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Yuri E Dubrova - One of the best experts on this subject based on the ideXlab platform.
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Germline Mutation induction at mouse repeat dna loci by chemical mutagens
Mutation Research, 2003Co-Authors: Carles Vilarinoguell, Andrew G Smith, Yuri E DubrovaAbstract:Mutation rates at two expanded simple tandem repeat (ESTR) loci were studied in the Germline of male mice exposed to two monofunctional alkylating agents, ethylnitrosourea (ENU) and isopropyl methanesulfonate (iPMS), and a topoisomerase II inhibitor, etoposide. Pre-meiotic exposure to the alkylating agents resulted in a highly significant increase in ESTR Mutation rate, but did not alter post-meiotically exposed cells. Pre-meiotic Mutation induction by ENU and iPMS was linear within the interval of doses from 12.5 to 25 mg/kg and reached a plateau at higher concentrations. Paternal exposure to etoposide resulted in ESTR Mutation induction at meiotic stages but did not affect post- or pre-meiotic cells. The pattern of ESTR Mutation induction after pre-meiotic and meiotic exposure to chemical mutagens was similar to that previously obtained by various traditional approaches for monitoring Germline Mutation in mice. The results of this study show that ESTR loci provide a new efficient experimental system for monitoring the genetic effects of chemical mutagens, capable of detecting increases in Mutation rates at low doses of exposure.
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a novel single molecule analysis of spontaneous and radiation induced Mutation at a mouse tandem repeat locus
Web Science, 2002Co-Authors: Carole L Yauk, Yuri E Dubrova, Gemma R Grant, Alec J JeffreysAbstract:Expanded simple tandem repeat (ESTR) loci include some of the most unstable DNA in the mouse genome and have been extensively used in pedigree studies of Germline Mutation. We now show that repeat DNA instability at the mouse ESTR locus Ms6-hm can also be monitored by single molecule PCR analysis of genomic DNA. Unlike unstable human minisatellites which mutate almost exclusively in the Germline by a meiotic recombination-based process, mouse Ms6-hm shows repeat instability both in germinal (sperm) DNA and in somatic (spleen, brain) DNA. There is no significant variation in Mutation frequency between mice of the same inbred strain. However, significant variation occurs between tissues, with mice showing the highest Mutation frequency in sperm. The size spectra of somatic and sperm mutants are indistinguishable and heavily biased towards gains and losses of only a few repeat units, suggesting repeat turnover by a mitotic replication slippage process operating both in the soma and in the Germline. Analysis of male mice following acute pre-meiotic exposure to X-rays showed a significant increase in sperm but not somatic Mutation frequency, though no change in the size spectrum of mutants. The level of radiation-induced Mutation at Ms6-hm was indistinguishable from that established by conventional pedigree analysis following paternal irradiation. This confirms that mouse ESTR loci are very sensitive to ionizing radiation and establishes that induced Germline Mutation results from radiation-induced mutant alleles being present in sperm, rather than from unrepaired sperm DNA lesions that subsequently lead to the appearance of mutants in the early embryo. This single molecule monitoring system has the potential to substantially reduce the number of mice needed for Germline Mutation monitoring, and can be used to study not only Germline Mutation but also somatic Mutation in vivo and in cell culture.
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Further evidence for elevated human minisatellite Mutation rate in Belarus eight years after the Chernobyl accident.
Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, 1997Co-Authors: Yuri E Dubrova, Valeri N Nesterov, Nicolay G Krouchinsky, Valdislav A Ostapenko, Gilles Vergnaud, F Giraudeau, J Buard, Alec John JeffreysAbstract:Analysis of Germline Mutation rate at human minisatellites among children born in areas of the Mogilev district of Belarus heavily polluted after the Chernobyl accident has been extended, both by recruiting more families from the affected region and by using five additional minisatellite probes, including multi-locus probe 33.6 and four hypervariable single-locus probes. These additional data confirmed a twofold higher Mutation rate in exposed families compared with non-irradiated families from the United Kingdom. An elevated rate was seen at all three independent sets of minisatellites (detected separately by multi-locus probes 33.15, 33.6 and six single-locus probes), indicating a generalised increase in minisatellite Germline Mutation rate in the Belarus families. Within the Belarus cohort, Mutation rate was significantly greater in families with higher parental radiation dose estimated for chronic external and internal exposure to caesium-137, consistent with radiation induction of Germline Mutation. The spectra of Mutation seen in the unexposed and exposed families were indistinguishable, suggesting that increased Mutation observed over multiple loci arises indirectly by some mechanism that enhances spontaneous minisatellite Mutation.
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human minisatellite Mutation rate after the chernobyl accident
Nature, 1996Co-Authors: Rita Neumann, Valeri N Nesterov, Nicolay G Krouchinsky, Valdislav A Ostapenko, Yuri E Dubrova, David L Neil, Alec John JeffreysAbstract:Germline Mutation at human minisatellite loci has been studied among children born in heavily polluted areas of the Mogilev district of Belarus after the Chernobyl accident and in a control population. The frequency of Mutation was found to be twice as high in the exposed families as in the control group. Mutation rate in the Mogilev families was correlated with the level of caesium-137 surface contamination, consistent with radiation induction of Germline Mutation.
Michael Goggins - One of the best experts on this subject based on the ideXlab platform.
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phenotypic variation in eight extended cdkn2a Germline Mutation familial atypical multiple mole melanoma pancreatic carcinoma prone families the familial atypical multiple mole melanoma pancreatic carcinoma syndrome
American Society of Clinical Oncology annual meeting, 2002Co-Authors: Henry T Lynch, Randall E Brand, David W Hogg, Carolyn A Deters, Ramon M Fusaro, Jane F Lynch, Ling Liu, Joseph Knezetic, Norman J Lassam, Michael GogginsAbstract:BACKGROUND. Hereditary pancreatic carcinoma shows extant phenotypic and genotypic heterogeneity as evidenced by its integral association with a variety of hereditary cancer syndromes inclusive of the familial atypical multiple mole melanoma (FAMMM) syndrome in concert with CDKN2A (p16) Germline Mutations. METHODS. Creighton University's familial pancreatic carcinoma resource comprises 159 families of which 19 (12%) show the FAMMM cutaneous phenotypes. The authors describe eight families with the FAMMM-pancreatic carcinoma (FAMMM-PC) association in concert with a CDKN2A Germline Mutation. Each family was thoroughly educated about all facets of the study, including the molecular genetics reduced penetrance of CDKN2A Mutations, and their variable expressivity. Genetic counseling was provided to each patient. RESULTS. Diversity in cancer presentation within and among the families was noteworthy, wherein melanoma predominated in certain of the families whereas pancreatic carcinoma predominated in others. Early-onset pancreatic carcinoma (at ages 35, 45, 46, and 49 years) appeared in some of the families whereas markedly later-onset pancreatic carcinoma occurred in others. There were four incidences of melanoma and pancreatic carcinoma as double primaries in the same individuals. One patient with melanoma and pancreatic carcinoma had a third primary of breast carcinoma. Another patient had sarcoma, esophageal carcinoma, and two melanoma primaries, whereas his daughter had sarcoma and was a carrier of a CDKN2A Mutation. CONCLUSIONS. The authors suggest that these tumors may collectively, in concert with CDKN2A Mutations, constitute a new putative hereditary carcinoma syndrome referred to as FAMMM-PC. More clinical and molecular genetic research on additional families with pancreatic carcinoma in concert with the FAMMM will be required.
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phenotypic variation in eight extended cdkn2a Germline Mutation familial atypical multiple mole melanoma pancreatic carcinoma prone families the familial atypical multiple mole melanoma pancreatic carcinoma syndrome
Cancer, 2002Co-Authors: Henry T Lynch, Randall E Brand, David W Hogg, Carolyn A Deters, Ramon M Fusaro, Jane F Lynch, Ling Liu, Joseph Knezetic, Norman J Lassam, Michael GogginsAbstract:BACKGROUND Hereditary pancreatic carcinoma shows extant phenotypic and genotypic heterogeneity as evidenced by its integral association with a variety of hereditary cancer syndromes inclusive of the familial atypical multiple mole melanoma (FAMMM) syndrome in concert with CDKN2A (p16) Germline Mutations. METHODS Creighton University's familial pancreatic carcinoma resource comprises 159 families of which 19 (12%) show the FAMMM cutaneous phenotypes. The authors describe eight families with the FAMMM–pancreatic carcinoma (FAMMM-PC) association in concert with a CDKN2A Germline Mutation. Each family was thoroughly educated about all facets of the study, including the molecular genetics, reduced penetrance of CDKN2A Mutations, and their variable expressivity. Genetic counseling was provided to each patient. RESULTS Diversity in cancer presentation within and among the families was noteworthy, wherein melanoma predominated in certain of the families whereas pancreatic carcinoma predominated in others. Early-onset pancreatic carcinoma (at ages 35, 45, 46, and 49 years) appeared in some of the families whereas markedly later-onset pancreatic carcinoma occurred in others. There were four incidences of melanoma and pancreatic carcinoma as double primaries in the same individuals. One patient with melanoma and pancreatic carcinoma had a third primary of breast carcinoma. Another patient had sarcoma, esophageal carcinoma, and two melanoma primaries, whereas his daughter had sarcoma and was a carrier of a CDKN2A Mutation. CONCLUSIONS The authors suggest that these tumors may collectively, in concert with CDKN2A Mutations, constitute a “new” putative hereditary carcinoma syndrome referred to as FAMMM-PC. More clinical and molecular genetic research on additional families with pancreatic carcinoma in concert with the FAMMM will be required. Cancer 2002;94:84–96. © 2002 American Cancer Society.
Judit Horvath - One of the best experts on this subject based on the ideXlab platform.
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performance of breast cancer polygenic risk scores in 760 female chek2 Germline Mutation carriers
Journal of the National Cancer Institute, 2020Co-Authors: Julika Borde, Jan Hauke, Corinna Ernst, Barbara Wappenschmidt, Dieter Niederacher, Konstantin Weberlassalle, Gunnar Schmidt, Anne S Quante, Nana Weberlassalle, Judit HorvathAbstract:BACKGROUND Genome-wide association studies (GWAS) suggest that the combined effects of breast cancer (BC)-associated single nucleotide polymorphisms (SNPs) can improve BC risk stratification using polygenic risk scores (PRSs). The performance of PRSs in GWAS-independent clinical cohorts is poorly studied in individuals carrying Mutations in moderately penetrant BC predisposition genes such as CHEK2. METHODS 760 female CHEK2 Mutation carriers were included; 561 women were affected with BC, of whom 74 developed metachronous contralateral BC (mCBC). For PRS calculations, two SNP sets covering 77 (SNP set 1, developed for BC risk stratification in women unselected for their BRCA1/2 Germline Mutation status) and 88 (SNP set 2, developed for BC risk stratification in female BRCA1/2 Mutation carriers) BC-associated SNPs were used. All statistical tests were two-sided. RESULTS Both SNP sets provided concordant PRS results at the individual level (r = 0.91, p < 2.20 × 10-16). Weighted cohort Cox regression analyses revealed statistically significant associations of PRSs with the risk for first BC. For SNP set 1, a hazard ratio (HR) of 1.71 per standard deviation of the PRS was observed (95% confidence interval [CI] = 1.36 to 2.15, p = 3.87x10-6). PRSs identify a subgroup of CHEK2 Mutation carriers with a predicted lifetime risk for first BC that exceeds the surveillance thresholds defined by international guidelines. Association of PRS with mCBC was examined via Cox regression analysis (SNP set 1 HR =: 1.23, 95%CI = 0.86 to 1.78, p = .26). CONCLUSION PRSs may be used to personalize risk-adapted preventive measures for women with CHEK2 Mutations. Larger studies are required to assess the role of PRSs in mCBC predisposition.
Alec John Jeffreys - One of the best experts on this subject based on the ideXlab platform.
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Further evidence for elevated human minisatellite Mutation rate in Belarus eight years after the Chernobyl accident.
Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, 1997Co-Authors: Yuri E Dubrova, Valeri N Nesterov, Nicolay G Krouchinsky, Valdislav A Ostapenko, Gilles Vergnaud, F Giraudeau, J Buard, Alec John JeffreysAbstract:Analysis of Germline Mutation rate at human minisatellites among children born in areas of the Mogilev district of Belarus heavily polluted after the Chernobyl accident has been extended, both by recruiting more families from the affected region and by using five additional minisatellite probes, including multi-locus probe 33.6 and four hypervariable single-locus probes. These additional data confirmed a twofold higher Mutation rate in exposed families compared with non-irradiated families from the United Kingdom. An elevated rate was seen at all three independent sets of minisatellites (detected separately by multi-locus probes 33.15, 33.6 and six single-locus probes), indicating a generalised increase in minisatellite Germline Mutation rate in the Belarus families. Within the Belarus cohort, Mutation rate was significantly greater in families with higher parental radiation dose estimated for chronic external and internal exposure to caesium-137, consistent with radiation induction of Germline Mutation. The spectra of Mutation seen in the unexposed and exposed families were indistinguishable, suggesting that increased Mutation observed over multiple loci arises indirectly by some mechanism that enhances spontaneous minisatellite Mutation.
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human minisatellite Mutation rate after the chernobyl accident
Nature, 1996Co-Authors: Rita Neumann, Valeri N Nesterov, Nicolay G Krouchinsky, Valdislav A Ostapenko, Yuri E Dubrova, David L Neil, Alec John JeffreysAbstract:Germline Mutation at human minisatellite loci has been studied among children born in heavily polluted areas of the Mogilev district of Belarus after the Chernobyl accident and in a control population. The frequency of Mutation was found to be twice as high in the exposed families as in the control group. Mutation rate in the Mogilev families was correlated with the level of caesium-137 surface contamination, consistent with radiation induction of Germline Mutation.
Henry T Lynch - One of the best experts on this subject based on the ideXlab platform.
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phenotypic variation in eight extended cdkn2a Germline Mutation familial atypical multiple mole melanoma pancreatic carcinoma prone families the familial atypical multiple mole melanoma pancreatic carcinoma syndrome
American Society of Clinical Oncology annual meeting, 2002Co-Authors: Henry T Lynch, Randall E Brand, David W Hogg, Carolyn A Deters, Ramon M Fusaro, Jane F Lynch, Ling Liu, Joseph Knezetic, Norman J Lassam, Michael GogginsAbstract:BACKGROUND. Hereditary pancreatic carcinoma shows extant phenotypic and genotypic heterogeneity as evidenced by its integral association with a variety of hereditary cancer syndromes inclusive of the familial atypical multiple mole melanoma (FAMMM) syndrome in concert with CDKN2A (p16) Germline Mutations. METHODS. Creighton University's familial pancreatic carcinoma resource comprises 159 families of which 19 (12%) show the FAMMM cutaneous phenotypes. The authors describe eight families with the FAMMM-pancreatic carcinoma (FAMMM-PC) association in concert with a CDKN2A Germline Mutation. Each family was thoroughly educated about all facets of the study, including the molecular genetics reduced penetrance of CDKN2A Mutations, and their variable expressivity. Genetic counseling was provided to each patient. RESULTS. Diversity in cancer presentation within and among the families was noteworthy, wherein melanoma predominated in certain of the families whereas pancreatic carcinoma predominated in others. Early-onset pancreatic carcinoma (at ages 35, 45, 46, and 49 years) appeared in some of the families whereas markedly later-onset pancreatic carcinoma occurred in others. There were four incidences of melanoma and pancreatic carcinoma as double primaries in the same individuals. One patient with melanoma and pancreatic carcinoma had a third primary of breast carcinoma. Another patient had sarcoma, esophageal carcinoma, and two melanoma primaries, whereas his daughter had sarcoma and was a carrier of a CDKN2A Mutation. CONCLUSIONS. The authors suggest that these tumors may collectively, in concert with CDKN2A Mutations, constitute a new putative hereditary carcinoma syndrome referred to as FAMMM-PC. More clinical and molecular genetic research on additional families with pancreatic carcinoma in concert with the FAMMM will be required.
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phenotypic variation in eight extended cdkn2a Germline Mutation familial atypical multiple mole melanoma pancreatic carcinoma prone families the familial atypical multiple mole melanoma pancreatic carcinoma syndrome
Cancer, 2002Co-Authors: Henry T Lynch, Randall E Brand, David W Hogg, Carolyn A Deters, Ramon M Fusaro, Jane F Lynch, Ling Liu, Joseph Knezetic, Norman J Lassam, Michael GogginsAbstract:BACKGROUND Hereditary pancreatic carcinoma shows extant phenotypic and genotypic heterogeneity as evidenced by its integral association with a variety of hereditary cancer syndromes inclusive of the familial atypical multiple mole melanoma (FAMMM) syndrome in concert with CDKN2A (p16) Germline Mutations. METHODS Creighton University's familial pancreatic carcinoma resource comprises 159 families of which 19 (12%) show the FAMMM cutaneous phenotypes. The authors describe eight families with the FAMMM–pancreatic carcinoma (FAMMM-PC) association in concert with a CDKN2A Germline Mutation. Each family was thoroughly educated about all facets of the study, including the molecular genetics, reduced penetrance of CDKN2A Mutations, and their variable expressivity. Genetic counseling was provided to each patient. RESULTS Diversity in cancer presentation within and among the families was noteworthy, wherein melanoma predominated in certain of the families whereas pancreatic carcinoma predominated in others. Early-onset pancreatic carcinoma (at ages 35, 45, 46, and 49 years) appeared in some of the families whereas markedly later-onset pancreatic carcinoma occurred in others. There were four incidences of melanoma and pancreatic carcinoma as double primaries in the same individuals. One patient with melanoma and pancreatic carcinoma had a third primary of breast carcinoma. Another patient had sarcoma, esophageal carcinoma, and two melanoma primaries, whereas his daughter had sarcoma and was a carrier of a CDKN2A Mutation. CONCLUSIONS The authors suggest that these tumors may collectively, in concert with CDKN2A Mutations, constitute a “new” putative hereditary carcinoma syndrome referred to as FAMMM-PC. More clinical and molecular genetic research on additional families with pancreatic carcinoma in concert with the FAMMM will be required. Cancer 2002;94:84–96. © 2002 American Cancer Society.