| 211. |
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| 212. |
- Zhang, Hong, et al.
(författare)
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K-ras mutations in colorectal adenocarcinomas and neighbouring transitional mucosa.
- 1998
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Ingår i: European Journal of Cancer. - 0959-8049 .- 1879-0852. ; 34:13, s. 2053-2057
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Tidskriftsartikel (refereegranskat)abstract
- The K-ras gene in codons 12 and 13 was investigated using allele-specific polymerase chain reaction in matched normal mucosa (n = 106), transitional mucosa (n = 69) and tumours (n = 149) from 149 patients with colorectal adenocarcinomas. K-ras mutations in codon 12 were detected in 41/149 (28%) of tumours and 4/69 (6%) of transitional mucosa samples, but not in the normal mucosa. Further, mutation rates were increased in younger patients (P = 0.001) and in mucinous carcinomas (50%) compared with well differentiated (17%), moderately differentiated (26%) or poorly differentiated (24%) tumours. Our findings indicate that mucinous carcinoma may represent a distinct genetic entity.
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| 213. |
- Zhuang, Shi-Mei, 1965-, et al.
(författare)
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Frequent mutations of the Trp53,Hras1 and beta-catenin (Catnb) genes in 1,3-butadiene-induced mammary adenocarcinomas in B6C3F1 mice
- 2002
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 0950-9232 .- 1476-5594. ; 21:36, s. 5643-5648
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Tidskriftsartikel (refereegranskat)abstract
- DNAs from 1,3-butadiene-induced mammary adenocarcinomas of B6C3F1 mice were examined for mutations in the Trp53 gene, the ras gene family and several components of the Wnt signaling pathway, including ▀-catenin (Catnb), Apc and Axin. Trp53 mutations were detected in 41% (7 out of 17) of tumors. Each tumor with a Trp53 mutation also exhibited loss of the wildtype Trp53 allele, supporting the importance of Trp53 inactivation during development of these tumors. Analyses of the Hras1, Kras2 and Aras proto-oncogenes revealed Hras1 mutations in 53% (9 out of 17) of tumors. Seven of these mutations were a G?C transversion in Hras1 codon 13, consistent with a 1,3-butadiene-specific Kras2 mutation previously reported in several other tumor types. Mutation screens in Catnb exon 2, the Apc mutation cluster region and the Catnb-binding domain of the Axin gene identified Catnb missense mutations in 3 out of 17 (18%) tumors. In total, mutations of the Trp53, Hras1 and/or Catnb genes were identified in 15 out of 17 1,3-butadiene-induced mammary adenocarcinomas. These results indicate that multiple genetic pathways are disrupted in chemically induced mammary tumors, and that studies in mouse models may help to understand the etiology of human breast cancers.
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| 214. |
- Zhuang, Shi-Mei, et al.
(författare)
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Genetic analysis of Raf1, Mdm2, c-Myc, Cdc25a and Cdc25b proto-oncogenes in 2′,3′-dideoxycytidine- and 1,3-butadiene-induced lymphomas in B6C3F1 mice
- 2000
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Ingår i: Mutation Research. - 1383-5742 .- 1388-2139. ; 452:1, s. 19-26
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Tidskriftsartikel (refereegranskat)abstract
- We have previously identified activation of ras proto-oncogenes and inactivation of tumor suppressor genes including p53, p16INK4a and p15INK4b in 2′,3′-dideoxycytidine (ddC)- and/or 1,3-butadiene (BD)-induced lymphomas derived from B6C3F1 (C57BL/6xC3H/He) mice, indicating that alterations of ras signaling pathway, p53 and pRb growth control pathways are important in the development of these chemically induced lymphomas. However, there is still a subset of tumors that displayed no changes in these genes. Thus, we investigated whether the Raf1, Mdm2, c-Myc, Cdc25a and Cdc25b proto-oncogenes, which are implicated in the ras or p53 or pRb pathways, are alternative oncogenic target genes. Analyses of gross genomic alterations by Southern blots failed to reveal rearrangement or amplification in any of the tumors examined. Frequent point mutations on the substrate binding domain of the Raf1 gene has been reported in 1-ethyl-1-nitrosourea (ENU)-induced murine lymphomas and lung tumors, along with a conspicuous lack of ras mutations [U. Naumann, I. Eisenmann-Tappe, U.R. Rapp, The role of raf kinases in development and growth of tumors, Recent Results Cancer Res., 143 (1997) 237–244]. To investigate whether Raf1 mutation is involved in our set of tumor especially those without ras mutations, the PCR-based single-strand conformation analyses (SSCA) and direct DNA sequencing were employed. No mutations but four genetic polymorphisms between C57BL/6 and C3H/He were found, with two of them reported as point mutations previously (op. cit.). The polymorphisms were utilized for allelic loss study of Raf1 locus. Losses of heterozygosity were found in six of 31 BD-induced lymphomas. These results indicate that genetic alterations of c-Myc, Cdc25, Raf1 and Mdm2 proto-oncogenes may not be involved in the development of ddC- and BD-induced lymphomas and the inactivation of tumor suppressor gene(s) located close to Raf1 gene might be important in the development of a subset of BD-induced lymphomas.
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| 215. |
- Zhuang, Shi-Mei, 1965-, et al.
(författare)
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Mutation analysis of the pRb pathway in 2',3'-dideoxycytidine- and 1,3-butadiene-induced mouse lymphomas
- 2000
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Ingår i: Cancer Letters. - 0304-3835 .- 1872-7980. ; 152:2, s. 129-134
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Tidskriftsartikel (refereegranskat)abstract
- The pRb pathway plays a key role in controlling the G1/S transition in cell cycle progression. Aberrations of various components of the pRb pathway, such as retinoblastoma protein and its upstream actors including cyclin D1, cyclin dependence kinase-4 and p16/p15 cyclin dependent kinase inhibitors, have been reported in a variety of human tumors. Furthermore, the alterations of retinoblastoma protein and its upstream components often occur in a reciprocal manner. Previously, we have reported frequent inactivation of the Cdkn2a/Cdkn2b loci encoding p16/p15 cyclin dependent kinase inhibitors in a subset of 2',3'-dideoxycytidine- and 1,3-butadiene-induced mouse lymphomas (S.-M. Zhuang, A. Schippert, A. Haugen-Strano, R.W. Wiseman, P. Soderkvist, Inactivation of p16(INK4a)-a, p16(INK4a)-▀ and p15(INK4b) genes in 2',3'-dideoxycytidine- and 1,3-butadiene-induced lymphomas, Oncogene 16 (1998) 803-808), indicating the involvement of pRb pathway in lymphomagenesis. To investigate whether alteration of other components in pRb pathway is an alternative mechanism underlying the development of these chemically induced lymphomas, we have examined the genetic status of Rb1, Ccnd1 and Cdk4 genes that encode retinoblastoma protein, cyclin D1 and cyclin dependence kinase-4, respectively. Gross alterations of the Rb1, Ccnd1, and Cdk4 genes were not detected by Southern analysis in any of the tumors examined. In addition, single-strand conformation analysis failed to reveal point mutations in the Cdk4 amino terminal domain that is important for its association with Cdkn2a gene products. These results indicate that the mechanisms underlying the development of 2',3'-dideoxycytidine- and 1,3-butadiene-induced lymphomas involve inactivation of p16/p15 cyclin-dependent kinase inhibitors but not genomic alterations of the Rb1, Ccnd1 and Cdk4 genes. Copyright (C) 2000 Elsevier Science Ireland Ltd.
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| 216. |
- Zimdahl Kahlin, Anna, et al.
(författare)
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Comprehensive study of thiopurine methyltransferase genotype, phenotype, and genotype-phenotype discrepancies in Sweden
- 2019
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Ingår i: Biochemical Pharmacology. - : PERGAMON-ELSEVIER SCIENCE LTD. - 0006-2952 .- 1356-1839. ; 164, s. 263-272
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Tidskriftsartikel (refereegranskat)abstract
- Thiopurines are widely used in the treatment of leukemia and inflammatory bowel diseases. Thiopurine metabolism varies among individuals because of differences in the polymorphic enzyme thiopurine methyltransferase (TPMT, EC 2.1.1.67), and to avoid severe adverse reactions caused by incorrect dosing it is recommended that the patients TPMT status be determined before the start of thiopurine treatment. This study describes the concordance between genotyping for common TPMT alleles and phenotyping in a Swedish cohort of 12,663 patients sampled before or during thiopurine treatment. The concordance between TPMT genotype and enzyme activity was 94.5%. Compared to the genotype, the first measurement of TPMT enzyme activity was lower than expected for 4.6% of the patients. Sequencing of all coding regions of the TPMT gene in genotype/phenotype discrepant individuals led to the identification of rare and novel TPMT alleles. Fifteen individuals (0.1%) with rare or novel genotypes were identified, and three TPMT alleles (TPMT*42, *43, and *44) are characterized here for the first time. These 15 patients would not have been detected as carrying a deviating TPMT genotype if only genotyping of the most common TPMT variants had been performed. This study highlights the benefit of combining TPMT genotype and phenotype determination in routine testing. More accurate dose recommendations can be made, which might decrease the number of adverse reactions and treatment failures during thiopurine treatment.
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| 217. |
- Österström, Anna, et al.
(författare)
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Expression of cytosolic and group X secretory phospholipase A2 genes in human colorectal adenocarcinomas
- 2002
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Ingår i: Cancer Letters. - 0304-3835 .- 1872-7980. ; 182:2, s. 175-182
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Tidskriftsartikel (refereegranskat)abstract
- Gene expression of cytosolic phospholipase A2 (cPLA2) and protein level of secretory PLA2 group X (sPLA2-X) are upregulated in human colorectal cancer and provide cyclooxygenase-2 (COX-2) with arachidonic acid, resulting in increased levels of PGE2. Mutated ras-genes are suggested to be involved in the regulatory pathway of cPLA2 in lung cancer cells. We analysed the gene expression of cPLA2 and sPLA2-X in 42 and 38 primary colorectal tumours, respectively, with and without K-ras mutations. We found an up-regulation of cPLA2 mRNA but the induction in tumour tissues does not correlate with Ras-gene mutations. Moreover, our results cannot consistently reflect an overexpression of sPLA2-X gene in colorectal cancer tissues.
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