed2005

Developmental stage-selective effect of somatically mutated leukemogenic transcription factor GATA1.

Acquired mutations in the hematopoietic transcription factor GATA binding protein-1 (GATA1) are found in megakaryoblasts from nearly all individuals with Down syndrome with transient myeloproliferative disorder (TMD, also called transient leukemia) and the related acute megakaryoblastic leukemia (DS-AMKL, also called DS-AML M7). These mutations lead to production of a variant GATA1 protein (GATA1s) that is truncated at its N terminus. To understand the biological properties of GATA1s and its relation to DS-AMKL and TMD, we used gene targeting to generate Gata1 alleles that express GATA1s in mice. We show that the dominant action of GATA1s leads to hyperproliferation of a unique, previously unrecognized yolk sac and fetal liver progenitor, which we propose accounts for the transient nature of TMD and the restriction of DS-AMKL to infants. Our observations raise the possibility that the target cells in other leukemias of infancy and early childhood are distinct from those in adult leukemias and underscore the interplay between specific oncoproteins and potential target cells.

Adult↗