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  • 1
    Publication Date: 2012-04-13
    Description: Primary triple-negative breast cancers (TNBCs), a tumour type defined by lack of oestrogen receptor, progesterone receptor and ERBB2 gene amplification, represent approximately 16% of all breast cancers. Here we show in 104 TNBC cases that at the time of diagnosis these cancers exhibit a wide and continuous spectrum of genomic evolution, with some having only a handful of coding somatic aberrations in a few pathways, whereas others contain hundreds of coding somatic mutations. High-throughput RNA sequencing (RNA-seq) revealed that only approximately 36% of mutations are expressed. Using deep re-sequencing measurements of allelic abundance for 2,414 somatic mutations, we determine for the first time-to our knowledge-in an epithelial tumour subtype, the relative abundance of clonal frequencies among cases representative of the population. We show that TNBCs vary widely in their clonal frequencies at the time of diagnosis, with the basal subtype of TNBC showing more variation than non-basal TNBC. Although p53 (also known as TP53), PIK3CA and PTEN somatic mutations seem to be clonally dominant compared to other genes, in some tumours their clonal frequencies are incompatible with founder status. Mutations in cytoskeletal, cell shape and motility proteins occurred at lower clonal frequencies, suggesting that they occurred later during tumour progression. Taken together, our results show that understanding the biology and therapeutic responses of patients with TNBC will require the determination of individual tumour clonal genotypes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3863681/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3863681/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shah, Sohrab P -- Roth, Andrew -- Goya, Rodrigo -- Oloumi, Arusha -- Ha, Gavin -- Zhao, Yongjun -- Turashvili, Gulisa -- Ding, Jiarui -- Tse, Kane -- Haffari, Gholamreza -- Bashashati, Ali -- Prentice, Leah M -- Khattra, Jaswinder -- Burleigh, Angela -- Yap, Damian -- Bernard, Virginie -- McPherson, Andrew -- Shumansky, Karey -- Crisan, Anamaria -- Giuliany, Ryan -- Heravi-Moussavi, Alireza -- Rosner, Jamie -- Lai, Daniel -- Birol, Inanc -- Varhol, Richard -- Tam, Angela -- Dhalla, Noreen -- Zeng, Thomas -- Ma, Kevin -- Chan, Simon K -- Griffith, Malachi -- Moradian, Annie -- Cheng, S-W Grace -- Morin, Gregg B -- Watson, Peter -- Gelmon, Karen -- Chia, Stephen -- Chin, Suet-Feung -- Curtis, Christina -- Rueda, Oscar M -- Pharoah, Paul D -- Damaraju, Sambasivarao -- Mackey, John -- Hoon, Kelly -- Harkins, Timothy -- Tadigotla, Vasisht -- Sigaroudinia, Mahvash -- Gascard, Philippe -- Tlsty, Thea -- Costello, Joseph F -- Meyer, Irmtraud M -- Eaves, Connie J -- Wasserman, Wyeth W -- Jones, Steven -- Huntsman, David -- Hirst, Martin -- Caldas, Carlos -- Marra, Marco A -- Aparicio, Samuel -- 5U01ES017154-02/ES/NIEHS NIH HHS/ -- R01 GM084875/GM/NIGMS NIH HHS/ -- R01GM084875/GM/NIGMS NIH HHS/ -- Cancer Research UK/United Kingdom -- England -- Nature. 2012 Apr 4;486(7403):395-9. doi: 10.1038/nature10933.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada. sshah@bccrc.ca〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22495314" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Breast Neoplasms/diagnosis/*genetics/*pathology ; Clone Cells/metabolism/pathology ; DNA Copy Number Variations/genetics ; DNA Mutational Analysis ; Disease Progression ; *Evolution, Molecular ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic/genetics ; Genotype ; High-Throughput Nucleotide Sequencing ; Humans ; INDEL Mutation/genetics ; Mutation/*genetics ; Point Mutation/genetics ; Precision Medicine ; Reproducibility of Results ; Sequence Analysis, RNA
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2014-12-04
    Description: Human cancers, including breast cancers, comprise clones differing in mutation content. Clones evolve dynamically in space and time following principles of Darwinian evolution, underpinning important emergent features such as drug resistance and metastasis. Human breast cancer xenoengraftment is used as a means of capturing and studying tumour biology, and breast tumour xenografts are generally assumed to be reasonable models of the originating tumours. However, the consequences and reproducibility of engraftment and propagation on the genomic clonal architecture of tumours have not been systematically examined at single-cell resolution. Here we show, using deep-genome and single-cell sequencing methods, the clonal dynamics of initial engraftment and subsequent serial propagation of primary and metastatic human breast cancers in immunodeficient mice. In all 15 cases examined, clonal selection on engraftment was observed in both primary and metastatic breast tumours, varying in degree from extreme selective engraftment of minor (〈5% of starting population) clones to moderate, polyclonal engraftment. Furthermore, ongoing clonal dynamics during serial passaging is a feature of tumours experiencing modest initial selection. Through single-cell sequencing, we show that major mutation clusters estimated from tumour population sequencing relate predictably to the most abundant clonal genotypes, even in clonally complex and rapidly evolving cases. Finally, we show that similar clonal expansion patterns can emerge in independent grafts of the same starting tumour population, indicating that genomic aberrations can be reproducible determinants of evolutionary trajectories. Our results show that measurement of genomically defined clonal population dynamics will be highly informative for functional studies using patient-derived breast cancer xenoengraftment.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Eirew, Peter -- Steif, Adi -- Khattra, Jaswinder -- Ha, Gavin -- Yap, Damian -- Farahani, Hossein -- Gelmon, Karen -- Chia, Stephen -- Mar, Colin -- Wan, Adrian -- Laks, Emma -- Biele, Justina -- Shumansky, Karey -- Rosner, Jamie -- McPherson, Andrew -- Nielsen, Cydney -- Roth, Andrew J L -- Lefebvre, Calvin -- Bashashati, Ali -- de Souza, Camila -- Siu, Celia -- Aniba, Radhouane -- Brimhall, Jazmine -- Oloumi, Arusha -- Osako, Tomo -- Bruna, Alejandra -- Sandoval, Jose L -- Algara, Teresa -- Greenwood, Wendy -- Leung, Kaston -- Cheng, Hongwei -- Xue, Hui -- Wang, Yuzhuo -- Lin, Dong -- Mungall, Andrew J -- Moore, Richard -- Zhao, Yongjun -- Lorette, Julie -- Nguyen, Long -- Huntsman, David -- Eaves, Connie J -- Hansen, Carl -- Marra, Marco A -- Caldas, Carlos -- Shah, Sohrab P -- Aparicio, Samuel -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2015 Feb 19;518(7539):422-6. doi: 10.1038/nature13952. Epub 2014 Nov 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada. ; Department of Medical Oncology, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada. ; Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada. ; 1] Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK [2] Cancer Research UK Cambridge Research Institute, University of Cambridge, Li Ka Shing Centre, Cambridge CB2 0RE, UK. ; 1] Centre for High-Throughput Biology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada [2] Department of Physics and Astronomy, University of British Columbia, Vancouver, British Columbia V6T 1Z1, Canada. ; 1] Department of Experimental Therapeutics, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] The Vancouver Prostate Centre, Vancouver General Hospital and Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada. ; Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 1L3, Canada. ; Centre for Translational and Applied Genomics, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada. ; 1] Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada [2] Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada. ; 1] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada [2] Centre for Translational and Applied Genomics, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada. ; 1] Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada [3] Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 1L3, Canada. ; 1] Department of Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada [2] Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 2B5, Canada [3] Michael Smith Genome Sciences Centre, Vancouver, British Columbia V5Z 1L3, Canada [4] Centre for Translational and Applied Genomics, BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25470049" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Breast Neoplasms/*genetics/*pathology/secondary ; Clone Cells/*metabolism/*pathology ; DNA Mutational Analysis ; Genome, Human/*genetics ; Genomics ; Genotype ; High-Throughput Nucleotide Sequencing ; Humans ; Mice ; Neoplasm Transplantation ; *Single-Cell Analysis ; Time Factors ; Transplantation, Heterologous ; *Xenograft Model Antitumor Assays/methods
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2012-04-24
    Description: The elucidation of breast cancer subgroups and their molecular drivers requires integrated views of the genome and transcriptome from representative numbers of patients. We present an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumours, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in ~40% of genes, with the landscape dominated by cis- and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, we identified putative cancer genes, including deletions in PPP2R2A, MTAP and MAP2K4. Unsupervised analysis of paired DNA-RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, oestrogen-receptor-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the 'CNA-devoid' subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Our results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3440846/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3440846/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Curtis, Christina -- Shah, Sohrab P -- Chin, Suet-Feung -- Turashvili, Gulisa -- Rueda, Oscar M -- Dunning, Mark J -- Speed, Doug -- Lynch, Andy G -- Samarajiwa, Shamith -- Yuan, Yinyin -- Graf, Stefan -- Ha, Gavin -- Haffari, Gholamreza -- Bashashati, Ali -- Russell, Roslin -- McKinney, Steven -- METABRIC Group -- Langerod, Anita -- Green, Andrew -- Provenzano, Elena -- Wishart, Gordon -- Pinder, Sarah -- Watson, Peter -- Markowetz, Florian -- Murphy, Leigh -- Ellis, Ian -- Purushotham, Arnie -- Borresen-Dale, Anne-Lise -- Brenton, James D -- Tavare, Simon -- Caldas, Carlos -- Aparicio, Samuel -- A7199/Cancer Research UK/United Kingdom -- P50HG02790/HG/NHGRI NIH HHS/ -- Cancer Research UK/United Kingdom -- England -- Nature. 2012 Apr 18;486(7403):346-52. doi: 10.1038/nature10983.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22522925" target="_blank"〉PubMed〈/a〉
    Keywords: Breast Neoplasms/classification/diagnosis/*genetics/*pathology ; DNA Copy Number Variations/*genetics ; Female ; *Gene Expression Profiling ; *Gene Expression Regulation, Neoplastic ; Gene Regulatory Networks/genetics ; Genes, Neoplasm/genetics ; Genome, Human/*genetics ; Genomics ; Humans ; Kaplan-Meier Estimate ; MAP Kinase Kinase 4/genetics ; Polymorphism, Single Nucleotide/genetics ; Prognosis ; Protein Phosphatase 2/genetics ; Treatment Outcome
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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