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  • 1
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    Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution (2009)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2009-10-09
    Description: Recent advances in next generation sequencing have made it possible to precisely characterize all somatic coding mutations that occur during the development and progression of individual cancers. Here we used these approaches to sequence the genomes (〉43-fold coverage) and transcriptomes of an oestrogen-receptor-alpha-positive metastatic lobular breast cancer at depth. We found 32 somatic non-synonymous coding mutations present in the metastasis, and measured the frequency of these somatic mutations in DNA from the primary tumour of the same patient, which arose 9 years earlier. Five of the 32 mutations (in ABCB11, HAUS3, SLC24A4, SNX4 and PALB2) were prevalent in the DNA of the primary tumour removed at diagnosis 9 years earlier, six (in KIF1C, USP28, MYH8, MORC1, KIAA1468 and RNASEH2A) were present at lower frequencies (1-13%), 19 were not detected in the primary tumour, and two were undetermined. The combined analysis of genome and transcriptome data revealed two new RNA-editing events that recode the amino acid sequence of SRP9 and COG3. Taken together, our data show that single nucleotide mutational heterogeneity can be a property of low or intermediate grade primary breast cancers and that significant evolution can occur with disease progression.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shah, Sohrab P -- Morin, Ryan D -- Khattra, Jaswinder -- Prentice, Leah -- Pugh, Trevor -- Burleigh, Angela -- Delaney, Allen -- Gelmon, Karen -- Guliany, Ryan -- Senz, Janine -- Steidl, Christian -- Holt, Robert A -- Jones, Steven -- Sun, Mark -- Leung, Gillian -- Moore, Richard -- Severson, Tesa -- Taylor, Greg A -- Teschendorff, Andrew E -- Tse, Kane -- Turashvili, Gulisa -- Varhol, Richard -- Warren, Rene L -- Watson, Peter -- Zhao, Yongjun -- Caldas, Carlos -- Huntsman, David -- Hirst, Martin -- Marra, Marco A -- Aparicio, Samuel -- England -- Nature. 2009 Oct 8;461(7265):809-13. doi: 10.1038/nature08489.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Oncology, BC Cancer Agency, 675 West 10th Avenue, Vancouver V5Z 1L3, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19812674" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Vesicular Transport/genetics ; Breast Neoplasms/*genetics/metabolism/*pathology ; DNA Mutational Analysis ; Disease Progression ; Estrogen Receptor alpha/metabolism ; Evolution, Molecular ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Genes, Neoplasm/*genetics ; Genome, Human/genetics ; Germ-Line Mutation/genetics ; Humans ; Mutagenesis/*genetics ; Mutation/*genetics ; Neoplasm Metastasis ; Nucleotides/*genetics ; RNA Editing/genetics ; Signal Recognition Particle/genetics ; Time Factors
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    The clonal and mutational evolution spectrum of primary triple-negative breast cancers (2012)
    Nature Publishing Group (NPG)
    Details
    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
    Published by Nature Publishing Group (NPG)
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  • 3
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    The shaping and functional consequences of the microRNA landscape in breast cancer (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-05-07
    Description: MicroRNAs (miRNAs) show differential expression across breast cancer subtypes, and have both oncogenic and tumour-suppressive roles. Here we report the miRNA expression profiles of 1,302 breast tumours with matching detailed clinical annotation, long-term follow-up and genomic and messenger RNA expression data. This provides a comprehensive overview of the quantity, distribution and variation of the miRNA population and provides information on the extent to which genomic, transcriptional and post-transcriptional events contribute to miRNA expression architecture, suggesting an important role for post-transcriptional regulation. The key clinical parameters and cellular pathways related to the miRNA landscape are characterized, revealing context-dependent interactions, for example with regards to cell adhesion and Wnt signalling. Notably, only prognostic miRNA signatures derived from breast tumours devoid of somatic copy-number aberrations (CNA-devoid) are consistently prognostic across several other subtypes and can be validated in external cohorts. We then use a data-driven approach to seek the effects of miRNAs associated with differential co-expression of mRNAs, and find that miRNAs act as modulators of mRNA-mRNA interactions rather than as on-off molecular switches. We demonstrate such an important modulatory role for miRNAs in the biology of CNA-devoid breast cancers, a common subtype in which the immune response is prominent. These findings represent a new framework for studying the biology of miRNAs in human breast cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dvinge, Heidi -- Git, Anna -- Graf, Stefan -- Salmon-Divon, Mali -- Curtis, Christina -- Sottoriva, Andrea -- Zhao, Yongjun -- Hirst, Martin -- Armisen, Javier -- Miska, Eric A -- Chin, Suet-Feung -- Provenzano, Elena -- Turashvili, Gulisa -- Green, Andrew -- Ellis, Ian -- Aparicio, Sam -- Caldas, Carlos -- 11832/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2013 May 16;497(7449):378-82. doi: 10.1038/nature12108. Epub 2013 May 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK Cambridge Institute and Department of Oncology, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23644459" target="_blank"〉PubMed〈/a〉
    Keywords: Algorithms ; Breast Neoplasms/*genetics/pathology ; DNA Copy Number Variations ; Female ; Follow-Up Studies ; Gene Expression Profiling ; *Gene Expression Regulation, Neoplastic ; Genome, Human/genetics ; Humans ; Kaplan-Meier Estimate ; MicroRNAs/*genetics/metabolism ; Prognosis ; Proportional Hazards Models ; RNA, Messenger/genetics/metabolism ; RNA, Neoplasm/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 4
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    The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups (2012)
    Nature Publishing Group (NPG)
    Details
    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
    Published by Nature Publishing Group (NPG)
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  • 5
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    The landscape of cancer genes and mutational processes in breast cancer (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-06-23
    Description: All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here we examine the genomes of 100 tumours for somatic copy number changes and mutations in the coding exons of protein-coding genes. The number of somatic mutations varied markedly between individual tumours. We found strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, and observed multiple mutational signatures, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides. Driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. Among the 100 tumours, we found driver mutations in at least 40 cancer genes and 73 different combinations of mutated cancer genes. The results highlight the substantial genetic diversity underlying this common disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3428862/" 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/PMC3428862/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stephens, Philip J -- Tarpey, Patrick S -- Davies, Helen -- Van Loo, Peter -- Greenman, Chris -- Wedge, David C -- Nik-Zainal, Serena -- Martin, Sancha -- Varela, Ignacio -- Bignell, Graham R -- Yates, Lucy R -- Papaemmanuil, Elli -- Beare, David -- Butler, Adam -- Cheverton, Angela -- Gamble, John -- Hinton, Jonathan -- Jia, Mingming -- Jayakumar, Alagu -- Jones, David -- Latimer, Calli -- Lau, King Wai -- McLaren, Stuart -- McBride, David J -- Menzies, Andrew -- Mudie, Laura -- Raine, Keiran -- Rad, Roland -- Chapman, Michael Spencer -- Teague, Jon -- Easton, Douglas -- Langerod, Anita -- Oslo Breast Cancer Consortium (OSBREAC) -- Lee, Ming Ta Michael -- Shen, Chen-Yang -- Tee, Benita Tan Kiat -- Huimin, Bernice Wong -- Broeks, Annegien -- Vargas, Ana Cristina -- Turashvili, Gulisa -- Martens, John -- Fatima, Aquila -- Miron, Penelope -- Chin, Suet-Feung -- Thomas, Gilles -- Boyault, Sandrine -- Mariani, Odette -- Lakhani, Sunil R -- van de Vijver, Marc -- van 't Veer, Laura -- Foekens, John -- Desmedt, Christine -- Sotiriou, Christos -- Tutt, Andrew -- Caldas, Carlos -- Reis-Filho, Jorge S -- Aparicio, Samuel A J R -- Salomon, Anne Vincent -- Borresen-Dale, Anne-Lise -- Richardson, Andrea L -- Campbell, Peter J -- Futreal, P Andrew -- Stratton, Michael R -- 077012/Z/05/Z/Wellcome Trust/United Kingdom -- 088340/Wellcome Trust/United Kingdom -- 093867/Wellcome Trust/United Kingdom -- 10118/Cancer Research UK/United Kingdom -- CA089393/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- WT088340MA/Wellcome Trust/United Kingdom -- Cancer Research UK/United Kingdom -- Chief Scientist Office/United Kingdom -- Department of Health/United Kingdom -- England -- Nature. 2012 May 16;486(7403):400-4. doi: 10.1038/nature11017.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722201" target="_blank"〉PubMed〈/a〉
    Keywords: Age Factors ; Breast Neoplasms/classification/*genetics/pathology ; Cell Transformation, Neoplastic/*genetics ; Cytosine/metabolism ; DNA Mutational Analysis ; Female ; Humans ; JNK Mitogen-Activated Protein Kinases/metabolism ; Mutagenesis/*genetics ; Mutation/*genetics ; Neoplasm Grading ; Oncogenes/*genetics ; Reproducibility of Results ; Signal Transduction/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
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    JointSNVMix: a probabilistic model for accurate detection of somatic mutations in normal/tumour paired next-generation sequencing data (2012)
    Oxford University Press
    Details
    Publication Date: 2012-03-31
    Description: Motivation: Identification of somatic single nucleotide variants (SNVs) in tumour genomes is a necessary step in defining the mutational landscapes of cancers. Experimental designs for genome-wide ascertainment of somatic mutations now routinely include next-generation sequencing (NGS) of tumour DNA and matched constitutional DNA from the same individual. This allows investigators to control for germline polymorphisms and distinguish somatic mutations that are unique to the tumour, thus reducing the burden of labour-intensive and expensive downstream experiments needed to verify initial predictions. In order to make full use of such paired datasets, computational tools for simultaneous analysis of tumour–normal paired sequence data are required, but are currently under-developed and under-represented in the bioinformatics literature. Results: In this contribution, we introduce two novel probabilistic graphical models called JointSNVMix1 and JointSNVMix2 for jointly analysing paired tumour–normal digital allelic count data from NGS experiments. In contrast to independent analysis of the tumour and normal data, our method allows statistical strength to be borrowed across the samples and therefore amplifies the statistical power to identify and distinguish both germline and somatic events in a unified probabilistic framework. Availability: The JointSNVMix models and four other models discussed in the article are part of the JointSNVMix software package available for download at http://compbio.bccrc.ca Contact: sshah@bccrc.ca Supplementary information: Supplementary data are available at Bioinformatics online.
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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