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Dive into the research topics where Jamie Rosner is active.

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Featured researches published by Jamie Rosner.


Nature | 2012

The clonal and mutational evolution spectrum of primary triple-negative breast cancers.

Sohrab P. Shah; Andrew Roth; Rodrigo Goya; Arusha Oloumi; Gavin Ha; Yongjun Zhao; Gulisa Turashvili; Jiarui Ding; Kane Tse; Gholamreza Haffari; Ali Bashashati; Leah M Prentice; Jaswinder Khattra; Angela Burleigh; Damian Yap; Virginie Bernard; Andrew McPherson; Karey Shumansky; Anamaria Crisan; Ryan Giuliany; Alireza Heravi-Moussavi; Jamie Rosner; Daniel Lai; Inanc Birol; Richard Varhol; Angela Tam; Noreen Dhalla; Thomas Zeng; Kevin Ma; Simon K. Chan

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.


Nature | 2015

Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution.

Peter Eirew; Adi Steif; Jaswinder Khattra; Gavin Ha; Damian Yap; Hossein Farahani; Karen A. Gelmon; Stephen Chia; Colin Mar; Adrian Wan; Emma Laks; Justina Biele; Karey Shumansky; Jamie Rosner; Andrew McPherson; Cydney Nielsen; Andrew Roth; Calvin Lefebvre; Ali Bashashati; Camila P. E. de Souza; Celia Siu; Radhouane Aniba; Jazmine Brimhall; Arusha Oloumi; Tomo Osako; Alejandra Bruna; Jose L. Sandoval; Teresa Ruiz de Algara; Wendy Greenwood; Kaston Leung

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.


The Journal of Pathology | 2013

Distinct evolutionary trajectories of primary high-grade serous ovarian cancers revealed through spatial mutational profiling

Ali Bashashati; Gavin Ha; Alicia A. Tone; Jiarui Ding; Leah M Prentice; Andrew Roth; Jamie Rosner; Karey Shumansky; Steve E. Kalloger; Janine Senz; Winnie Yang; Melissa K. McConechy; Nataliya Melnyk; Michael S. Anglesio; Margaret Luk; Kane Tse; Thomas Zeng; Richard G. Moore; Yongjun Zhao; Marco A. Marra; Blake Gilks; Stephen Yip; David Huntsman; Jessica N. McAlpine; Sohrab P. Shah

High‐grade serous ovarian cancer (HGSC) is characterized by poor outcome, often attributed to the emergence of treatment‐resistant subclones. We sought to measure the degree of genomic diversity within primary, untreated HGSCs to examine the natural state of tumour evolution prior to therapy. We performed exome sequencing, copy number analysis, targeted amplicon deep sequencing and gene expression profiling on 31 spatially and temporally separated HGSC tumour specimens (six patients), including ovarian masses, distant metastases and fallopian tube lesions. We found widespread intratumoural variation in mutation, copy number and gene expression profiles, with key driver alterations in genes present in only a subset of samples (eg PIK3CA, CTNNB1, NF1). On average, only 51.5% of mutations were present in every sample of a given case (range 10.2–91.4%), with TP53 as the only somatic mutation consistently present in all samples. Complex segmental aneuploidies, such as whole‐genome doubling, were present in a subset of samples from the same individual, with divergent copy number changes segregating independently of point mutation acquisition. Reconstruction of evolutionary histories showed one patient with mixed HGSC and endometrioid histology, with common aetiologic origin in the fallopian tube and subsequent selection of different driver mutations in the histologically distinct samples. In this patient, we observed mixed cell populations in the early fallopian tube lesion, indicating that diversity arises at early stages of tumourigenesis. Our results revealed that HGSCs exhibit highly individual evolutionary trajectories and diverse genomic tapestries prior to therapy, exposing an essential biological characteristic to inform future design of personalized therapeutic solutions and investigation of drug‐resistance mechanisms.


BMC Genomics | 2008

A salmonid EST genomic study: genes, duplications, phylogeny and microarrays

Ben F. Koop; Kristian R. von Schalburg; Jong Leong; Neil Walker; Ryan Lieph; Glenn A. Cooper; Adrienne Robb; Marianne Beetz-Sargent; Robert A. Holt; Richard A. Moore; Sonal Brahmbhatt; Jamie Rosner; Caird E. Rexroad; Colin R. McGowan; William S. Davidson

BackgroundSalmonids are of interest because of their relatively recent genome duplication, and their extensive use in wild fisheries and aquaculture. A comprehensive gene list and a comparison of genes in some of the different species provide valuable genomic information for one of the most widely studied groups of fish.Results298,304 expressed sequence tags (ESTs) from Atlantic salmon (69% of the total), 11,664 chinook, 10,813 sockeye, 10,051 brook trout, 10,975 grayling, 8,630 lake whitefish, and 3,624 northern pike ESTs were obtained in this study and have been deposited into the public databases. Contigs were built and putative full-length Atlantic salmon clones have been identified. A database containing ESTs, assemblies, consensus sequences, open reading frames, gene predictions and putative annotation is available. The overall similarity between Atlantic salmon ESTs and those of rainbow trout, chinook, sockeye, brook trout, grayling, lake whitefish, northern pike and rainbow smelt is 93.4, 94.2, 94.6, 94.4, 92.5, 91.7, 89.6, and 86.2% respectively. An analysis of 78 transcript sets show Salmo as a sister group to Oncorhynchus and Salvelinus within Salmoninae, and Thymallinae as a sister group to Salmoninae and Coregoninae within Salmonidae. Extensive gene duplication is consistent with a genome duplication in the common ancestor of salmonids. Using all of the available EST data, a new expanded salmonid cDNA microarray of 32,000 features was created. Cross-species hybridizations to this cDNA microarray indicate that this resource will be useful for studies of all 68 salmonid species.ConclusionAn extensive collection and analysis of salmonid RNA putative transcripts indicate that Pacific salmon, Atlantic salmon and charr are 94–96% similar while the more distant whitefish, grayling, pike and smelt are 93, 92, 89 and 86% similar to salmon. The salmonid transcriptome reveals a complex history of gene duplication that is consistent with an ancestral salmonid genome duplication hypothesis. Genome resources, including a new 32 K microarray, provide valuable new tools to study salmonids.


Genome Research | 2012

Integrative analysis of genome-wide loss of heterozygosity and monoallelic expression at nucleotide resolution reveals disrupted pathways in triple-negative breast cancer

Gavin Ha; Andrew Roth; Daniel Lai; Ali Bashashati; Jiarui Ding; Rodrigo Goya; Ryan Giuliany; Jamie Rosner; Arusha Oloumi; Karey Shumansky; Suet-Feung Chin; Gulisa Turashvili; Martin Hirst; Carlos Caldas; Marco A. Marra; Samuel Aparicio; Sohrab P. Shah

Loss of heterozygosity (LOH) and copy number alteration (CNA) feature prominently in the somatic genomic landscape of tumors. As such, karyotypic aberrations in cancer genomes have been studied extensively to discover novel oncogenes and tumor-suppressor genes. Advances in sequencing technology have enabled the cost-effective detection of tumor genome and transcriptome mutation events at single-base-pair resolution; however, computational methods for predicting segmental regions of LOH in this context are not yet fully explored. Consequently, whole transcriptome, nucleotide-level resolution analysis of monoallelic expression patterns associated with LOH has not yet been undertaken in cancer. We developed a novel approach for inference of LOH from paired tumor/normal sequence data and applied it to a cohort of 23 triple-negative breast cancer (TNBC) genomes. Following extensive benchmarking experiments, we describe the nucleotide-resolution landscape of LOH in TNBC and assess the consequent effect of LOH on the transcriptomes of these tumors using RNA-seq-derived measurements of allele-specific expression. We show that the majority of monoallelic expression in the transcriptomes of triple-negative breast cancer can be explained by genomic regions of LOH and establish an upper bound for monoallelic expression that may be explained by other tumor-specific modifications such as epigenetics or mutations. Monoallelically expressed genes associated with LOH reveal that cell cycle, homologous recombination and actin-cytoskeletal functions are putatively disrupted by LOH in TNBC. Finally, we show how inference of LOH can be used to interpret allele frequencies of somatic mutations and postulate on temporal ordering of mutations in the evolutionary history of these tumors.


Genome Research | 2014

TITAN: inference of copy number architectures in clonal cell populations from tumor whole-genome sequence data

Gavin Ha; Andrew Roth; Jaswinder Khattra; Julie Ho; Damian Yap; Leah M Prentice; Nataliya Melnyk; Andrew McPherson; Ali Bashashati; Emma Laks; Justina Biele; Jiarui Ding; Alan Le; Jamie Rosner; Karey Shumansky; Marco A. Marra; C. Blake Gilks; David Huntsman; Jessica N. McAlpine; Samuel Aparicio; Sohrab P. Shah

The evolution of cancer genomes within a single tumor creates mixed cell populations with divergent somatic mutational landscapes. Inference of tumor subpopulations has been disproportionately focused on the assessment of somatic point mutations, whereas computational methods targeting evolutionary dynamics of copy number alterations (CNA) and loss of heterozygosity (LOH) in whole-genome sequencing data remain underdeveloped. We present a novel probabilistic model, TITAN, to infer CNA and LOH events while accounting for mixtures of cell populations, thereby estimating the proportion of cells harboring each event. We evaluate TITAN on idealized mixtures, simulating clonal populations from whole-genome sequences taken from genomically heterogeneous ovarian tumor sites collected from the same patient. In addition, we show in 23 whole genomes of breast tumors that the inference of CNA and LOH using TITAN critically informs population structure and the nature of the evolving cancer genome. Finally, we experimentally validated subclonal predictions using fluorescence in situ hybridization (FISH) and single-cell sequencing from an ovarian cancer patient sample, thereby recapitulating the key modeling assumptions of TITAN.


Genome Biology | 2012

DriverNet: uncovering the impact of somatic driver mutations on transcriptional networks in cancer

Ali Bashashati; Gholamreza Haffari; Jiarui Ding; Gavin Ha; Kenneth Lui; Jamie Rosner; David Huntsman; Carlos Caldas; Samuel Aparicio; Sohrab P. Shah

Simultaneous interrogation of tumor genomes and transcriptomes is underway in unprecedented global efforts. Yet, despite the essential need to separate driver mutations modulating gene expression networks from transcriptionally inert passenger mutations, robust computational methods to ascertain the impact of individual mutations on transcriptional networks are underdeveloped. We introduce a novel computational framework, DriverNet, to identify likely driver mutations by virtue of their effect on mRNA expression networks. Application to four cancer datasets reveals the prevalence of rare candidate driver mutations associated with disrupted transcriptional networks and a simultaneous modulation of oncogenic and metabolic networks, induced by copy number co-modification of adjacent oncogenic and metabolic drivers. DriverNet is available on Bioconductor or at http://compbio.bccrc.ca/software/drivernet/.


Nature Genetics | 2016

Divergent modes of clonal spread and intraperitoneal mixing in high-grade serous ovarian cancer

Andrew McPherson; Andrew Roth; Emma Laks; Tehmina Masud; Ali Bashashati; Allen W. Zhang; Gavin Ha; Justina Biele; Damian Yap; Adrian Wan; Leah M Prentice; Jaswinder Khattra; Maia A. Smith; Cydney Nielsen; Sarah C. Mullaly; Steve E. Kalloger; Anthony N. Karnezis; Karey Shumansky; Celia Siu; Jamie Rosner; Hector Li Chan; Julie Ho; Nataliya Melnyk; Janine Senz; Winnie Yang; Richard G. Moore; Andrew J. Mungall; Marco A. Marra; Alexandre Bouchard-Côté; C. Blake Gilks

We performed phylogenetic analysis of high-grade serous ovarian cancers (68 samples from seven patients), identifying constituent clones and quantifying their relative abundances at multiple intraperitoneal sites. Through whole-genome and single-nucleus sequencing, we identified evolutionary features including mutation loss, convergence of the structural genome and temporal activation of mutational processes that patterned clonal progression. We then determined the precise clonal mixtures comprising each tumor sample. The majority of sites were clonally pure or composed of clones from a single phylogenetic clade. However, each patient contained at least one site composed of polyphyletic clones. Five patients exhibited monoclonal and unidirectional seeding from the ovary to intraperitoneal sites, and two patients demonstrated polyclonal spread and reseeding. Our findings indicate that at least two distinct modes of intraperitoneal spread operate in clonal dissemination and highlight the distribution of migratory potential over clonal populations comprising high-grade serous ovarian cancers.


PLOS Medicine | 2016

Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study

Robert Kridel; Fong Chun Chan; Anja Mottok; Merrill Boyle; Pedro Farinha; King Tan; Barbara Meissner; Ali Bashashati; Andrew McPherson; Andrew Roth; Karey Shumansky; Damian Yap; Susana Ben-Neriah; Jamie Rosner; Maia A. Smith; Cydney Nielsen; Eva Giné; Adele Telenius; Daisuke Ennishi; Andrew J. Mungall; Richard A. Moore; Ryan D. Morin; Nathalie A. Johnson; Laurie H. Sehn; Thomas Tousseyn; Ahmet Dogan; Joseph M. Connors; David W. Scott; Christian Steidl; Marco A. Marra

Background Follicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories. Methods and Findings Using a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly mutated in diagnostic specimens of patients with early progression, including TP53, BTG1, MKI67, and XBP1. Conclusions Our results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implications for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.


Nature Communications | 2017

CLK-dependent exon recognition and conjoined gene formation revealed with a novel small molecule inhibitor

Tyler Funnell; Shinya Tasaki; Arusha Oloumi; Shinsuke Araki; Esther Kong; Damian Yap; Yusuke Nakayama; Christopher S. Hughes; S.-W. Grace Cheng; Hirokazu Tozaki; Misa Iwatani; Satoshi Sasaki; Tomohiro Ohashi; Tohru Miyazaki; Nao Morishita; Daisuke Morishita; Mari Ogasawara-Shimizu; Momoko Ohori; Shoichi Nakao; Masatoshi Karashima; Masaya Sano; Aiko Murai; Toshiyuki Nomura; Noriko Uchiyama; Tomohiro Kawamoto; Ryujiro Hara; Osamu Nakanishi; Karey Shumansky; Jamie Rosner; Adrian Wan

CDC-like kinase phosphorylation of serine/arginine-rich proteins is central to RNA splicing reactions. Yet, the genomic network of CDC-like kinase-dependent RNA processing events remains poorly defined. Here, we explore the connectivity of genomic CDC-like kinase splicing functions by applying graduated, short-exposure, pharmacological CDC-like kinase inhibition using a novel small molecule (T3) with very high potency, selectivity, and cell-based stability. Using RNA-Seq, we define CDC-like kinase-responsive alternative splicing events, the large majority of which monotonically increase or decrease with increasing CDC-like kinase inhibition. We show that distinct RNA-binding motifs are associated with T3 response in skipped exons. Unexpectedly, we observe dose-dependent conjoined gene transcription, which is associated with motif enrichment in the last and second exons of upstream and downstream partners, respectively. siRNA knockdown of CLK2-associated genes significantly increases conjoined gene formation. Collectively, our results reveal an unexpected role for CDC-like kinase in conjoined gene formation, via regulation of 3′-end processing and associated splicing factors.The phosphorylation of serine/arginine-rich proteins by CDC-like kinase is a central regulatory mechanism for RNA splicing reactions. Here, the authors synthesize a novel small molecule CLK inhibitor and map CLK-responsive alternative splicing events and discover an effect on conjoined gene transcription.

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Karey Shumansky

University of British Columbia

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Andrew Roth

University of British Columbia

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Sohrab P. Shah

University of British Columbia

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Jiarui Ding

University of British Columbia

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Marco A. Marra

University of British Columbia

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Arusha Oloumi

University of British Columbia

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