The Experts below are selected from a list of 10950 Experts worldwide ranked by ideXlab platform

Barbara Wappenschmidt - One of the best experts on this subject based on the ideXlab platform.

  • A genetic variant in the pre-miR-27a oncogene is associated with a reduced Familial Breast Cancer risk
    Breast Cancer Research and Treatment, 2009
    Co-Authors: Rongxi Yang, Kari Hemminki, Christian Sutter, Barbara Wappenschmidt, Bernhard H. F. Weber, Peter Bugert, B. Schlehe, Juliane Volkmann, Raymonda Varon, Dieter Niederacher
    Abstract:

    MicroRNAs (miRNAs) regulate pathways involved in cell differentiation, proliferation, development, and apoptosis by degradation of target mRNAs and/or repression of their translation. Although the single nucleotide polymorphisms (SNPs) in miRNAs target sites have been studied, the effects of SNPs in miRNAs are largely unknown. In our study, we first systematically sequenced miRNA genes reported to be involved in Breast Cancer to identify/verify SNPs. We analyzed four SNPs, one located in the pre-miRNA and the other three located in miRNA flanking regions, for a putative association with Breast Cancer risk. The SNP rs895819, located in the terminal loop of pre-miRNA-27a, showed a protective effect. In a large Familial Breast Cancer study cohort, the rare [G] allele of rs895819 was found to be less frequent in the cases than in the controls, indicating a reduced Familial Breast Cancer risk ([G] vs. [A]: OR = 0.88, 95% CI 0.78-0.99, = 0.0287). Furthermore, age stratification revealed that the protective effect was mainly observed in the age group 

  • A genetic variant in the pre-miR-27a oncogene is associated with a reduced Familial Breast Cancer risk
    Breast cancer research and treatment, 2009
    Co-Authors: Rongxi Yang, Kari Hemminki, Christian Sutter, Barbara Wappenschmidt, Bernhard H. F. Weber, Peter Bugert, B. Schlehe, Juliane Volkmann, Raymonda Varon, Dieter Niederacher
    Abstract:

    MicroRNAs (miRNAs) regulate pathways involved in cell differentiation, proliferation, development, and apoptosis by degradation of target mRNAs and/or repression of their translation. Although the single nucleotide polymorphisms (SNPs) in miRNAs target sites have been studied, the effects of SNPs in miRNAs are largely unknown. In our study, we first systematically sequenced miRNA genes reported to be involved in Breast Cancer to identify/verify SNPs. We analyzed four SNPs, one located in the pre-miRNA and the other three located in miRNA flanking regions, for a putative association with Breast Cancer risk. The SNP rs895819, located in the terminal loop of pre-miRNA-27a, showed a protective effect. In a large Familial Breast Cancer study cohort, the rare [G] allele of rs895819 was found to be less frequent in the cases than in the controls, indicating a reduced Familial Breast Cancer risk ([G] vs. [A]: OR = 0.88, 95% CI 0.78–0.99, P = 0.0287). Furthermore, age stratification revealed that the protective effect was mainly observed in the age group < 50 years of age ([G] vs. [A]: OR = 0.83, 95% CI 0.70–0.98, P = 0.0314), whereas no significant effect was observed in the age group ≥ 50 years of age, indicating a possible hormone-related effect. It has been shown that artificial mutations in the terminal loop of miR-27a can block the maturation process of the miRNA. We hypothesize that the G-variant of rs895819 might impair the maturation of the oncogenic miR-27a and thus, is associated with Familial Breast Cancer risk.

  • SNPs in ultraconserved elements and Familial Breast Cancer risk.
    Carcinogenesis, 2008
    Co-Authors: Rongxi Yang, Kari Hemminki, Christian Sutter, Rita K. Schmutzler, Barbara Wappenschmidt, Marion Kiechle, Bernd Frank, Peter Bugert, Claus R. Bartram, Norbert Arnold
    Abstract:

    Ultraconserved elements (UCEs) are segments of >200 bp length showing absolute sequence identity between orthologous regions of human, rat and mouse genomes. The selection factors acting on these UCEs are still unknown. Recent studies have shown that UCEs function as long-range enhancers of flanking genes or are involved in splicing when overlapping with exons. The depletion of UCEs among copy number variation as well as the significant under-representation of single-nucleotide polymorphisms (SNPs) within UCEs have also revealed their evolutional and functional importance indicating their potential impact on disease, such as Cancer. In the present study, we investigated the influence of six SNPs within UCEs on Familial Breast Cancer risk. Two out of six SNPs showed an association with Familial Breast Cancer risk. Whereas rs9572903 showed only a borderline significant association, the frequency of the rare [G] allele of rs2056116 was higher in cases than in controls indicating an increased Familial Breast Cancer risk ([G] versus [A]: odds ratio (OR) = 1.18, 95% confidence interval (CI) 1.06-1.30, P = 0.0020; [GG] versus [AA]: OR = 1.41, 95% CI 1.15-1.74, P = 0.0011). Interestingly, comparing with the older age group, the ORs were increased in woman younger than 50 years of age ([G] versus [A]: OR = 1.27, 95% CI 1.11-1.45, P = 0.0005; [GG] versus [AA]: OR = 1.60, 95% CI 1.22-2.10, P = 0.0007) pointing to an age- or hormone-related effect. This is the first study indicating that SNPs in UCEs might be associated with Cancer risk.

  • The functional genetic variant Ile646Val located in the kinase binding domain of the A-kinase anchoring protein 10 is associated with Familial Breast Cancer.
    Carcinogenesis, 2006
    Co-Authors: Michael Wirtenberger, Kari Hemminki, Julia Schmutzhard, Christian Sutter, Rita K. Schmutzler, Alfons Meindl, Barbara Wappenschmidt, Marion Kiechle, Norbert Arnold, Bernhard H. F. Weber
    Abstract:

    Overexpression of cAMP-dependent protein kinase A (PKA) is a hallmark of the great majority of human Cancers including Breast Cancer. A-kinase anchoring proteins (AKAPs) coordinate the specificity of PKA signalling by localizing the kinase to its subcellular sites. We tested the hypothesis whether the functional amino acid exchange Ile646Val, located in the kinase-binding domain of AKAP10, is a low-penetrance Familial Breast Cancer risk factor. Ile646Val alters the binding of AKAP10 to PKA and is associated with morbidity. The analysis of 787 BRCA1/2 mutation-negative Familial Breast Cancer patients and 993 controls revealed an association of the AKAP10 Ile646Val polymorphism with increased Familial Breast Cancer risk [odds ratio (OR)=1.25, 95% confidence interval (CI) 1.03-1.51, P=0.024]. Our previous study has shown that AKAP13 Lys526Gln is associated with Familial Breast Cancer (OR=1.58). Here, we discovered that carriers of both variants, AKAP10 Ile646Val and AKAP13 Lys526Gln, are at a further enhanced Breast Cancer risk (OR=2.41, 95% CI 1.30-4.46, P=0.005). PKA is a major target of therapeutic antiCancer strategies. Phosphorylation of the estrogen receptor (ER) alpha by PKA induces resistance against the anti-estrogen tamoxifen. Our results indicate for the first time the importance of AKAP10 Ile646Val for Familial Breast Cancer susceptibility. Due to the impact of Ile646Val on the subcellular localization of PKA, it will be interesting to investigate whether this polymorphism influences the effectiveness of PKA and tamoxifen based therapeutic antiCancer concepts.

  • Aurora kinases A and B and Familial Breast Cancer risk.
    Cancer letters, 2006
    Co-Authors: Sandrine Tchatchou, Michael Wirtenberger, Kari Hemminki, Christian Sutter, Rita K. Schmutzler, Alfons Meindl, Barbara Wappenschmidt, Marion Kiechle, Peter Bugert, Claus R. Bartram
    Abstract:

    Aurora genes play a crucial role in tumourigenesis and are overexpressed in many kinds of Cancers. We investigated whether coding variants within the Aurora genes are associated with Familial Breast Cancer risk. While AURKA Phe31Ile (1712T>A) and AURKB Thr298Met (893G>A) showed no association, the synonymous AURKB Ser295Ser (885A>G) polymorphism resulted in an increased Breast Cancer risk for carriers of the homozygous 885G genotype (OR=1.45, 95% CI=1.05-2.0, P=0.02). Due to the impact of aurora kinases in the loss of chromosomal integrity during carcinogenesis, this variant may also influence the therapy outcome in Breast Cancer.

Kari Hemminki - One of the best experts on this subject based on the ideXlab platform.

  • A genetic variant in the pre-miR-27a oncogene is associated with a reduced Familial Breast Cancer risk
    Breast Cancer Research and Treatment, 2009
    Co-Authors: Rongxi Yang, Kari Hemminki, Christian Sutter, Barbara Wappenschmidt, Bernhard H. F. Weber, Peter Bugert, B. Schlehe, Juliane Volkmann, Raymonda Varon, Dieter Niederacher
    Abstract:

    MicroRNAs (miRNAs) regulate pathways involved in cell differentiation, proliferation, development, and apoptosis by degradation of target mRNAs and/or repression of their translation. Although the single nucleotide polymorphisms (SNPs) in miRNAs target sites have been studied, the effects of SNPs in miRNAs are largely unknown. In our study, we first systematically sequenced miRNA genes reported to be involved in Breast Cancer to identify/verify SNPs. We analyzed four SNPs, one located in the pre-miRNA and the other three located in miRNA flanking regions, for a putative association with Breast Cancer risk. The SNP rs895819, located in the terminal loop of pre-miRNA-27a, showed a protective effect. In a large Familial Breast Cancer study cohort, the rare [G] allele of rs895819 was found to be less frequent in the cases than in the controls, indicating a reduced Familial Breast Cancer risk ([G] vs. [A]: OR = 0.88, 95% CI 0.78-0.99, = 0.0287). Furthermore, age stratification revealed that the protective effect was mainly observed in the age group 

  • A genetic variant in the pre-miR-27a oncogene is associated with a reduced Familial Breast Cancer risk
    Breast cancer research and treatment, 2009
    Co-Authors: Rongxi Yang, Kari Hemminki, Christian Sutter, Barbara Wappenschmidt, Bernhard H. F. Weber, Peter Bugert, B. Schlehe, Juliane Volkmann, Raymonda Varon, Dieter Niederacher
    Abstract:

    MicroRNAs (miRNAs) regulate pathways involved in cell differentiation, proliferation, development, and apoptosis by degradation of target mRNAs and/or repression of their translation. Although the single nucleotide polymorphisms (SNPs) in miRNAs target sites have been studied, the effects of SNPs in miRNAs are largely unknown. In our study, we first systematically sequenced miRNA genes reported to be involved in Breast Cancer to identify/verify SNPs. We analyzed four SNPs, one located in the pre-miRNA and the other three located in miRNA flanking regions, for a putative association with Breast Cancer risk. The SNP rs895819, located in the terminal loop of pre-miRNA-27a, showed a protective effect. In a large Familial Breast Cancer study cohort, the rare [G] allele of rs895819 was found to be less frequent in the cases than in the controls, indicating a reduced Familial Breast Cancer risk ([G] vs. [A]: OR = 0.88, 95% CI 0.78–0.99, P = 0.0287). Furthermore, age stratification revealed that the protective effect was mainly observed in the age group < 50 years of age ([G] vs. [A]: OR = 0.83, 95% CI 0.70–0.98, P = 0.0314), whereas no significant effect was observed in the age group ≥ 50 years of age, indicating a possible hormone-related effect. It has been shown that artificial mutations in the terminal loop of miR-27a can block the maturation process of the miRNA. We hypothesize that the G-variant of rs895819 might impair the maturation of the oncogenic miR-27a and thus, is associated with Familial Breast Cancer risk.

  • SNPs in ultraconserved elements and Familial Breast Cancer risk.
    Carcinogenesis, 2008
    Co-Authors: Rongxi Yang, Kari Hemminki, Christian Sutter, Rita K. Schmutzler, Barbara Wappenschmidt, Marion Kiechle, Bernd Frank, Peter Bugert, Claus R. Bartram, Norbert Arnold
    Abstract:

    Ultraconserved elements (UCEs) are segments of >200 bp length showing absolute sequence identity between orthologous regions of human, rat and mouse genomes. The selection factors acting on these UCEs are still unknown. Recent studies have shown that UCEs function as long-range enhancers of flanking genes or are involved in splicing when overlapping with exons. The depletion of UCEs among copy number variation as well as the significant under-representation of single-nucleotide polymorphisms (SNPs) within UCEs have also revealed their evolutional and functional importance indicating their potential impact on disease, such as Cancer. In the present study, we investigated the influence of six SNPs within UCEs on Familial Breast Cancer risk. Two out of six SNPs showed an association with Familial Breast Cancer risk. Whereas rs9572903 showed only a borderline significant association, the frequency of the rare [G] allele of rs2056116 was higher in cases than in controls indicating an increased Familial Breast Cancer risk ([G] versus [A]: odds ratio (OR) = 1.18, 95% confidence interval (CI) 1.06-1.30, P = 0.0020; [GG] versus [AA]: OR = 1.41, 95% CI 1.15-1.74, P = 0.0011). Interestingly, comparing with the older age group, the ORs were increased in woman younger than 50 years of age ([G] versus [A]: OR = 1.27, 95% CI 1.11-1.45, P = 0.0005; [GG] versus [AA]: OR = 1.60, 95% CI 1.22-2.10, P = 0.0007) pointing to an age- or hormone-related effect. This is the first study indicating that SNPs in UCEs might be associated with Cancer risk.

  • The functional genetic variant Ile646Val located in the kinase binding domain of the A-kinase anchoring protein 10 is associated with Familial Breast Cancer.
    Carcinogenesis, 2006
    Co-Authors: Michael Wirtenberger, Kari Hemminki, Julia Schmutzhard, Christian Sutter, Rita K. Schmutzler, Alfons Meindl, Barbara Wappenschmidt, Marion Kiechle, Norbert Arnold, Bernhard H. F. Weber
    Abstract:

    Overexpression of cAMP-dependent protein kinase A (PKA) is a hallmark of the great majority of human Cancers including Breast Cancer. A-kinase anchoring proteins (AKAPs) coordinate the specificity of PKA signalling by localizing the kinase to its subcellular sites. We tested the hypothesis whether the functional amino acid exchange Ile646Val, located in the kinase-binding domain of AKAP10, is a low-penetrance Familial Breast Cancer risk factor. Ile646Val alters the binding of AKAP10 to PKA and is associated with morbidity. The analysis of 787 BRCA1/2 mutation-negative Familial Breast Cancer patients and 993 controls revealed an association of the AKAP10 Ile646Val polymorphism with increased Familial Breast Cancer risk [odds ratio (OR)=1.25, 95% confidence interval (CI) 1.03-1.51, P=0.024]. Our previous study has shown that AKAP13 Lys526Gln is associated with Familial Breast Cancer (OR=1.58). Here, we discovered that carriers of both variants, AKAP10 Ile646Val and AKAP13 Lys526Gln, are at a further enhanced Breast Cancer risk (OR=2.41, 95% CI 1.30-4.46, P=0.005). PKA is a major target of therapeutic antiCancer strategies. Phosphorylation of the estrogen receptor (ER) alpha by PKA induces resistance against the anti-estrogen tamoxifen. Our results indicate for the first time the importance of AKAP10 Ile646Val for Familial Breast Cancer susceptibility. Due to the impact of Ile646Val on the subcellular localization of PKA, it will be interesting to investigate whether this polymorphism influences the effectiveness of PKA and tamoxifen based therapeutic antiCancer concepts.

  • Aurora kinases A and B and Familial Breast Cancer risk.
    Cancer letters, 2006
    Co-Authors: Sandrine Tchatchou, Michael Wirtenberger, Kari Hemminki, Christian Sutter, Rita K. Schmutzler, Alfons Meindl, Barbara Wappenschmidt, Marion Kiechle, Peter Bugert, Claus R. Bartram
    Abstract:

    Aurora genes play a crucial role in tumourigenesis and are overexpressed in many kinds of Cancers. We investigated whether coding variants within the Aurora genes are associated with Familial Breast Cancer risk. While AURKA Phe31Ile (1712T>A) and AURKB Thr298Met (893G>A) showed no association, the synonymous AURKB Ser295Ser (885A>G) polymorphism resulted in an increased Breast Cancer risk for carriers of the homozygous 885G genotype (OR=1.45, 95% CI=1.05-2.0, P=0.02). Due to the impact of aurora kinases in the loss of chromosomal integrity during carcinogenesis, this variant may also influence the therapy outcome in Breast Cancer.

Rita K. Schmutzler - One of the best experts on this subject based on the ideXlab platform.

  • SNPs in ultraconserved elements and Familial Breast Cancer risk.
    Carcinogenesis, 2008
    Co-Authors: Rongxi Yang, Kari Hemminki, Christian Sutter, Rita K. Schmutzler, Barbara Wappenschmidt, Marion Kiechle, Bernd Frank, Peter Bugert, Claus R. Bartram, Norbert Arnold
    Abstract:

    Ultraconserved elements (UCEs) are segments of >200 bp length showing absolute sequence identity between orthologous regions of human, rat and mouse genomes. The selection factors acting on these UCEs are still unknown. Recent studies have shown that UCEs function as long-range enhancers of flanking genes or are involved in splicing when overlapping with exons. The depletion of UCEs among copy number variation as well as the significant under-representation of single-nucleotide polymorphisms (SNPs) within UCEs have also revealed their evolutional and functional importance indicating their potential impact on disease, such as Cancer. In the present study, we investigated the influence of six SNPs within UCEs on Familial Breast Cancer risk. Two out of six SNPs showed an association with Familial Breast Cancer risk. Whereas rs9572903 showed only a borderline significant association, the frequency of the rare [G] allele of rs2056116 was higher in cases than in controls indicating an increased Familial Breast Cancer risk ([G] versus [A]: odds ratio (OR) = 1.18, 95% confidence interval (CI) 1.06-1.30, P = 0.0020; [GG] versus [AA]: OR = 1.41, 95% CI 1.15-1.74, P = 0.0011). Interestingly, comparing with the older age group, the ORs were increased in woman younger than 50 years of age ([G] versus [A]: OR = 1.27, 95% CI 1.11-1.45, P = 0.0005; [GG] versus [AA]: OR = 1.60, 95% CI 1.22-2.10, P = 0.0007) pointing to an age- or hormone-related effect. This is the first study indicating that SNPs in UCEs might be associated with Cancer risk.

  • The functional genetic variant Ile646Val located in the kinase binding domain of the A-kinase anchoring protein 10 is associated with Familial Breast Cancer.
    Carcinogenesis, 2006
    Co-Authors: Michael Wirtenberger, Kari Hemminki, Julia Schmutzhard, Christian Sutter, Rita K. Schmutzler, Alfons Meindl, Barbara Wappenschmidt, Marion Kiechle, Norbert Arnold, Bernhard H. F. Weber
    Abstract:

    Overexpression of cAMP-dependent protein kinase A (PKA) is a hallmark of the great majority of human Cancers including Breast Cancer. A-kinase anchoring proteins (AKAPs) coordinate the specificity of PKA signalling by localizing the kinase to its subcellular sites. We tested the hypothesis whether the functional amino acid exchange Ile646Val, located in the kinase-binding domain of AKAP10, is a low-penetrance Familial Breast Cancer risk factor. Ile646Val alters the binding of AKAP10 to PKA and is associated with morbidity. The analysis of 787 BRCA1/2 mutation-negative Familial Breast Cancer patients and 993 controls revealed an association of the AKAP10 Ile646Val polymorphism with increased Familial Breast Cancer risk [odds ratio (OR)=1.25, 95% confidence interval (CI) 1.03-1.51, P=0.024]. Our previous study has shown that AKAP13 Lys526Gln is associated with Familial Breast Cancer (OR=1.58). Here, we discovered that carriers of both variants, AKAP10 Ile646Val and AKAP13 Lys526Gln, are at a further enhanced Breast Cancer risk (OR=2.41, 95% CI 1.30-4.46, P=0.005). PKA is a major target of therapeutic antiCancer strategies. Phosphorylation of the estrogen receptor (ER) alpha by PKA induces resistance against the anti-estrogen tamoxifen. Our results indicate for the first time the importance of AKAP10 Ile646Val for Familial Breast Cancer susceptibility. Due to the impact of Ile646Val on the subcellular localization of PKA, it will be interesting to investigate whether this polymorphism influences the effectiveness of PKA and tamoxifen based therapeutic antiCancer concepts.

  • Aurora kinases A and B and Familial Breast Cancer risk.
    Cancer letters, 2006
    Co-Authors: Sandrine Tchatchou, Michael Wirtenberger, Kari Hemminki, Christian Sutter, Rita K. Schmutzler, Alfons Meindl, Barbara Wappenschmidt, Marion Kiechle, Peter Bugert, Claus R. Bartram
    Abstract:

    Aurora genes play a crucial role in tumourigenesis and are overexpressed in many kinds of Cancers. We investigated whether coding variants within the Aurora genes are associated with Familial Breast Cancer risk. While AURKA Phe31Ile (1712T>A) and AURKB Thr298Met (893G>A) showed no association, the synonymous AURKB Ser295Ser (885A>G) polymorphism resulted in an increased Breast Cancer risk for carriers of the homozygous 885G genotype (OR=1.45, 95% CI=1.05-2.0, P=0.02). Due to the impact of aurora kinases in the loss of chromosomal integrity during carcinogenesis, this variant may also influence the therapy outcome in Breast Cancer.

  • Associations of genetic variants in the estrogen receptor coactivators PPARGC1A, PPARGC1B and EP300 with Familial Breast Cancer
    Carcinogenesis, 2006
    Co-Authors: Michael Wirtenberger, Sandrine Tchatchou, Kari Hemminki, Julia Schmutzhard, Christian Sutter, Rita K. Schmutzler, Alfons Meindl, Barbara Wappenschmidt, Marion Kiechle, Norbert Arnold
    Abstract:

    The mitogen effect of the ovarian steroid estrogen is a strong risk factor for Breast Cancer development. This effect is mainly mediated by the estrogen receptor alpha, a hormone inducible transcription factor, which activates gene expression through recruiting multiple coactivators, such as PPARGC1A, PPARGC1B and EP300. We tested the hypothesis that non-conservative, putative functional amino acid exchanges in PPARGC1A, PPARGC1B and EP300 act as low-penetrance Familial Breast Cancer risk factors. The analysis of 816 BRCA1/2 mutation-negative Familial Breast Cancer patients and 1012 controls revealed an association of the PPARGC1A Thr612Met polymorphism with Familial Breast Cancer (OR = 1.35, 95% CI 1.00-1.81, P = 0.049), high-risk Familial Breast Cancer (OR = 1.51, 95% CI 1.08-2.12, P = 0.017) and bilateral Familial Breast Cancer (OR = 2.30, 95% CI 1.24-4.28, P = 0.009). Logistic regression analyses of the PPARGC1B Ala203Pro variant showed an increased Familial Breast Cancer risk of heterozygous and homozygous variant allele carriers (OR = 1.48, 95% CI 1.15-1.91, P = 0.002). The genotype-combination analysis of the associated PPARGC1A Thr612Met variant and the associated PPARGC1B Ala203Pro variant suggests an allele dose-dependent Breast Cancer risk (P(trend) = 0.0004). Our results indicate for the first time the importance of inherited variants in the estrogen receptor coactivator genes PPARGC1A and PPARGC1B for Familial Breast Cancer susceptibility. Owing to their impact on estrogen signaling, these polymorphisms might also influence adjuvant anti-estrogen therapy, using agents such as tamoxifen and raloxifen, and outcome of Breast Cancer patients.

  • Interaction of Werner and Bloom syndrome genes with p53 in Familial Breast Cancer.
    Carcinogenesis, 2006
    Co-Authors: Michael Wirtenberger, Kari Hemminki, Rita K. Schmutzler, Alfons Meindl, Barbara Wappenschmidt, Marion Kiechle, Norbert Arnold, Bernd Frank, Riidiger Klaes, Bernhard H. F. Weber
    Abstract:

    Mutations of the human RecQ helicase genes WRN and BLM lead to rare autosomal recessive disorders, Werner and Bloom syndromes, which are associated with premature ageing and Cancer predisposition. We tested the hypothesis whether three polymorphic, non-conservative amino acid exchanges in WRN and BLM act as low-penetrance Familial Breast Cancer risk factors. Moreover, we examined the putative impact of p53 MspI 1798G>A, which is completely linked to p53PIN3, a 16 bp insertion/duplication that has been associated with reduced p53 expression, on Familial Breast Cancer risk. Genotyping analyses, performed on 816 BRCA1/2 mutation-negative German Familial Breast Cancer patients and 1012 German controls, revealed a significant association of the WRN Cys1367Arg polymorphism with Familial Breast Cancer (OR = 1.28, 95% CI 1.06-1.54) and high-risk Familial Breast Cancer (OR = 1.32, 95% CI 1.06-1.65). The analysis of p53 MspI 1798G>A, which is completely linked to p53PIN3, showed a significantly increased Familial Breast Cancer risk for carriers of the 16 bp insertion/duplication, following a recessive mode (OR = 2.15, 95% CI = 1.12-4.11). WRN Cys1367Arg, located in the C-terminus, the binding site of p53, is predicted to be damaging. The joint effect of WRN Cys1367Arg and p53 MspI resulted in an increased Breast Cancer risk compared to the single polymorphisms (OR = 3.39, 95% CI 1.19-9.71). In conclusion, our study indicates the importance of inherited variants in the WRN and p53 genes for Familial Breast Cancer susceptibility.

Claus R. Bartram - One of the best experts on this subject based on the ideXlab platform.

  • SNPs in ultraconserved elements and Familial Breast Cancer risk.
    Carcinogenesis, 2008
    Co-Authors: Rongxi Yang, Kari Hemminki, Christian Sutter, Rita K. Schmutzler, Barbara Wappenschmidt, Marion Kiechle, Bernd Frank, Peter Bugert, Claus R. Bartram, Norbert Arnold
    Abstract:

    Ultraconserved elements (UCEs) are segments of >200 bp length showing absolute sequence identity between orthologous regions of human, rat and mouse genomes. The selection factors acting on these UCEs are still unknown. Recent studies have shown that UCEs function as long-range enhancers of flanking genes or are involved in splicing when overlapping with exons. The depletion of UCEs among copy number variation as well as the significant under-representation of single-nucleotide polymorphisms (SNPs) within UCEs have also revealed their evolutional and functional importance indicating their potential impact on disease, such as Cancer. In the present study, we investigated the influence of six SNPs within UCEs on Familial Breast Cancer risk. Two out of six SNPs showed an association with Familial Breast Cancer risk. Whereas rs9572903 showed only a borderline significant association, the frequency of the rare [G] allele of rs2056116 was higher in cases than in controls indicating an increased Familial Breast Cancer risk ([G] versus [A]: odds ratio (OR) = 1.18, 95% confidence interval (CI) 1.06-1.30, P = 0.0020; [GG] versus [AA]: OR = 1.41, 95% CI 1.15-1.74, P = 0.0011). Interestingly, comparing with the older age group, the ORs were increased in woman younger than 50 years of age ([G] versus [A]: OR = 1.27, 95% CI 1.11-1.45, P = 0.0005; [GG] versus [AA]: OR = 1.60, 95% CI 1.22-2.10, P = 0.0007) pointing to an age- or hormone-related effect. This is the first study indicating that SNPs in UCEs might be associated with Cancer risk.

  • Aurora kinases A and B and Familial Breast Cancer risk.
    Cancer letters, 2006
    Co-Authors: Sandrine Tchatchou, Michael Wirtenberger, Kari Hemminki, Christian Sutter, Rita K. Schmutzler, Alfons Meindl, Barbara Wappenschmidt, Marion Kiechle, Peter Bugert, Claus R. Bartram
    Abstract:

    Aurora genes play a crucial role in tumourigenesis and are overexpressed in many kinds of Cancers. We investigated whether coding variants within the Aurora genes are associated with Familial Breast Cancer risk. While AURKA Phe31Ile (1712T>A) and AURKB Thr298Met (893G>A) showed no association, the synonymous AURKB Ser295Ser (885A>G) polymorphism resulted in an increased Breast Cancer risk for carriers of the homozygous 885G genotype (OR=1.45, 95% CI=1.05-2.0, P=0.02). Due to the impact of aurora kinases in the loss of chromosomal integrity during carcinogenesis, this variant may also influence the therapy outcome in Breast Cancer.

  • The single nucleotide polymorphism IVS1+309 in mouse double minute 2 does not affect risk of Familial Breast Cancer.
    Cancer research, 2006
    Co-Authors: Stefan Wilkening, Rita K. Schmutzler, Alfons Meindl, Barbara Wappenschmidt, Justo Lorenzo Bermejo, Peter Bugert, Claus R. Bartram, Barbara Burwinkel, Rüdiger Klaes, Michael Untch
    Abstract:

    The mouse double minute 2 (MDM2) oncoprotein promotes cell survival and cell cycle progression by inhibiting the p53 tumor suppressor protein. Further, MDM2 overexpression can inhibit DNA double-strand break repair in a p53-independent manner. Recently, it was shown that a single nucleotide polymorphism (SNP) in the MDM2 promoter was associated with an accelerated tumor formation in individuals with a p53 mutation. The present case-control study investigated the association of this SNP (IVS1+309) with the risk and the age of onset of Familial Breast Cancer in patients with unknown p53 mutation status. Data from 549 women affected by Familial Breast Cancer and 1,065 healthy controls were analyzed. The cases did not carry BRCA1/2 mutations. Cases and controls showed a similar genotype distribution and the SNP did not seem to modify the age of onset of Familial Breast Cancer. The data were also examined taking into account the presence of any additional Cancer after Breast Cancer and the family history of cases; however, no association was found. These results suggest that the SNP IVS1+309 alone affects neither the risk nor the age of onset of heritable Breast Cancer.

  • Association of genetic variants in the Rho guanine nucleotide exchange factor AKAP13 with Familial Breast Cancer.
    Carcinogenesis, 2005
    Co-Authors: Michael Wirtenberger, Sandrine Tchatchou, Kari Hemminki, Rita K. Schmutzler, Alfons Meindl, Barbara Wappenschmidt, Riidiger Klaes, Justo Lorenzo Bermejo, Bowang Chen, Claus R. Bartram
    Abstract:

    The A-kinase anchor protein 13 (AKAP13, alias BRX and lbc) tethers cAMP-dependent protein kinase to its subcellular environment and catalyses Rho GTPases activity as a guanine nucleotide exchange factor. The crucial role of members of the Rho family of GTPases in carcinogenesis is well established and targeting Rho proteins with antineoplastic compounds has become a major effort in the fight against Cancer. Thus, genetic alterations within the candidate Cancer susceptibility gene AKAP13 would be expected to provoke a constitutive Rho signalling, thereby facilitating the development of Cancer. Here, we analysed the potential impact of four polymorphic non-conservative amino acid exchanges (Arg494Trp, Lys526Gln, Asn1086Asp and Gly2461Ser) in AKAP13 on Familial Breast Cancer. We performed a case-control study using genomic DNA of BRCA1/2 mutation-negative German female index patients from 601 unrelated families, among a subset of 356 high-risk families, and 1053 German female unrelated controls. The newfound Lys526Gln polymorphism revealed a significant association with Familial Breast Cancer (OR = 1.58, 95% CI = 1.07-2.35) and an even stronger association with high-risk Familial Breast Cancer (OR = 1.85, 95% CI = 1.19-2.88). Haplotype analyses were in line with genotype results displaying a similar significance as analyses of individual polymorphisms. Due to the pivotal role of AKAP13 in the Rho GTPases signalling network, this variant might affect the susceptibility to other Cancers as well.

  • The rare ERBB2 variant Ile654Val is associated with an increased Familial Breast Cancer risk
    Breast Cancer Research, 2005
    Co-Authors: Bernd Frank, Michael Wirtenberger, Kari Hemminki, Rita K. Schmutzler, Barbara Wappenschmidt, Riidiger Klaes, Justo Lorenzo Bermejo, Peter Bugert, Claus R. Bartram, Barbara Burwinkel
    Abstract:

    Overexpression of the proto-oncogene ERBB2 (HER2/NEU) has been observed in 20-30 % of Breast Cancers involving poor prognosis. Genetic alterations within ERBB2 have been shown to induce carcinogenesis and metastasis. We tested eight annotated single nucleotide polymorphisms for occurrence in Familial Breast Cancer samples. The confirmed variants Ile654Val, Ile655Val and Ala1170Pro were analysed in subsequent epidemiological studies on Familial Breast Cancer risk. While Ala1170Pro resides within a C-terminally located regulatory domain, both adjacent polymorphisms Ile654Val and Ile655Val are part of the transmembrane domain. The case-controls study analysing a cohort of 348 German Familial Breast Cancer cases and 960 corresponding controls showed no significant association of both Ile655Val (OR = 1.05, 95 % C.I. = 0.82-1.34, p = 0.728) and Ala1170Pro (OR = 0.94, 95 %

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  • The functional genetic variant Ile646Val located in the kinase binding domain of the A-kinase anchoring protein 10 is associated with Familial Breast Cancer.
    Carcinogenesis, 2006
    Co-Authors: Michael Wirtenberger, Kari Hemminki, Julia Schmutzhard, Christian Sutter, Rita K. Schmutzler, Alfons Meindl, Barbara Wappenschmidt, Marion Kiechle, Norbert Arnold, Bernhard H. F. Weber
    Abstract:

    Overexpression of cAMP-dependent protein kinase A (PKA) is a hallmark of the great majority of human Cancers including Breast Cancer. A-kinase anchoring proteins (AKAPs) coordinate the specificity of PKA signalling by localizing the kinase to its subcellular sites. We tested the hypothesis whether the functional amino acid exchange Ile646Val, located in the kinase-binding domain of AKAP10, is a low-penetrance Familial Breast Cancer risk factor. Ile646Val alters the binding of AKAP10 to PKA and is associated with morbidity. The analysis of 787 BRCA1/2 mutation-negative Familial Breast Cancer patients and 993 controls revealed an association of the AKAP10 Ile646Val polymorphism with increased Familial Breast Cancer risk [odds ratio (OR)=1.25, 95% confidence interval (CI) 1.03-1.51, P=0.024]. Our previous study has shown that AKAP13 Lys526Gln is associated with Familial Breast Cancer (OR=1.58). Here, we discovered that carriers of both variants, AKAP10 Ile646Val and AKAP13 Lys526Gln, are at a further enhanced Breast Cancer risk (OR=2.41, 95% CI 1.30-4.46, P=0.005). PKA is a major target of therapeutic antiCancer strategies. Phosphorylation of the estrogen receptor (ER) alpha by PKA induces resistance against the anti-estrogen tamoxifen. Our results indicate for the first time the importance of AKAP10 Ile646Val for Familial Breast Cancer susceptibility. Due to the impact of Ile646Val on the subcellular localization of PKA, it will be interesting to investigate whether this polymorphism influences the effectiveness of PKA and tamoxifen based therapeutic antiCancer concepts.

  • Aurora kinases A and B and Familial Breast Cancer risk.
    Cancer letters, 2006
    Co-Authors: Sandrine Tchatchou, Michael Wirtenberger, Kari Hemminki, Christian Sutter, Rita K. Schmutzler, Alfons Meindl, Barbara Wappenschmidt, Marion Kiechle, Peter Bugert, Claus R. Bartram
    Abstract:

    Aurora genes play a crucial role in tumourigenesis and are overexpressed in many kinds of Cancers. We investigated whether coding variants within the Aurora genes are associated with Familial Breast Cancer risk. While AURKA Phe31Ile (1712T>A) and AURKB Thr298Met (893G>A) showed no association, the synonymous AURKB Ser295Ser (885A>G) polymorphism resulted in an increased Breast Cancer risk for carriers of the homozygous 885G genotype (OR=1.45, 95% CI=1.05-2.0, P=0.02). Due to the impact of aurora kinases in the loss of chromosomal integrity during carcinogenesis, this variant may also influence the therapy outcome in Breast Cancer.

  • Associations of genetic variants in the estrogen receptor coactivators PPARGC1A, PPARGC1B and EP300 with Familial Breast Cancer
    Carcinogenesis, 2006
    Co-Authors: Michael Wirtenberger, Sandrine Tchatchou, Kari Hemminki, Julia Schmutzhard, Christian Sutter, Rita K. Schmutzler, Alfons Meindl, Barbara Wappenschmidt, Marion Kiechle, Norbert Arnold
    Abstract:

    The mitogen effect of the ovarian steroid estrogen is a strong risk factor for Breast Cancer development. This effect is mainly mediated by the estrogen receptor alpha, a hormone inducible transcription factor, which activates gene expression through recruiting multiple coactivators, such as PPARGC1A, PPARGC1B and EP300. We tested the hypothesis that non-conservative, putative functional amino acid exchanges in PPARGC1A, PPARGC1B and EP300 act as low-penetrance Familial Breast Cancer risk factors. The analysis of 816 BRCA1/2 mutation-negative Familial Breast Cancer patients and 1012 controls revealed an association of the PPARGC1A Thr612Met polymorphism with Familial Breast Cancer (OR = 1.35, 95% CI 1.00-1.81, P = 0.049), high-risk Familial Breast Cancer (OR = 1.51, 95% CI 1.08-2.12, P = 0.017) and bilateral Familial Breast Cancer (OR = 2.30, 95% CI 1.24-4.28, P = 0.009). Logistic regression analyses of the PPARGC1B Ala203Pro variant showed an increased Familial Breast Cancer risk of heterozygous and homozygous variant allele carriers (OR = 1.48, 95% CI 1.15-1.91, P = 0.002). The genotype-combination analysis of the associated PPARGC1A Thr612Met variant and the associated PPARGC1B Ala203Pro variant suggests an allele dose-dependent Breast Cancer risk (P(trend) = 0.0004). Our results indicate for the first time the importance of inherited variants in the estrogen receptor coactivator genes PPARGC1A and PPARGC1B for Familial Breast Cancer susceptibility. Owing to their impact on estrogen signaling, these polymorphisms might also influence adjuvant anti-estrogen therapy, using agents such as tamoxifen and raloxifen, and outcome of Breast Cancer patients.

  • Interaction of Werner and Bloom syndrome genes with p53 in Familial Breast Cancer.
    Carcinogenesis, 2006
    Co-Authors: Michael Wirtenberger, Kari Hemminki, Rita K. Schmutzler, Alfons Meindl, Barbara Wappenschmidt, Marion Kiechle, Norbert Arnold, Bernd Frank, Riidiger Klaes, Bernhard H. F. Weber
    Abstract:

    Mutations of the human RecQ helicase genes WRN and BLM lead to rare autosomal recessive disorders, Werner and Bloom syndromes, which are associated with premature ageing and Cancer predisposition. We tested the hypothesis whether three polymorphic, non-conservative amino acid exchanges in WRN and BLM act as low-penetrance Familial Breast Cancer risk factors. Moreover, we examined the putative impact of p53 MspI 1798G>A, which is completely linked to p53PIN3, a 16 bp insertion/duplication that has been associated with reduced p53 expression, on Familial Breast Cancer risk. Genotyping analyses, performed on 816 BRCA1/2 mutation-negative German Familial Breast Cancer patients and 1012 German controls, revealed a significant association of the WRN Cys1367Arg polymorphism with Familial Breast Cancer (OR = 1.28, 95% CI 1.06-1.54) and high-risk Familial Breast Cancer (OR = 1.32, 95% CI 1.06-1.65). The analysis of p53 MspI 1798G>A, which is completely linked to p53PIN3, showed a significantly increased Familial Breast Cancer risk for carriers of the 16 bp insertion/duplication, following a recessive mode (OR = 2.15, 95% CI = 1.12-4.11). WRN Cys1367Arg, located in the C-terminus, the binding site of p53, is predicted to be damaging. The joint effect of WRN Cys1367Arg and p53 MspI resulted in an increased Breast Cancer risk compared to the single polymorphisms (OR = 3.39, 95% CI 1.19-9.71). In conclusion, our study indicates the importance of inherited variants in the WRN and p53 genes for Familial Breast Cancer susceptibility.

  • Association of genetic variants in the Rho guanine nucleotide exchange factor AKAP13 with Familial Breast Cancer.
    Carcinogenesis, 2005
    Co-Authors: Michael Wirtenberger, Sandrine Tchatchou, Kari Hemminki, Rita K. Schmutzler, Alfons Meindl, Barbara Wappenschmidt, Riidiger Klaes, Justo Lorenzo Bermejo, Bowang Chen, Claus R. Bartram
    Abstract:

    The A-kinase anchor protein 13 (AKAP13, alias BRX and lbc) tethers cAMP-dependent protein kinase to its subcellular environment and catalyses Rho GTPases activity as a guanine nucleotide exchange factor. The crucial role of members of the Rho family of GTPases in carcinogenesis is well established and targeting Rho proteins with antineoplastic compounds has become a major effort in the fight against Cancer. Thus, genetic alterations within the candidate Cancer susceptibility gene AKAP13 would be expected to provoke a constitutive Rho signalling, thereby facilitating the development of Cancer. Here, we analysed the potential impact of four polymorphic non-conservative amino acid exchanges (Arg494Trp, Lys526Gln, Asn1086Asp and Gly2461Ser) in AKAP13 on Familial Breast Cancer. We performed a case-control study using genomic DNA of BRCA1/2 mutation-negative German female index patients from 601 unrelated families, among a subset of 356 high-risk families, and 1053 German female unrelated controls. The newfound Lys526Gln polymorphism revealed a significant association with Familial Breast Cancer (OR = 1.58, 95% CI = 1.07-2.35) and an even stronger association with high-risk Familial Breast Cancer (OR = 1.85, 95% CI = 1.19-2.88). Haplotype analyses were in line with genotype results displaying a similar significance as analyses of individual polymorphisms. Due to the pivotal role of AKAP13 in the Rho GTPases signalling network, this variant might affect the susceptibility to other Cancers as well.