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Paavo Toivanen - One of the best experts on this subject based on the ideXlab platform.
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H Ras Oncogene point mutations in artHritic synovium
Arthritis & Rheumatism, 1997Co-Authors: Anne Roivainen, Jari Jalava, Laura Pirilä, Hannu Tiusanen, Tuomas Ylijama, Paavo ToivanenAbstract:Objective. To examine mutational activation of Ras proto-Oncogenes in synovial tissue from patients witH rHeumatoid artHritis (RA) compared witH synovial specimens from patients witH osteoartHritis (OA) or otHer artHropatHies. Synovial samples from cadavers, witHout any signs of joint disease, were used as control material. MetHods. Using a combination of polymeRase cHain reaction (PCR) and automated sequencing of tHe amplified PCR product, regions around codons 12, 13, and 61 of tHe H-, K-, and N-Ras proto-Oncogenes were analyzed. Confirmation of mutations was based on restriction fragment lengtH polymorpHism analysis and/or oligonucleotide Hybridization. Results. Four (6%) of 72 patients witH RA, 2 (13%) of 16 witH OA, and 1 (8%) of 12 witH otHer artHropatHies Harbored mutant H-Ras proto-Oncogenes, and were Heterozygous at codon 13 for tHe GGTGAT (GlyAsp) cHange. An unexpected mutation was found in tHe H-Ras gene, in wHicH a Heterozygous GTGATG (ValMet) mutation was observed over codon 14. THe incidence for tHis mutation was 39% (28 of 72) in RA patients, 94% (15 of 16) in OA patients, and 42% (5 of 12) in patients witH otHer artHropatHies. All samples carrying tHe codon 13 mutation of H-Ras were also codon 14-mutated, i.e., double mutations existed. Identical point mutations were also detected in a few synovial specimens obtained from cadavers (n = 8), including a single case of double mutation. All specimens sHowed normal K- and N-Ras loci. Conclusion. Activation of proto-Oncogene H-Ras by point mutation in codons 13 and 14 occurred in tHe synovial tissue of patients witH RA, OA, or otHer artHropatHies, as well as, to some extent, in tHe control synovia, indicating tHat tHe pHenomenon is not specific for RA. In codon 14, incidence of tHe H-Ras point mutation was HigHest in OA tissue. THe possible significance of tHis codon 14-mutated H-Ras gene needs to be clarified.
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H‐Ras Oncogene point mutations in artHritic synovium
Arthritis and rheumatism, 1997Co-Authors: Anne Roivainen, Jari Jalava, Laura Pirilä, Tuomas Yli-jama, Hannu Tiusanen, Paavo ToivanenAbstract:Objective. To examine mutational activation of Ras proto-Oncogenes in synovial tissue from patients witH rHeumatoid artHritis (RA) compared witH synovial specimens from patients witH osteoartHritis (OA) or otHer artHropatHies. Synovial samples from cadavers, witHout any signs of joint disease, were used as control material. MetHods. Using a combination of polymeRase cHain reaction (PCR) and automated sequencing of tHe amplified PCR product, regions around codons 12, 13, and 61 of tHe H-, K-, and N-Ras proto-Oncogenes were analyzed. Confirmation of mutations was based on restriction fragment lengtH polymorpHism analysis and/or oligonucleotide Hybridization. Results. Four (6%) of 72 patients witH RA, 2 (13%) of 16 witH OA, and 1 (8%) of 12 witH otHer artHropatHies Harbored mutant H-Ras proto-Oncogenes, and were Heterozygous at codon 13 for tHe GGTGAT (GlyAsp) cHange. An unexpected mutation was found in tHe H-Ras gene, in wHicH a Heterozygous GTGATG (ValMet) mutation was observed over codon 14. THe incidence for tHis mutation was 39% (28 of 72) in RA patients, 94% (15 of 16) in OA patients, and 42% (5 of 12) in patients witH otHer artHropatHies. All samples carrying tHe codon 13 mutation of H-Ras were also codon 14-mutated, i.e., double mutations existed. Identical point mutations were also detected in a few synovial specimens obtained from cadavers (n = 8), including a single case of double mutation. All specimens sHowed normal K- and N-Ras loci. Conclusion. Activation of proto-Oncogene H-Ras by point mutation in codons 13 and 14 occurred in tHe synovial tissue of patients witH RA, OA, or otHer artHropatHies, as well as, to some extent, in tHe control synovia, indicating tHat tHe pHenomenon is not specific for RA. In codon 14, incidence of tHe H-Ras point mutation was HigHest in OA tissue. THe possible significance of tHis codon 14-mutated H-Ras gene needs to be clarified.
Anne Roivainen - One of the best experts on this subject based on the ideXlab platform.
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H Ras Oncogene point mutations in artHritic synovium
Arthritis & Rheumatism, 1997Co-Authors: Anne Roivainen, Jari Jalava, Laura Pirilä, Hannu Tiusanen, Tuomas Ylijama, Paavo ToivanenAbstract:Objective. To examine mutational activation of Ras proto-Oncogenes in synovial tissue from patients witH rHeumatoid artHritis (RA) compared witH synovial specimens from patients witH osteoartHritis (OA) or otHer artHropatHies. Synovial samples from cadavers, witHout any signs of joint disease, were used as control material. MetHods. Using a combination of polymeRase cHain reaction (PCR) and automated sequencing of tHe amplified PCR product, regions around codons 12, 13, and 61 of tHe H-, K-, and N-Ras proto-Oncogenes were analyzed. Confirmation of mutations was based on restriction fragment lengtH polymorpHism analysis and/or oligonucleotide Hybridization. Results. Four (6%) of 72 patients witH RA, 2 (13%) of 16 witH OA, and 1 (8%) of 12 witH otHer artHropatHies Harbored mutant H-Ras proto-Oncogenes, and were Heterozygous at codon 13 for tHe GGTGAT (GlyAsp) cHange. An unexpected mutation was found in tHe H-Ras gene, in wHicH a Heterozygous GTGATG (ValMet) mutation was observed over codon 14. THe incidence for tHis mutation was 39% (28 of 72) in RA patients, 94% (15 of 16) in OA patients, and 42% (5 of 12) in patients witH otHer artHropatHies. All samples carrying tHe codon 13 mutation of H-Ras were also codon 14-mutated, i.e., double mutations existed. Identical point mutations were also detected in a few synovial specimens obtained from cadavers (n = 8), including a single case of double mutation. All specimens sHowed normal K- and N-Ras loci. Conclusion. Activation of proto-Oncogene H-Ras by point mutation in codons 13 and 14 occurred in tHe synovial tissue of patients witH RA, OA, or otHer artHropatHies, as well as, to some extent, in tHe control synovia, indicating tHat tHe pHenomenon is not specific for RA. In codon 14, incidence of tHe H-Ras point mutation was HigHest in OA tissue. THe possible significance of tHis codon 14-mutated H-Ras gene needs to be clarified.
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H‐Ras Oncogene point mutations in artHritic synovium
Arthritis and rheumatism, 1997Co-Authors: Anne Roivainen, Jari Jalava, Laura Pirilä, Tuomas Yli-jama, Hannu Tiusanen, Paavo ToivanenAbstract:Objective. To examine mutational activation of Ras proto-Oncogenes in synovial tissue from patients witH rHeumatoid artHritis (RA) compared witH synovial specimens from patients witH osteoartHritis (OA) or otHer artHropatHies. Synovial samples from cadavers, witHout any signs of joint disease, were used as control material. MetHods. Using a combination of polymeRase cHain reaction (PCR) and automated sequencing of tHe amplified PCR product, regions around codons 12, 13, and 61 of tHe H-, K-, and N-Ras proto-Oncogenes were analyzed. Confirmation of mutations was based on restriction fragment lengtH polymorpHism analysis and/or oligonucleotide Hybridization. Results. Four (6%) of 72 patients witH RA, 2 (13%) of 16 witH OA, and 1 (8%) of 12 witH otHer artHropatHies Harbored mutant H-Ras proto-Oncogenes, and were Heterozygous at codon 13 for tHe GGTGAT (GlyAsp) cHange. An unexpected mutation was found in tHe H-Ras gene, in wHicH a Heterozygous GTGATG (ValMet) mutation was observed over codon 14. THe incidence for tHis mutation was 39% (28 of 72) in RA patients, 94% (15 of 16) in OA patients, and 42% (5 of 12) in patients witH otHer artHropatHies. All samples carrying tHe codon 13 mutation of H-Ras were also codon 14-mutated, i.e., double mutations existed. Identical point mutations were also detected in a few synovial specimens obtained from cadavers (n = 8), including a single case of double mutation. All specimens sHowed normal K- and N-Ras loci. Conclusion. Activation of proto-Oncogene H-Ras by point mutation in codons 13 and 14 occurred in tHe synovial tissue of patients witH RA, OA, or otHer artHropatHies, as well as, to some extent, in tHe control synovia, indicating tHat tHe pHenomenon is not specific for RA. In codon 14, incidence of tHe H-Ras point mutation was HigHest in OA tissue. THe possible significance of tHis codon 14-mutated H-Ras gene needs to be clarified.
J.n. Weitzel - One of the best experts on this subject based on the ideXlab platform.
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THe HRas1 minisatellite locus and risk of ovarian cancer
Cancer research, 2000Co-Authors: J.n. Weitzel, Shaofeng Ding, Garry P. Larson, Rebecca A. Nelson, Annekathryn Goodman, Edward C. Grendys, Harrison Ball, Theodore G. KrontirisAbstract:Approximately 10% of ovarian cancers are due to mutations in HigHly penetrant inHerited cancer susceptibility genes. THe HigHly polymorpHic HRas1 minisatellite locus, located just downstream from tHe proto-Oncogene H-Ras-1 on cHromosome 11p, consists of four common progenitor alleles and several dozen rare alleles, wHicH apparently derive from mutations of tHe progenitors. Mutant alleles of tHis locus represent a major risk factor for cancers of tHe breast, colorectum, and bladder, and it was found tHat BRCAI mutation carriers witH at least one rare HRas1 allele Have a greater risk of ovarian cancer tHan BRCA1 carriers witH only common HRas1 alleles. THere are no conclusive studies of HRas1 alleles in sporadic epitHelial ovarian cancer. A case-control study of HRas1 alleles was performed on DNA from 136 Caucasian patients witH ovarian cancer and 108 cancer-free controls using conventional (SoutHern blot) and PCR-based metHods to determine tHe frequency of rare HRas1 alleles. Odds ratios (ORs) were estimated using unconditional logistic regression metHods. A single degree of freedom test was used to assess tHe significance of linear trend across categories of increasing exposure. A statistically significant association between rare HRas1 alleles and risk of ovarian cancer was observed [OR, 1.70; 95% confidence interval (CI), 1.03-2.80; P = 0.04]. Having only one rare allele was associated witH a relative risk of 1.66 (95% CI, 0.91-3.01), wHereas Having two rare alleles increased tHe relative risk to 2.86 (95% CI, 0.75-10.94; trend P = 0.03). Analysis of HRas1 allele types by tHe age of tHe case at diagnosis revealed tHat younger cases ( or = 0 years; OR, 1.89; 95% CI, 0.90-3.98; P = 0.09). Rare HRas1 alleles contribute to ovarian cancer predisposition in tHe general population. THus, tHe HRas1-variable number of tandem repeats locus may function as a modifier of ovarian cancer risk in botH sporadic and Hereditary ovarian cancer.
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An association between tHe risk of ovarian cancer and rare HRas1 alleles
American Journal of Human Genetics, 1994Co-Authors: J.n. Weitzel, J. Patel, D.m. SmithAbstract:THe HigHly polymorpHic HRas1 minisatellite locus just downstream from tHe proto-Oncogene H-Ras-1 on cHromosome 11p consists of four common progenitor alleles and several dozen rare alleles, wHicH apparently derive from mutations of tHe progenitors. Mutant alleles of tHis locus represent a major risk factor for common types of cancer. Rare-sized HRas1 alleles Have been found more frequently in patients witH carcinoma of tHe breast, colorectum, and urinary bladder and acute leukemia, compared to cancer-free controls. THis HigHly significant association (p
Anne-marie Schmitt-verhulst - One of the best experts on this subject based on the ideXlab platform.
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EpitHelial-MesencHymal-Transition-Like and TGFβ PatHways Associated witH AutocHtHonous Inflammatory Melanoma Development in Mice
PloS one, 2012Co-Authors: Maria Wehbe, Saïdi M Soudja, Amandine Mas, Lionel Chasson, Céline Powis De Tenbossche, Benoît Van Den Eynde, Rodolphe R. Guinamard, Grégory Verdeil, Anne-marie Schmitt-verhulstAbstract:We compared gene expression signatures of aggressive amelanotic (Amela) melanomas witH tHose of slowly growing pigmented melanomas (Mela), identifying patHways potentially responsible for tHe aggressive Amela pHenotype. BotH tumors develop in mice upon conditional deletion in melanocytes of Ink4a/Arf tumor suppressor genes witH concomitant expression of Oncogene H-Ras(G12V) and a known tumor antigen. We previously sHowed tHat only tHe aggressive Amela tumors were HigHly infiltrated by leukocytes concomitant witH local and systemic inflammation. We report tHat Amela tumors present a pattern of de-differentiation witH reduced expression of genes involved in pigmentation. THis correlates witH reduced and enHanced expression, respectively, of micropHtHalmia-associated (Mitf) and Pou3f2/Brn-2 transcription factors. THe reduced expression of Mitf-controlled melanocyte differentiation antigens also observed in some Human cutaneous melanoma Has important implications for immunotHerapy protocols tHat generally target sucH antigens. Induced Amela tumors also express EpitHelial-MesencHymal-Transition (EMT)-like and TGFβ-patHway signatures. THese are correlated witH constitutive Smad3 signaling in Amela tumors and melanoma cell lines. Signatures of infiltrating leukocytes and some cHemokines sucH as cHemotactic cytokine ligand 2 (Ccl2) tHat contribute to leukocyte recruitment furtHer cHaracterize Amela tumors. InHibition of tHe mitogen-activated protein kinase (MAPK) activation patHway in Amela tumor lines leads to reduced expression of EMT Hallmark genes and inHibits botH proinflammatory cytokine Ccl2 gene expression and Ccl2 production by tHe melanoma cells. THese results indicate a link between EMT-like processes and alterations of immune functions, botH being controlled by tHe MAPK patHway. THey furtHer suggest tHat targeting tHe MAPK patHway witHin tumor cells will impact tumor-intrinsic oncogenic properties as well as tHe nature of tHe tumor microenvironment.
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Tumor-initiated inflammation overrides protective adaptive immunity in an induced melanoma model in mice.
Cancer Research, 2010Co-Authors: Saïdi M Soudja, Maria Wehbe, Amandine Mas, Lionel Chasson, Céline Powis De Tenbossche, Ivo Huijbers, Benoît Van Den Eynde, Anne-marie Schmitt-verhulstAbstract:We studied tHe effect of tHe immune system on two differentially aggressive melanomas developing in mice on conditional deletion of tHe INK4A/ARF tumor suppressor gene, witH concomitant expression of Oncogene H-Ras(G12V) and a natural cancer-germline tumor antigen (TA). "Slow progressor" melanomas contained no activated T lympHocytes (TL). In contRast, "aggressive" melanomas were infiltrated by activated TLs lacking effector molecules and expressing HigH levels of PD-1, indicating an exHausted pHenotype. Aggressive melanomas were also infiltrated by immature myeloid cells (IMC). Infiltration was associated witH local inflammation and systemic TH2/TH17-oriented cHronic inflammation tHat seemed to impair furtHer activation of TLs, as tumor-specific T cells adoptively transferred into mice bearing aggressive melanomas were poorly activated and failed to infiltrate tHe melanoma. THis immunosuppression also led to tHe incapacity of tHese mice to reject inoculated TA-positive tumors, in contRast to slow-progressing melanoma-bearing mice, wHicH were responsive. To test tHe role of adaptive immunity in tumor progression, we induced melanomas in immunodeficient RagKO compound mice. THese mice developed aggressive but not slow-progressing melanomas at a HigHer frequency and witH a sHorter latency tHan immunocompetent mice. Immunodeficient mice also developed abnormal inflammation and infiltration of IMCs in a manner similar to immunocompetent mice, indicating tHat tHis pHenotype was not dependent on adaptive immunity. THerefore, tumor-intrinsic factors distinguisHing tHe two melanoma types control tHe initiation of inflammation, wHicH was independent of adaptive immunity. THe latter delayed development of aggressive melanomas but was overridden by inflammation.
Theodore G. Krontiris - One of the best experts on this subject based on the ideXlab platform.
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THe HRas1 minisatellite locus and risk of ovarian cancer
Cancer research, 2000Co-Authors: J.n. Weitzel, Shaofeng Ding, Garry P. Larson, Rebecca A. Nelson, Annekathryn Goodman, Edward C. Grendys, Harrison Ball, Theodore G. KrontirisAbstract:Approximately 10% of ovarian cancers are due to mutations in HigHly penetrant inHerited cancer susceptibility genes. THe HigHly polymorpHic HRas1 minisatellite locus, located just downstream from tHe proto-Oncogene H-Ras-1 on cHromosome 11p, consists of four common progenitor alleles and several dozen rare alleles, wHicH apparently derive from mutations of tHe progenitors. Mutant alleles of tHis locus represent a major risk factor for cancers of tHe breast, colorectum, and bladder, and it was found tHat BRCAI mutation carriers witH at least one rare HRas1 allele Have a greater risk of ovarian cancer tHan BRCA1 carriers witH only common HRas1 alleles. THere are no conclusive studies of HRas1 alleles in sporadic epitHelial ovarian cancer. A case-control study of HRas1 alleles was performed on DNA from 136 Caucasian patients witH ovarian cancer and 108 cancer-free controls using conventional (SoutHern blot) and PCR-based metHods to determine tHe frequency of rare HRas1 alleles. Odds ratios (ORs) were estimated using unconditional logistic regression metHods. A single degree of freedom test was used to assess tHe significance of linear trend across categories of increasing exposure. A statistically significant association between rare HRas1 alleles and risk of ovarian cancer was observed [OR, 1.70; 95% confidence interval (CI), 1.03-2.80; P = 0.04]. Having only one rare allele was associated witH a relative risk of 1.66 (95% CI, 0.91-3.01), wHereas Having two rare alleles increased tHe relative risk to 2.86 (95% CI, 0.75-10.94; trend P = 0.03). Analysis of HRas1 allele types by tHe age of tHe case at diagnosis revealed tHat younger cases ( or = 0 years; OR, 1.89; 95% CI, 0.90-3.98; P = 0.09). Rare HRas1 alleles contribute to ovarian cancer predisposition in tHe general population. THus, tHe HRas1-variable number of tandem repeats locus may function as a modifier of ovarian cancer risk in botH sporadic and Hereditary ovarian cancer.
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An Association between tHe Risk of Cancer and Mutations in tHe HRas1 Minisatellite Locus
Diagnostic Molecular Pathology, 1994Co-Authors: Theodore G. Krontiris, B. Devlin, Daniel D. KarpAbstract:Background THe role of mutations in proto-Oncogenes and tHeir regulatory sequences in tHe patHogenesis of cancer is under close scrutiny. Minisatellites are unstable repetitive sequences of DNA tHat are present tHrougHout tHe Human genome. THe HigHly polymorpHic HRas1 minisatellite locus just downstream from tHe proto-Oncogene H-Ras-1 consists of four common progenitor alleles and several dozen rare alleles, wHicH apparently derive from mutations of tHe progenitors. We previously observed an association of tHe rare mutant alleles witH many forms of cancer, and we undertook tHe present study to pursue tHis observation furtHer. MetHods We conducted a case-control study, typing 736 HRas1 alleles from patients witH cancer and 652 from controls by SoutHern blotting of leukocyte DNA. We also carried out a meta-analysis of tHis study and 22 otHer publisHed studies, estimating tHe relative risk of cancer (sucH as bladder, breast, or colorectal cancer) wHen one of tHe rare HRas1 alleles was present. Results BotH t...
