The Experts below are selected from a list of 33249 Experts worldwide ranked by ideXlab platform

Gunther Boysen - One of the best experts on this subject based on the ideXlab platform.

  • spop mutation leads to Genomic Instability in prostate cancer
    eLife, 2015
    Co-Authors: Gunther Boysen, Mirjam Blattner, Christopher E Barbieri, Sungsuk Chae, Srilakshmi Nataraj, Davide Prandi, Arun Dahija, Dennis Huang
    Abstract:

    Prostate cancer is the most common type of cancer in men in the UK and USA. Cancers develop when cells in the body acquire genetic mutations that allow the cells to grow rapidly and form a mass known as a tumor. Prostate cancer cells from different individuals can carry different genetic mutations, which affects whether the disease progresses and how the tumors respond to medical treatments. This genetic variety arises in cancer cells partly from a phenomenon known as Genomic Instability, in which DNA mutations accumulate due to defects in DNA repair. Genetic studies of biopsies taken from human prostate cancers have shown that Genomic Instability causes chromosomes—the structures in which the cell's DNA is organized—to break and then be stuck back together haphazardly. As a result, fragments of chromosomes can end up in the wrong position, be duplicated, or be lost altogether. All of these mutations could spur on the growth of the tumor. However, it is currently not clear why some prostate cancers are more Genomically unstable than others, or what exactly causes this Instability. Boysen, Barbieri et al. studied prostate cancer cells taken from patients before they started medical treatment. The experiments show that the cancer cells with high levels of Genomic Instability also often had mutations in a gene that encodes a protein called SPOP. These mutations occur in about 10 percent of men with prostate cancer and appear early in the development of the tumors. Next, they studied the SPOP protein in zebrafish (which is nearly identical to human SPOP), as well as in mouse and human cells. The experiments show that SPOP normally helps the cell to accurately repair DNA that has been damaged. Mutations in SPOP change the DNA repair process, which lead to Genomic Instability by increasing the likelihood that broken chromosomes will be stuck back together incorrectly. Further experiments tested drugs known as PARP inhibitors on mouse and human prostate cancer cells. The drugs, which have been recently tested successfully in patients with prostate cancer, block a different method of DNA repair that operates separately to the one that involves SPOP. When both of these pathways were inactivated—one by the SPOP mutation, the other by the drug—the cancer cells died more quickly. Therefore, men that are diagnosed with types of prostate cancer in which the gene that encodes SPOP is mutated might benefit from treatment with PARP inhibitors or other therapies that affect DNA repair.

  • abstract 1108 spop mutation leads to Genomic Instability in prostate cancer
    Cancer Research, 2015
    Co-Authors: Gunther Boysen, Mirjam Blattner, Christopher E Barbieri, Sungsuk Chae, Srilakshmi Nataraj, Davide Prandi, Clarisse Marotz, Paola Lecca, Sagar Chhangawala, Pengbo Zou
    Abstract:

    Background: Genomic Instability is a fundamental feature of human cancer, and DNA repair defects resulting in impaired genome maintenance promote pathogenesis of many types of cancers. In prostate cancer, structural Genomic rearrangements, including translocations and copy number aberrations, are a key mechanism driving tumorigenesis. Recently, whole genome sequencing revealed a striking abundance, complexity, and heterogeneity of Genomic rearrangements, potentially suggesting distinct mechanisms of Instability in different molecular classes of prostate cancer. However, the somatic alterations underlying these phenomena remain largely undefined. Recurrent mutations in SPOP, the substrate-recognition component of an E3-ubiquitin ligase, represent the most common point mutations in primary prostate cancer, occurring in about 10% of tumors. SPOP mutations define a distinct molecular class of prostate cancer; they are mutually exclusive with TMPRSS2-ERG fusions, but harbor distinct patterns of copy number aberrations. Here, we report that SPOP mutant prostate cancers also harbor increased numbers of Genomic rearrangements, and functional data suggest that SPOP mutation alters repair of DNA double strand breaks (DSB). Methods: We systematically investigated somatic alterations associated with Genomic rearrangements, using a composite data set of 402 clinically localized prostate cancers. Functional analyses in vitro and in vivo were used to define pathways affected, and interrogate DNA repair phenotypes. Results: In human prostate cancers, SPOP mutation is an early event specifically associated with increased intrachromosomal Genomic rearrangements. Using a zebrafish model, SPOP mutation results in a transcriptional response consistent with BRCA1 inactivation, implicating altered repair of DSB. In vitro data suggest that SPOP participates in repair of DSB, and SPOP mutation impairs homology-directed repair (HDR), instead promoting error-prone non-homologous end joining (NHEJ). Finally, SPOP mutation sensitizes prostate cancer cells to DNA damaging therapeutic agents such as PARP inhibitors. Conclusions: These results implicate SPOP as a novel participant in DSB repair, suggest that SPOP mutation drives prostate tumorigenesis in part through Genomic Instability, and indicate that SPOP mutant prostate cancer may be selectively responsive to DNA damaging therapeutics. Citation Format: Gunther Boysen, Christopher E. Barbieri, Davide Prandi, Sung-Suk Chae, Srilakshmi Nataraj, Mirjam Blattner, Clarisse Marotz, Limei Xu, Paola Lecca, Sagar Chhangawala, Pengbo Zou, Andrea Sboner, Francesca Demichelis, Yariv Houvras, Mark A. Rubin. SPOP mutation leads to Genomic Instability in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1108. doi:10.1158/1538-7445.AM2015-1108

  • abstract ng01 spop mutation is associated with Genomic Instability in prostate cancer
    Cancer Research, 2015
    Co-Authors: Christopher E Barbieri, Gunther Boysen, Mirjam Blattner, Sungsuk Chae, Srilakshmi Nataraj, Davide Prandi, Clarisse Marotz, Arun Dahiya, Julie Huang, Paola Lecca
    Abstract:

    Background: Genomic Instability is a fundamental feature of human cancer, and DNA repair defects resulting in impaired genome maintenance promote pathogenesis of many types of cancers. In prostate cancer, structural Genomic rearrangements, including translocations and copy number aberrations, are a key mechanism driving tumorigenesis. Recently, whole genome sequencing revealed a striking abundance, complexity, and heterogeneity of Genomic rearrangements, potentially suggesting distinct mechanisms of Instability in different molecular classes of prostate cancer. However, the somatic alterations underlying these phenomena remain largely undefined. Recurrent mutations in SPOP, the substrate-recognition component of an E3-ubiquitin ligase, represent the most common point mutations in primary prostate cancer, occurring in about 10% of tumors. SPOP mutations define a distinct molecular class of prostate cancer; they are mutually exclusive with TMPRSS2-ERG fusions, but harbor distinct patterns of copy number aberrations. Here, we report that SPOP mutant prostate cancers also harbor increased numbers of Genomic rearrangements, and functional data suggest that SPOP mutation alters repair of DNA double strand breaks (DSB). Methods: We systematically investigated somatic alterations associated with Genomic rearrangements, using a composite data set of 402 clinically localized prostate cancers. Functional analyses in vitro and in vivo were used to define pathways affected, and interrogate DNA repair phenotypes. Results: In human prostate cancers, SPOP mutation is an early event specifically associated with increased intrachromosomal Genomic rearrangements. Using a zebrafish model, SPOP mutation results in a transcriptional response consistent with BRCA1 inactivation, implicating altered repair of DSB. In vitro data suggest that SPOP participates in repair of DSB, and SPOP mutation impairs homology-directed repair (HDR), instead promoting error-prone non-homologous end joining (NHEJ). Finally, SPOP mutation sensitizes prostate cancer cells to DNA damaging therapeutic agents such as PARP inhibitors. Conclusions: These results implicate SPOP as a novel participant in DSB repair, suggest that SPOP mutation drives prostate tumorigenesis in part through Genomic Instability, and indicate that SPOP mutant prostate cancer may be selectively responsive to DNA damaging therapeutics. Citation Format: Christopher E. Barbieri, Gunther Boysen, Davide Prandi, Sung-Suk Chae, Arun Dahiya, Srilakshmi Nataraj, Mirjam Blattner, Clarisse Marotz, Limei Xu, Julie Huang, Paola Lecca, Sagar Chhangawala, Pengbo Zhou, Andrea Sboner, Francesca Demichelis, Yariv Houvras, Mark A. Rubin. SPOP mutation is associated with Genomic Instability in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr NG01. doi:10.1158/1538-7445.AM2015-NG01

Christopher E Barbieri - One of the best experts on this subject based on the ideXlab platform.

  • spop mutation leads to Genomic Instability in prostate cancer
    eLife, 2015
    Co-Authors: Gunther Boysen, Mirjam Blattner, Christopher E Barbieri, Sungsuk Chae, Srilakshmi Nataraj, Davide Prandi, Arun Dahija, Dennis Huang
    Abstract:

    Prostate cancer is the most common type of cancer in men in the UK and USA. Cancers develop when cells in the body acquire genetic mutations that allow the cells to grow rapidly and form a mass known as a tumor. Prostate cancer cells from different individuals can carry different genetic mutations, which affects whether the disease progresses and how the tumors respond to medical treatments. This genetic variety arises in cancer cells partly from a phenomenon known as Genomic Instability, in which DNA mutations accumulate due to defects in DNA repair. Genetic studies of biopsies taken from human prostate cancers have shown that Genomic Instability causes chromosomes—the structures in which the cell's DNA is organized—to break and then be stuck back together haphazardly. As a result, fragments of chromosomes can end up in the wrong position, be duplicated, or be lost altogether. All of these mutations could spur on the growth of the tumor. However, it is currently not clear why some prostate cancers are more Genomically unstable than others, or what exactly causes this Instability. Boysen, Barbieri et al. studied prostate cancer cells taken from patients before they started medical treatment. The experiments show that the cancer cells with high levels of Genomic Instability also often had mutations in a gene that encodes a protein called SPOP. These mutations occur in about 10 percent of men with prostate cancer and appear early in the development of the tumors. Next, they studied the SPOP protein in zebrafish (which is nearly identical to human SPOP), as well as in mouse and human cells. The experiments show that SPOP normally helps the cell to accurately repair DNA that has been damaged. Mutations in SPOP change the DNA repair process, which lead to Genomic Instability by increasing the likelihood that broken chromosomes will be stuck back together incorrectly. Further experiments tested drugs known as PARP inhibitors on mouse and human prostate cancer cells. The drugs, which have been recently tested successfully in patients with prostate cancer, block a different method of DNA repair that operates separately to the one that involves SPOP. When both of these pathways were inactivated—one by the SPOP mutation, the other by the drug—the cancer cells died more quickly. Therefore, men that are diagnosed with types of prostate cancer in which the gene that encodes SPOP is mutated might benefit from treatment with PARP inhibitors or other therapies that affect DNA repair.

  • abstract 1108 spop mutation leads to Genomic Instability in prostate cancer
    Cancer Research, 2015
    Co-Authors: Gunther Boysen, Mirjam Blattner, Christopher E Barbieri, Sungsuk Chae, Srilakshmi Nataraj, Davide Prandi, Clarisse Marotz, Paola Lecca, Sagar Chhangawala, Pengbo Zou
    Abstract:

    Background: Genomic Instability is a fundamental feature of human cancer, and DNA repair defects resulting in impaired genome maintenance promote pathogenesis of many types of cancers. In prostate cancer, structural Genomic rearrangements, including translocations and copy number aberrations, are a key mechanism driving tumorigenesis. Recently, whole genome sequencing revealed a striking abundance, complexity, and heterogeneity of Genomic rearrangements, potentially suggesting distinct mechanisms of Instability in different molecular classes of prostate cancer. However, the somatic alterations underlying these phenomena remain largely undefined. Recurrent mutations in SPOP, the substrate-recognition component of an E3-ubiquitin ligase, represent the most common point mutations in primary prostate cancer, occurring in about 10% of tumors. SPOP mutations define a distinct molecular class of prostate cancer; they are mutually exclusive with TMPRSS2-ERG fusions, but harbor distinct patterns of copy number aberrations. Here, we report that SPOP mutant prostate cancers also harbor increased numbers of Genomic rearrangements, and functional data suggest that SPOP mutation alters repair of DNA double strand breaks (DSB). Methods: We systematically investigated somatic alterations associated with Genomic rearrangements, using a composite data set of 402 clinically localized prostate cancers. Functional analyses in vitro and in vivo were used to define pathways affected, and interrogate DNA repair phenotypes. Results: In human prostate cancers, SPOP mutation is an early event specifically associated with increased intrachromosomal Genomic rearrangements. Using a zebrafish model, SPOP mutation results in a transcriptional response consistent with BRCA1 inactivation, implicating altered repair of DSB. In vitro data suggest that SPOP participates in repair of DSB, and SPOP mutation impairs homology-directed repair (HDR), instead promoting error-prone non-homologous end joining (NHEJ). Finally, SPOP mutation sensitizes prostate cancer cells to DNA damaging therapeutic agents such as PARP inhibitors. Conclusions: These results implicate SPOP as a novel participant in DSB repair, suggest that SPOP mutation drives prostate tumorigenesis in part through Genomic Instability, and indicate that SPOP mutant prostate cancer may be selectively responsive to DNA damaging therapeutics. Citation Format: Gunther Boysen, Christopher E. Barbieri, Davide Prandi, Sung-Suk Chae, Srilakshmi Nataraj, Mirjam Blattner, Clarisse Marotz, Limei Xu, Paola Lecca, Sagar Chhangawala, Pengbo Zou, Andrea Sboner, Francesca Demichelis, Yariv Houvras, Mark A. Rubin. SPOP mutation leads to Genomic Instability in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1108. doi:10.1158/1538-7445.AM2015-1108

  • abstract ng01 spop mutation is associated with Genomic Instability in prostate cancer
    Cancer Research, 2015
    Co-Authors: Christopher E Barbieri, Gunther Boysen, Mirjam Blattner, Sungsuk Chae, Srilakshmi Nataraj, Davide Prandi, Clarisse Marotz, Arun Dahiya, Julie Huang, Paola Lecca
    Abstract:

    Background: Genomic Instability is a fundamental feature of human cancer, and DNA repair defects resulting in impaired genome maintenance promote pathogenesis of many types of cancers. In prostate cancer, structural Genomic rearrangements, including translocations and copy number aberrations, are a key mechanism driving tumorigenesis. Recently, whole genome sequencing revealed a striking abundance, complexity, and heterogeneity of Genomic rearrangements, potentially suggesting distinct mechanisms of Instability in different molecular classes of prostate cancer. However, the somatic alterations underlying these phenomena remain largely undefined. Recurrent mutations in SPOP, the substrate-recognition component of an E3-ubiquitin ligase, represent the most common point mutations in primary prostate cancer, occurring in about 10% of tumors. SPOP mutations define a distinct molecular class of prostate cancer; they are mutually exclusive with TMPRSS2-ERG fusions, but harbor distinct patterns of copy number aberrations. Here, we report that SPOP mutant prostate cancers also harbor increased numbers of Genomic rearrangements, and functional data suggest that SPOP mutation alters repair of DNA double strand breaks (DSB). Methods: We systematically investigated somatic alterations associated with Genomic rearrangements, using a composite data set of 402 clinically localized prostate cancers. Functional analyses in vitro and in vivo were used to define pathways affected, and interrogate DNA repair phenotypes. Results: In human prostate cancers, SPOP mutation is an early event specifically associated with increased intrachromosomal Genomic rearrangements. Using a zebrafish model, SPOP mutation results in a transcriptional response consistent with BRCA1 inactivation, implicating altered repair of DSB. In vitro data suggest that SPOP participates in repair of DSB, and SPOP mutation impairs homology-directed repair (HDR), instead promoting error-prone non-homologous end joining (NHEJ). Finally, SPOP mutation sensitizes prostate cancer cells to DNA damaging therapeutic agents such as PARP inhibitors. Conclusions: These results implicate SPOP as a novel participant in DSB repair, suggest that SPOP mutation drives prostate tumorigenesis in part through Genomic Instability, and indicate that SPOP mutant prostate cancer may be selectively responsive to DNA damaging therapeutics. Citation Format: Christopher E. Barbieri, Gunther Boysen, Davide Prandi, Sung-Suk Chae, Arun Dahiya, Srilakshmi Nataraj, Mirjam Blattner, Clarisse Marotz, Limei Xu, Julie Huang, Paola Lecca, Sagar Chhangawala, Pengbo Zhou, Andrea Sboner, Francesca Demichelis, Yariv Houvras, Mark A. Rubin. SPOP mutation is associated with Genomic Instability in prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr NG01. doi:10.1158/1538-7445.AM2015-NG01

Taku Tokuyasu - One of the best experts on this subject based on the ideXlab platform.

  • breast tumor copy number aberration phenotypes and Genomic Instability
    BMC Cancer, 2006
    Co-Authors: Jane Fridlyand, Antoine M Snijders, Bauke Ylstra, Adam B Olshen, Richard Segraves, Shanaz Dairkee, Taku Tokuyasu
    Abstract:

    Background: Genomic DNA copy number aberrations are frequent in solid tumors, although the underlying causes of chromosomal Instability in tumors remain obscure. Genes likely to have Genomic Instability phenotypes when mutated (e.g. those involved in mitosis, replication, repair, and telomeres) are rarely mutated in chromosomally unstable sporadic tumors, even though such mutations are associated with some heritable cancer prone syndromes. Methods: We applied array comparative Genomic hybridization (CGH) to the analysis of breast tumors. The variation in the levels of Genomic Instability amongst tumors prompted us to investigate whether alterations in processes/genes involved in maintenance and/or manipulation of the genome were associated with particular types of Genomic Instability. Results: We discriminated three breast tumor subtypes based on Genomic DNA copy number alterations. The subtypes varied with respect to level of Genomic Instability. We find that shorter telomeres and altered telomere related gene expression are associated with amplification, implicating telomere attrition as a promoter of this type of aberration in breast cancer. On the other hand, the numbers of chromosomal alterations, particularly low level changes, are associated with altered expression of genes in other functional classes (mitosis, cell cycle, DNA replication and repair). Further, although loss of function Instability phenotypes have been demonstrated for

  • breast tumor copy number aberration phenotypes and Genomic Instability
    BMC Cancer, 2006
    Co-Authors: Jane Fridlyand, Antoine M Snijders, Bauke Ylstra, Adam B Olshen, Richard Segraves, Shanaz Dairkee, Taku Tokuyasu
    Abstract:

    Genomic DNA copy number aberrations are frequent in solid tumors, although the underlying causes of chromosomal Instability in tumors remain obscure. Genes likely to have Genomic Instability phenotypes when mutated (e.g. those involved in mitosis, replication, repair, and telomeres) are rarely mutated in chromosomally unstable sporadic tumors, even though such mutations are associated with some heritable cancer prone syndromes. We applied array comparative Genomic hybridization (CGH) to the analysis of breast tumors. The variation in the levels of Genomic Instability amongst tumors prompted us to investigate whether alterations in processes/genes involved in maintenance and/or manipulation of the genome were associated with particular types of Genomic Instability. We discriminated three breast tumor subtypes based on Genomic DNA copy number alterations. The subtypes varied with respect to level of Genomic Instability. We find that shorter telomeres and altered telomere related gene expression are associated with amplification, implicating telomere attrition as a promoter of this type of aberration in breast cancer. On the other hand, the numbers of chromosomal alterations, particularly low level changes, are associated with altered expression of genes in other functional classes (mitosis, cell cycle, DNA replication and repair). Further, although loss of function Instability phenotypes have been demonstrated for many of the genes in model systems, we observed enhanced expression of most genes in tumors, indicating that over expression, rather than deficiency underlies Instability. Many of the genes associated with higher frequency of copy number aberrations are direct targets of E2F, supporting the hypothesis that deregulation of the Rb pathway is a major contributor to chromosomal Instability in breast tumors. These observations are consistent with failure to find mutations in sporadic tumors in genes that have roles in maintenance or manipulation of the genome.

Bauke Ylstra - One of the best experts on this subject based on the ideXlab platform.

  • breast tumor copy number aberration phenotypes and Genomic Instability
    BMC Cancer, 2006
    Co-Authors: Jane Fridlyand, Antoine M Snijders, Bauke Ylstra, Adam B Olshen, Richard Segraves, Shanaz Dairkee, Taku Tokuyasu
    Abstract:

    Background: Genomic DNA copy number aberrations are frequent in solid tumors, although the underlying causes of chromosomal Instability in tumors remain obscure. Genes likely to have Genomic Instability phenotypes when mutated (e.g. those involved in mitosis, replication, repair, and telomeres) are rarely mutated in chromosomally unstable sporadic tumors, even though such mutations are associated with some heritable cancer prone syndromes. Methods: We applied array comparative Genomic hybridization (CGH) to the analysis of breast tumors. The variation in the levels of Genomic Instability amongst tumors prompted us to investigate whether alterations in processes/genes involved in maintenance and/or manipulation of the genome were associated with particular types of Genomic Instability. Results: We discriminated three breast tumor subtypes based on Genomic DNA copy number alterations. The subtypes varied with respect to level of Genomic Instability. We find that shorter telomeres and altered telomere related gene expression are associated with amplification, implicating telomere attrition as a promoter of this type of aberration in breast cancer. On the other hand, the numbers of chromosomal alterations, particularly low level changes, are associated with altered expression of genes in other functional classes (mitosis, cell cycle, DNA replication and repair). Further, although loss of function Instability phenotypes have been demonstrated for

  • breast tumor copy number aberration phenotypes and Genomic Instability
    BMC Cancer, 2006
    Co-Authors: Jane Fridlyand, Antoine M Snijders, Bauke Ylstra, Adam B Olshen, Richard Segraves, Shanaz Dairkee, Taku Tokuyasu
    Abstract:

    Genomic DNA copy number aberrations are frequent in solid tumors, although the underlying causes of chromosomal Instability in tumors remain obscure. Genes likely to have Genomic Instability phenotypes when mutated (e.g. those involved in mitosis, replication, repair, and telomeres) are rarely mutated in chromosomally unstable sporadic tumors, even though such mutations are associated with some heritable cancer prone syndromes. We applied array comparative Genomic hybridization (CGH) to the analysis of breast tumors. The variation in the levels of Genomic Instability amongst tumors prompted us to investigate whether alterations in processes/genes involved in maintenance and/or manipulation of the genome were associated with particular types of Genomic Instability. We discriminated three breast tumor subtypes based on Genomic DNA copy number alterations. The subtypes varied with respect to level of Genomic Instability. We find that shorter telomeres and altered telomere related gene expression are associated with amplification, implicating telomere attrition as a promoter of this type of aberration in breast cancer. On the other hand, the numbers of chromosomal alterations, particularly low level changes, are associated with altered expression of genes in other functional classes (mitosis, cell cycle, DNA replication and repair). Further, although loss of function Instability phenotypes have been demonstrated for many of the genes in model systems, we observed enhanced expression of most genes in tumors, indicating that over expression, rather than deficiency underlies Instability. Many of the genes associated with higher frequency of copy number aberrations are direct targets of E2F, supporting the hypothesis that deregulation of the Rb pathway is a major contributor to chromosomal Instability in breast tumors. These observations are consistent with failure to find mutations in sporadic tumors in genes that have roles in maintenance or manipulation of the genome.

Adam B Olshen - One of the best experts on this subject based on the ideXlab platform.

  • breast tumor copy number aberration phenotypes and Genomic Instability
    BMC Cancer, 2006
    Co-Authors: Jane Fridlyand, Antoine M Snijders, Bauke Ylstra, Adam B Olshen, Richard Segraves, Shanaz Dairkee, Taku Tokuyasu
    Abstract:

    Background: Genomic DNA copy number aberrations are frequent in solid tumors, although the underlying causes of chromosomal Instability in tumors remain obscure. Genes likely to have Genomic Instability phenotypes when mutated (e.g. those involved in mitosis, replication, repair, and telomeres) are rarely mutated in chromosomally unstable sporadic tumors, even though such mutations are associated with some heritable cancer prone syndromes. Methods: We applied array comparative Genomic hybridization (CGH) to the analysis of breast tumors. The variation in the levels of Genomic Instability amongst tumors prompted us to investigate whether alterations in processes/genes involved in maintenance and/or manipulation of the genome were associated with particular types of Genomic Instability. Results: We discriminated three breast tumor subtypes based on Genomic DNA copy number alterations. The subtypes varied with respect to level of Genomic Instability. We find that shorter telomeres and altered telomere related gene expression are associated with amplification, implicating telomere attrition as a promoter of this type of aberration in breast cancer. On the other hand, the numbers of chromosomal alterations, particularly low level changes, are associated with altered expression of genes in other functional classes (mitosis, cell cycle, DNA replication and repair). Further, although loss of function Instability phenotypes have been demonstrated for

  • breast tumor copy number aberration phenotypes and Genomic Instability
    BMC Cancer, 2006
    Co-Authors: Jane Fridlyand, Antoine M Snijders, Bauke Ylstra, Adam B Olshen, Richard Segraves, Shanaz Dairkee, Taku Tokuyasu
    Abstract:

    Genomic DNA copy number aberrations are frequent in solid tumors, although the underlying causes of chromosomal Instability in tumors remain obscure. Genes likely to have Genomic Instability phenotypes when mutated (e.g. those involved in mitosis, replication, repair, and telomeres) are rarely mutated in chromosomally unstable sporadic tumors, even though such mutations are associated with some heritable cancer prone syndromes. We applied array comparative Genomic hybridization (CGH) to the analysis of breast tumors. The variation in the levels of Genomic Instability amongst tumors prompted us to investigate whether alterations in processes/genes involved in maintenance and/or manipulation of the genome were associated with particular types of Genomic Instability. We discriminated three breast tumor subtypes based on Genomic DNA copy number alterations. The subtypes varied with respect to level of Genomic Instability. We find that shorter telomeres and altered telomere related gene expression are associated with amplification, implicating telomere attrition as a promoter of this type of aberration in breast cancer. On the other hand, the numbers of chromosomal alterations, particularly low level changes, are associated with altered expression of genes in other functional classes (mitosis, cell cycle, DNA replication and repair). Further, although loss of function Instability phenotypes have been demonstrated for many of the genes in model systems, we observed enhanced expression of most genes in tumors, indicating that over expression, rather than deficiency underlies Instability. Many of the genes associated with higher frequency of copy number aberrations are direct targets of E2F, supporting the hypothesis that deregulation of the Rb pathway is a major contributor to chromosomal Instability in breast tumors. These observations are consistent with failure to find mutations in sporadic tumors in genes that have roles in maintenance or manipulation of the genome.