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PubMed2003

Reduced switching in SCID B cells is associated with altered somatic mutation of recombined S regions.

Deoxyribonucleic acid double-stranded breaks act as intermediates in Ig V(D)J recombination and probably perform a similar function in class switch recombination between IgH C genes. In SCID mice, V(D)J recombination is blocked because the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) protein is defective. We show in this study that switching to all isotypes examined was detectable when the SCID mutation was introduced into anti-hen egg lysozyme transgenic B cells capable of undergoing class switch recombination, but switching was significantly reduced in comparison with control B cells of the same specificity lacking the RAG1 gene. Thus, DNA-PKcs is involved in switching to all isotypes, but plays a lesser role in the switching process than it does in V(D)J-coding joint formation. The higher level of switching observed by us in SCID B cells compared with that observed by others in DNA-PKcs(null) cells raises the possibility that kinase-deficient DNA-PKcs can function in switching. Point mutation of G:C base pairs with cytidines on the sense strand was greatly reduced in recombined switch regions from SCID cells compared with control RAG1(-/-) B cells. The preferential loss of sense strand cytidine mutations from hybrid S regions in SCID cells suggests the possibility that nicks might form in S regions of activated B cells on the template strand independently of activation-induced cytidine deaminase and are converted to double-strand breaks when activation-induced cytidine deaminase deaminates the non-template strand.

Animals↗
PubMed1999

Germline hMSH2 and differential somatic mutations in patients with Turcot's syndrome.

Turcot's syndrome is characterized clinically by the occurrence of primary brain tumor and colorectal tumor and has in previous reports been shown to be associated with germline mutations in the genes APC, hMLH1, and hPMS2. Here we describe three patients with Turcot's syndrome, each having colorectal adenocarcinoma and malignant glioma. All the colorectal and brain tumors from these patients showed replication errors in most of the microsatellite loci investigated. Search for underlying germline mutations in the nucleotide mismatch repair genes revealed three different hMSH2 mutations. All colorectal tumors showed a frameshift in the A(10) tract in the coding sequence of the transforming growth factor beta type II receptor (TGFBRII) gene, but no such change was detected in any of the brain tumors. Frameshift mutation in the BAX gene was found in one colon carcinoma and mutations in insulin-like growth factor type II receptor (IGFIIR) gene in one glioma. Our data have broadened the possible mutation spectrum of patients with Turcot's syndrome. The difference in the mutation spectrum of TGFBRII, BAX, and IGFIIR between brain and colorectal tumors in these individuals suggests that the mutator phenotype may target different pathogenic pathways in the oncogenic process of the two organs.

Adenomatous Polyposis Coli↗
PubMed2000

Somatic mutations of the APC, KRAS, and TP53 genes in nonpolypoid colorectal adenomas.

Colorectal adenomas are macroscopically visible morphological changes of the mucosa that can develop focal carcinoma in the absence of surgical intervention. The successive molecular changes proposed to occur at different stages in the adenoma-carcinoma sequence were primarily based on DNA studies of exophytic, polypoid-type adenomas. Not all colorectal lesions, however, display an exophytic phenotype and a presumed distinct colorectal neoplasm, the nonpolypoid adenoma, was subsequently described as a precursor of colorectal cancer. The low incidence of KRAS mutations in nonpolypoid colorectal adenomas reported previously suggested a different genetic basis for the transformation process in these lesions. We have pursued the identification of genetic changes in benign sporadic nonpolypoid colorectal adenomas in a selected Swedish patient group with no family history of colorectal cancer. Mutation screening of the adenomatous polyposis coli (APC), KRAS, and TP53 genes was conducted using the protein truncation test, heteroduplex-single-strand conformation polymorphism analysis, and denaturing gradient gel electrophoresis on PCR-amplified fragments. Fourteen mutations in the APC gene were characterized in 10/20 samples. Mutations in the KRAS and TP53 genes were identified in 3/57 and 4/51 adenomas, respectively. The mutation frequencies and distribution of mutations in APC correlate with published data on exophytic adenomas. The low mutation frequency of the TP53 gene is consistent with the benign nature of the research material. KRAS activation (an early event in polypoid colorectal adenomas) apparently does not play a significant role in nonpolypoid adenoma development but may result in the development of a polypoid configuration. Genes Chromosomes Cancer 27:202-208, 2000.

Adenoma↗
PubMedDate not supplied

Somatic mutation and homozygous deletion of PTEN/MMAC1 gene of 10q23 in renal cell carcinoma.

We studied chromosome 10q loss of heterozygosity and PTEN/MMAC1 gene inactivation in renal cell carcinoma (RCC). Fifty-four cases of RCCs were analysed by three 10q RFLP markers. Forty one of them were heterozygous for at least one of the markers, of which fourteen showed LOH (34%). Six tumors which showed 10q deletion for RFLP markers and six randomly selected tumors without RFLP LOH were included in an extended study of 10q by eight microsatellite markers. Eight of these cases showed LOH with two smallest deleted regions (SRO) at 10q23 delineated by markers D10S541 and D10S579 while the other distal SRO is between markers D10S587 and D10S212 at 10q25-26. The five tumors with LOH covering 10q23 were selected for mutation analysis of PTEN/MMAC1 gene. One tumor without LOH of 10q23 was selected as a control. Using direct sequencing of nine exons, we found three different base pair changes in three tumors with LOH. Nine RCC cell lines were analysed for PTEN/MMAC1 gene inactivation. One homozygous deletion was detected in the cell line UOK147. No expression of PTEN/MMAC1 gene was detect by RT-PCR in the cell line UOK 147.

Base Sequence↗
PubMed2000

Somatic mutation rates and specificities at TC/AG and GT/CA microsatellite sequences in nontumorigenic human lymphoblastoid cells.

We have examined mutational events at TC/AG microsatellites, the second most abundant dinucleotide repetitive motif in the human genome. Mutational targets were constructed containing TC/AG alleles up to 20 units in-frame within the coding region of the herpes simplex virus thymidine kinase (HSV-tk) gene. These targets were incorporated into oriP shuttle vectors, which replicate episomally in human lymphoblastoid cells. The overall HSV-tk mutant frequencies measured after 10 population doublings in cells derived from a clinically normal donor were slightly increased over the background of mutations recovered in Escherichia coli. DNA sequence analyses revealed that replication of TC/AG vectors in human cells increased the mutation frequencies at the microsatellite motif up to 3-fold, relative to background. Additionally, the median HSV-tk mutation rate of single-cell clones carrying the [TC/AG]17 vector was significantly different from that of clones harboring the control vector. The median rate of allele length alterations within the [TC/AG]11 tract was 2 x 10(-6) mutations/cell generation, with an equivalent rate of deletion and expansion mutations. In contrast, a [GT/CA]10 vector showed no increase in microsatellite mutation frequency after replication in human cells, and mutation rates of clones carrying a [GT/CA]16 vector were not significantly different from controls. Intriguingly, replication in human cells of all microsatellite-containing vectors resulted in elevated mutation frequencies at the downstream HSV-tk coding sequence of up to 20-fold, an effect not observed for the control vector. These results demonstrate that the frequency of mutational events at TC/AG motifs is slightly greater than at GT/CA motifs of similar allele length. This is the first report to our knowledge of the mutation rates at TC/AG microsatellite alleles in eukaryotic or prokaryotic cells.

Base Sequence↗
PubMed2000

Higher-grade transformation of follicle center lymphoma is associated with somatic mutation of the 5' noncoding regulatory region of the BCL-6 gene.

Follicle center lymphoma (FCL) is an indolent low-grade B-cell non-Hodgkin's lymphoma (NHL) that frequently transforms to aggressive diffuse large B-cell lymphoma (DLBCL). Histologic transformation of FCL is commonly associated with accumulation of secondary genetic alterations. The BCL-6 gene is altered by chromosomal rearrangements and mutations clustering in its 5' noncoding regulatory region in up to 70% of primary DLBCL, but in a significantly smaller subset of FCL. Previous studies have shown that both chromosomal rearrangements and mutations could deregulate BCL-6 expression. To evaluate the association between progressive accumulation of BCL-6 regulatory region mutations and the histologic transformation of FCL, we analyzed by extensive cloning and sequencing paired biopsy specimens obtained at the time of FCL diagnosis and transformation (6 patients) or FCL relapse (3 patients). In an additional patient, biopsy specimens obtained at the time of diagnosis, FCL relapse, and subsequent transformation to DLBCL were evaluated. The presence of identical mutations in the paired diagnosis and posttransformation DLBCL specimens confirmed the common clonal origin of both the pretransformation and the posttransformation lymphomas. No new mutations in the 5' noncoding regulatory region of the BCL-6 gene were detected in any of the specimens evaluated at the time of FCL relapse. In contrast, 5 of the 7 transformed specimens contained new mutations not found in the paired original biopsy specimens obtained at the time of FCL diagnosis or relapse. The number of these new mutations ranged from 1 to 6 per specimen. Some of the new mutations tended to cluster in certain areas of the 5' noncoding regulatory region of the BCL-6 gene. Our results show that transformation of FCL to DLBCL is associated with accumulation of new mutations in the 5' noncoding regulatory region of the BCL-6 gene, that by deregulation of the BCL-6 gene expression may play a role in lymphoma transformation. (Blood. 2000;96:635-639)

Biopsy↗
PubMed2000

Somatic mutation of PTEN in vulvar cancer.

PTEN, a candidate tumor suppressor gene located at chromosome 10q23.3, has been shown to be mutated in approximately 40% of endometrial cancers. Such mutations have also been identified in endometrial hyperplasia, indicating that inactivation of the PTEN tumor suppressor gene is an early event in the genesis of some endometrial cancers. In this study, we have extended the analysis of PTEN in gynecological cancer to include adenocarcinoma of the cervix and vulvar carcinomas. Microdissected tissue (including normal tissues), preneoplastic, and neoplastic lesions were analyzed from 9 patients with cervical cancer and 10 patients with vulvar cancer. Only 1 cervical adenocarcinoma displayed a PTEN mutation. In contrast, five of eight vulvar carcinomas studied harbored PTEN mutations. Alterations were identified in carcinoma in situ as well as squamous cell carcinoma of the vulva. In two patients, PTEN mutations were identified in mucosal regions with mild or focal dysplasia. These results suggest that PTEN is frequently altered in vulvar carcinomas and can be found associated with early dysplastic changes in vulvar mucosa.

Adenocarcinoma↗
PubMed2001

Somatic mutation of mitochondrial DNA in cancerous and noncancerous liver tissue in individuals with hepatocellular carcinoma.

Unlike other types of cancer, hepatocellular carcinoma (HCC) is usually preceded by chronic inflammation caused by viral infection. The mutation of mitochondrial DNA (mtDNA) in hepatocarcinogenesis associated with viral infection was investigated. Compared with control liver tissue, the frequency of mtDNA mutations was markedly increased in both noncancerous and cancerous liver specimens from individuals with HCC. The accumulation of mtDNA mutations in HCC tissue reflected the degree of malignancy. The frequency of mtDNA mutations in HCC tissue was also greater than that described previously for other types of tumors. These observations suggest that the repeated destruction and regeneration of liver tissue associated with chronic viral hepatitis lead to the accumulation of mtDNA mutations. The genetic instability that results in the high rate of mtDNA mutation in cancerous liver tissue is also consistent with the multicentric hepatocarcinogenesis detected clinically.

Carcinoma, Hepatocellular↗
PubMed2001

Somatic mutations in the DNA damage-response genes ATR and CHK1 in sporadic stomach tumors with microsatellite instability.

Maintenance of genomic stability depends on the appropriate cellular responses to DNA damage and the integrity of the DNA repair systems. We analyzed stomach tumors with microsatellite instability (MSI) for frameshift mutations in several potential targets of the mutator phenotype involved in DNA damage-response pathways, such as the ataxia telangiectasia mutated protein-related protein (ATR)-CHK1-Cdc25c pathway, and DNA repair. High frequency of mutations was found within ATR [5 (21%) of 23], MED1 [10 (43%) of 23], hMSH3 [13 (56%) of 23], and hMSH6 [10 (43%) of 23] genes. Also, a low frequency of mutations within the CHK1 gene was detected in 9% (2 of 23) of tumors. No mutations of hMLH3, ATM, BRCA1, or NBS1 genes were detected. These results confirm ATR, MED1, and CHK1 as targets of the mutator pathway in stomach tumorigenesis, and also suggest a potential role of MED1 increasing, together with hMSH3 and hMSH6, the genomic instability in the mutator pathway as a secondary mutator. Furthermore, these results suggest that the inhibition of the ATR-CHK1 DNA damage-response pathway might be involved in the tumorigenesis of gastric cancer with microsatellite instability.

Ataxia Telangiectasia Mutated Proteins↗
PubMed2001

[Epitope of somatic mutations in the hepatocyte growth factor receptor naturally processed and presented by HLA-A2 on human hepatocellular carcinoma].

OBJECTIVE: To isolate and identify peptides bound to HLA I on human hepatocellular carcinoma. METHODS: MHC-associated peptides were extracted by mild acid wash of viable hepatocellular carcinomas cells, collected by gel filtration, and fractioned by reversed phase high pressured liquid chromatography (RP-HPLC). Peptides of individual fractions were reconstitution of T cell epitopes and were identified by cytotoxicity T lymophacyte assay. Actively extracted sample analyses were performed by HPLC-MS-MS (tandom mass spectrometry). Protein database in the internet was used as an additional tool for structure analysis and for determination of protein source of the eluted peptides. RESULT: RP-HPLC showed that there were over 20 different fractions of peptides derived from human hepatocellular carcinoma, and only two active peaks were identified by cytotoxicity T lymophocyte assay. The most promising candidate for T cell epitope was nonamers peptide (SLIVHLNEV), derived from met/hepatocyte growth factor receptor, point mutation was 1180F to L. CONCLUSION: Sensitive sequencing by HPLC-MS may provide a powerful method of identifying tumor specific antigenic peptides, and nonamers peptide (SLIVHLNEV) is the hepatocellular carcinoma antigenic peptide.

Amino Acid Sequence↗