Samuel Aparicio

Professor

Relevant Degree Programs

 

Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - Mar 2019)
Tumour evolution at single-cell resolution (2018)

No abstract available.

Charting clonal heterogeneity in breast cancers : from bulk tumor genomes to single-cell genotypes (2015)

Traditional classifications and treatment of human cancers have operated with limitations surrounding tumor homogeneity and mutational stasis. Clinical metrics of malignant tumors focused on descriptive and behavioral properties such as tissue of origin, cellular morphologic features and extent of spread. Missing has been an understanding of the dynamics of cellular subpopulations that underpin divergent functional properties in space and time. This dissertation is focused on the development and application of methods, including next generation DNA sequencing, computational modeling, and single-cell genotyping protocols to elucidate breast tumor heterogeneity and clonal evolution at single nucleotide and single-cell resolution. First, I present advances in our knowledge of the mutational spectrum that may occur and evolve in an individual epithelial cancer, namely a lobular breast cancer metastases and matched primary tumor separated by a nine year interval. This seminal study demonstrated clonal evolution in a patient’s breast cancer and the successful application of targeted deep sequencing for determining digital allelic prevalences and clonal genotypes in bulk tumors. Second, I describe the diversity of genomic sequence and clonal heterogeneity in tumors of the triple-negative breast cancer subtype. The study uncovered wide clonal diversity in these primary tumors at first diagnosis. Third, I demonstrate via genotyping single tumor cells, that computational inferences of tumor clonal architecture can be made reliably from bulk tissue-derived data sets. This was performed using both somatic point mutations and loss of heterozygosity loci as clonal marks. And fourth, I applied single-cell analysis to study the clonal evolution in breast tumor murine xenografts following engraftment and serial passaging. This research uncovered a range of outcomes in tumor clonal composition upon initial engraftment and serial passaging. The same clonal groups were found to arise independently in separate xenografts derived from the same primary tumor, suggesting selection of functionally significant genotypes. Comprehensive capabilities in the measurement and analysis of clonal structure in cancers offers improved classification and combinatorial treatments of subpopulations in heterogeneous tumors and better use of murine xenograft models. Functionally relevant subpopulations of tumor cells, irrespective of numerical abundance or spatiotemporal persistence, can thereby be targeted using clonally informative genomic profiles.

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Functional studies of PPP2R2A in breast cancer (2015)

PPP2R2A is a regulatory subunit of protein phosphatase 2A (PP2A). Genomic analysis based on 2000 breast cancer cases identified PPP2R2A as one of the deletion hotspots in breast cancer genomes and 63% of PPP2R2A deletions were found in estrogen receptor positive (ER+) breast cancers. We hypothesized that the high frequency deletion of PPP2R2A, as well as its correlation with ER expression status, implies its functional roles in breast cancer development. In this thesis, I investigated the functional impacts of PPP2R2A deletion in breast cancer development from the aspects of ER signaling, PP2A complex composition, and cell morphological changes. First, I studied ER signaling activity and mechanism in T47D cells with the analysis of transcriptome, ER binding specificity and ER co-factor recruitment, etc. Second, I studied PP2A complex composition in three breast cell models with targeted quantitative mass spectrometry (MRM). Last, I studied morphological changes in mammary breast cell models, 184-hTERT and MCF10A, in terms of cell proliferation, surface protein localization, and cell mobility based on transcriptome and signaling network analysis. As a result, reduced expression of PPP2R2A led to differential expression of ER response genes, alterations in ER binding specificity, and changes in ER co-factor composition. SPDEF was particularly up regulated and recruited in ER transcriptional machinery. Analysis in clinical samples also confirmed the correlation of SPDEF up regulation with ER expression status and PPP2R2A copy number loss. In addition, MRM analysis revealed changes in PP2A complex composition after PPP2R2A knockdown with increased relative abundance of STRN in PP2A complexes in ER positive cell models. Finally, my morphological studies demonstrated mislocalization of cell surface proteins and enhanced cell mobility in breast mammary epithelial cell models with reduced PPP2R2A expression. In conclusion, PPP2R2A plays an important role in regulating cell signaling activity and cellular morphology and its genomic deletion would significantly contribute to the development of breast cancer.

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Probabilistic approaches for profiling copy number aberrations and loss of heterozygosity landscapes in cancer genomes (2014)

Genomic aberrations such as copy number alterations (CNA) and loss of heterozygosity (LOH) are hallmarks of human malignancies. These genomic abnormalities can have a measurable effect on the structure and dosage of chromosomal regions. Tumour suppressors and oncogenes altered by CNAs often contribute to a tumourigenic phenotype of increased proliferation. CNA and LOH can accrue through the process of branched evolution, resulting in the emergence of divergent clones with distinct aberrations present at diagnosis. Therefore, measuring and modeling how CNA/LOH distribute in cell populations can elucidate the abundance of specific clones and, ultimately, enable the study of clonal evolution. CNA/LOH events in tumours can be profiled using SNP genotyping arrays and whole genome sequencing (WGS). However, to maximize biological interpretability from these data, accurate and statistically robust computational methods for inferring CNA/LOH are necessary.I present three novel probabilistic approaches that apply hidden Markov models (HMM) to analyze CNA/LOH in tumour genomes. The first method is HMM-Dosage, which distinguishes somatic and germline copy number events. This tool was used to profile 2000 breast cancers, the largest study of this kind in the world. The second method is APOLLOH, which was one of the earliest methods developed to profile LOH in tumour WGS data. Its application to WGS of 23 triple negative breast cancers (TNBC) represents the first time that LOH and its effects on allelic expression were jointly analyzed from sequencing data. The third method is TITAN, which simultaneously infers CNA/LOH and the clonal population dynamics from tumour WGS data. This method provides an analytical route to studying the degree of clonal evolution driven by CNA/LOH. I applied TITAN to a novel set of primary breast tumours and corresponding mouse xenografts, presenting the results of distinct modes of temporal clonal selection patterns. In conclusion, this dissertation presents a suite of novel approaches and their application to real-world cancer datasets, contributing to significant discoveries in breast and ovarian cancers. Future applications of these approaches will further facilitate the elucidation of cancer evolution, the genetic basis of metastatic potential, and therapeutic response and resistance.

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Regulatory mechanisms governing mammary epithelial and progenitor cell growth (2011)

The processes involved in mammary gland development are intimately linked withthose that drive breast oncogenesis. Regulation of growth, tissue polarity and genomestability are a few of the factors the maintain homeostasis in breast epithelium and preventmalignant progression. In this work, a series of clonal 184-hTERT cell lines were generatedthat modeled the in vitro growth characteristics of bi-potent mammary progenitor cells; theywere dependent upon fibroblasts for low-density growth and formed dual-lineage acini in 3Dculture. These lines were subsequently used in a genome-wide siRNA screen to identify thefactors that regulate fibroblast-driven epithelial cell growth. Fibroblasts constitute themajority of cells within stroma, which plays a major role in supporting mammary progenitorcell growth. From this screen, 49 surface and secreted factors were identified that putativelytransduce the signals emanating from the fibroblasts that are required for epithelial cellgrowth. These factors were more potent than any of the previously described growth factorreceptors. When assessed in primary tissue, Gpr39, Scarb2, Ntn1, Efna4, Nptx1, and Ctnna1were found to have the greatest effect on overall progenitor cell growth, while SerpinH1differentially suppressed luminal progenitor cells, and Nkain4 and Kcnj5 differentiallysuppressed bi-potent progenitor cells. Further profiling of these lines identified the planarcell polarity protein Celsr1 as differentially regulated under fibroblast-dependent conditions.Silencing of Celsr1 increased the number of bi-potent progenitor cells detected in the colonyformingassay. Furthermore, it induced branching morphogenesis within normally sphericalacini and disrupted the apical polarity of these structures in 3D culture. Within this system,Celsr1 is suspected of signaling through Shisa4. This is the first description of a noncanonicalCelsr1 interactor. Finally, a curious variant line was identified amongst thecollection of 184-hTERT cells generated for this work. This line harbours mitotic spindleand cell cycle checkpoint defects, and rapidly gains chromosome 20 during passaging.Through an elimination process, de novo promoter hypomethylation and subsequentoverexpression of CENPI was identified as likely being responsible for this phenotype. Thisis the first description of CENPI deregulation and one of a few descriptions of gene promoterhypomethylation resulting in genome instability.

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The kisspeptin and GPR54 ligand-receptor pair in autocrine and endocrine signalling in cancer (2009)

Kisspeptins and their receptor, GPR54, mediate sex hormone release through stimulation of the hypothalamic-pituitary-gonadal axis and have been implicated as metastasis suppressors. Expression of kisspeptin and GPR54 has been associated with less invasive cancers as determined by RNA expression, and a multitude of in vitro studies has consistently shown that overexpression of either ligand or receptor in malignant cell lines results in a less invasive phenotype. We hypothesized that expression of GPR54/kisspeptin in epithelial malignancies is predictive of disease outcome and altering endogenous GPR54 signalling in malignant breast and ovarian epithelial cells could alter their metastatic properties. We have determined by immunohistochemistry that kisspeptin and GPR54 are independent favourable prognostic markers for ovarian carcinoma and are specific for the clear cell cancer subtype; the least characterized of the subtypes. Additionally, loss of GPR54 is associated with poor prognosis in node positive breast cancer patients and is also lost in prostate cancer and testicular germ cell nonseminomas as compared to more benign disease. Moreover, secreted kisspeptin is elevated above physiological levels in the plasma of women with gynaecological cancers, including ovarian cancer. We evaluated GPR54 expression across a panel of breast and ovarian cancer cell lines to create an in vitro model system with which to knockdown GPR54 expression using RNA interference. However, we discovered that endogenous GPR54 was internalized rather than localized to the plasma membrane of these cancer cell lines. Consequently, internal GPR54 was unable to signal through its canonical Gαq pathway. To discover novel genes involved in kisspeptin-GPR54 signalling, we assessed gene expression differences between the Gpr54 and Kiss1 knockout mice as compared to wildtype mice. Our novel candidate list provides insight into physiological signalling in the hypothalamus that can then be applied to epithelial anti-metastatic signalling. Our results also support the sex hormone negative feedback effect on kisspeptin expression as reported in the current literature.In summary, we have confirmed kisspeptin and GPR54 as favourable prognostic markers, are the first to report the intracellular localization of GPR54 in endogenously expressing cancer cell lines, and we have introduced a list of novel genes involved in signalling.

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Master's Student Supervision (2010-2017)
Simulating human tumour heterogeneity using cancer cell line mixtures (2015)

Tumours comprise (epi)genetically and phenotypically diverse cellular subpopulationsevolving over space and time. This heterogeneity can be observed as differences in morphologyor immunohistology of tumour sections, gene expression levels, genomic sequence and structure,proliferative potential, or metastatic ability. In order to unravel how this heterogeneity persists,one may study the clonal structure and evolution of tumours. Understanding intra-tumorheterogeneity, or the differences amongst cells in a single tumour, is of particular importance tofacilitate treatment combinations that effectively target all clinically relevant subclones. Thisclonality-informed approach requires identification and monitoring of clonal cell populationswithin a tumour. In this study I simulated tumour heterogeneity using cancer cells lines inidealised mixtures. Deep allelic measurements using next generation DNA amplicon sequencingwere integrated in a computational modelling program (PyClone), to retrieve cellularprevalence’s and clonal structure within these cell line mixtures. This approach to modelingheterogeneity employed both diploid and aneuploid cell lines with genomic analysis focused onheterozygous alleles and changes in the prevalence of theses alleles when cell lines were mixedin different proportions. As a result I first identified that using NGS and PyClone modelingenables elucidation of population clonal structure as predicted from idealised mixtures of diploidcell lines. However, the aneuploidy cell line mixtures demonstrated a requirement for copynumber information to be included as a prior input to clonality modeling in order to avoidmisleading interpretations of cellular prevalence and clonal structure. Defining and monitoringclonal heterogeneity in patient tumours is of importance to track functionally relevantsubpopulations of tumour cells, enabling oncologists to administer cocktails of therapeutic agentstargeting relevant clones irrespective of their numerical abundance. This clonality-informediiitreatment approach is a promising development to tackle the growing challenge of therapy resistantsubclones and thus limit cancer recurrence.

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Mutation discovery in regions of segmental cancer genome amplifications from next generation sequencing of tumours (2010)

Next generation sequencing has now enabled a cost-effective enumeration of the full mutational complement of a tumour genome - in particular single nucleotide variants (SNVs). However, most current computational and statistical models for analyzing next generation sequencing data do not account for cancer-specific biological properties, including somatic segmental copy number alterations (CNAs), which require special treatment of the data. Here we present CoNAn-SNV (Copy Number Annotated –SNV): a novel algorithm for the inference of single nucleotide variants (SNVs) that overlap copy number alterations. The method is based on modelling the notion that genomic regions of segmental duplication and amplification induce an extended ‘genotype space’ where a subset of genotypes will exhibit heavily skewed allelic distributions in SNVs (and therefore render them undetectable by methods that assume diploidy). CoNAn-SNV introduces the concept of modelling allelic counts from sequencing data using a panel of Binomial mixture models where the number of mixtures for a given locus in the genome is informed by a discrete copy number state given as input. We applied CoNAn-SNV to a previously published whole genome shotgun data set obtained from a lobular breast cancer and show that it is able to detect 24 experimentally revalidated somatic non-synonymous mutations that were not detected using copy number insensitive SNV discovery algorithms. Importantly, ROC analysis shows that the increased sensitivity of CoNAn-SNV does not result in disproportionate loss of specificity. Our results indicate that in genomically unstable tumours, copy number annotation for SNV detection will be critical to fully characterize the mutational landscape of cancer genomes. The Binomial mixture model framework, however, is unable to fully cope with the complexity of tumour sequence data. We explore substituting the Binomial mixture model framework with the Beta-Binomial framework to overcome this limitation. The effectiveness of this substitution is compared against the lobular breast carcinoma and the 30 exon capture data sets all derived from triple negative breast cancers. The performance of Binomial and Beta-Binomial mixture model is evaluated against a cohort of exon capture test cases and we report ROC and f-measures.

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Recent Tri-Agency Grants

The following is a selection of grants for which the faculty member was principal investigator or co-investigator. Currently, the list only covers Canadian Tri-Agency grants from years 2013/14-2016/17 and excludes grants from any other agencies.

  • Centre for Epigenome Mapping Technologies (CEMT) - Canadian Institutes of Health Research (CIHR) - CEEHRC Phase II: Platform Centres Renewal (2016/2017)
  • Targeted radiopharmaceuticals to improve cancer diagnosis and treatment - Canadian Institutes of Health Research (CIHR) - Foundation Scheme: 2015 2nd Live Pilot - Stage 2 (2016/2017)
  • Targeting the dynamics and genomics of clonal evolution in cancer patients - Canadian Institutes of Health Research (CIHR) - Foundation Scheme: 2015 2nd Live Pilot - Stage 2 (2016/2017)
  • Canada Research Chair in Molecular Oncology for Dr. Samuel Aparicio - Canada Research Chairs - Canada Research Chair Tier I (CIHR) (2015/2016)
  • The clonal dynamics of ovarian cancers: phylogenetic models of chemosensitivity and resistance - Canadian Institutes of Health Research (CIHR) - Foundation Scheme : 2014 1st Live Pilot - Stage 2 (2015/2016)
  • The role of tumor microenvironment in cancer progression: Identification and therapeutic intervention of novel targets - Canadian Institutes of Health Research (CIHR) - Foundation Scheme : 2014 1st Live Pilot - Stage 2 (2015/2016)
  • SFU 13-876736 Gorski Top-up - Canadian Institutes of Health Research (CIHR) - Operating Grant Priority Announcement (2014/2015)
  • The terry fox foundation strategic health research training program in molecular pathology of cancer - Canadian Institutes of Health Research (CIHR) - Strategic Training Program Grant - CIHR (2013/2014)
  • Recurrent somatic DICER 1 mutations: Funcitional implication and role in oncogenesis - Canadian Institutes of Health Research (CIHR) - Operating Grant (2013/2014)
  • Linking clonal genomes to tumour evolution and therapeutics - Canadian Institutes of Health Research (CIHR) - Operating Grant (2013/2014)
  • Centre for epigenomic mapping techniques - Canadian Institutes of Health Research (CIHR) - Team Grant: Canadian Epigenetics, Environment, and Health Research Consortium (CEEHRC) (2013/2014)
  • PP2A protein serin/theonine phosphatase mutations in cancer: functional consequences and clinical relevance - Canadian Institutes of Health Research (CIHR) - Operating Grant (2013/2014)
  • Mutations in the SWI/SNF chromatin remodeling complex genes: an alternative mechanism for ovarian carcinogenesis - Canadian Institutes of Health Research (CIHR) - Operating Grant (2013/2014)
  • The Terry Fox New Frontiers Project in the genomics of form fruste tumours - new vistas on cancer biology and management - Canadian Institutes of Health Research (CIHR) - CIHR Team Grant Program (2013/2014)
  • Canada Research Chair in Molecular Oncology for Dr. Samuel Aparicio - Canada Research Chairs - Canada Research Chair Tier II (CIHR) (2013/2014)

Publications

  • clonealign: statistical integration of independent single-cell RNA & DNA-seq from human cancers (2018)

    Campbell, Kieran R and Steif, Adi and Laks, Emma and Zahn, Hans and Lai, Daniel and McPherson, Andrew and Farahani, Hossein and Kabeer, Farhia and O'Flanagan, Ciara and Biele, Justina and Brimhall, Jazmine and Wang, Beixi and Walters, Array, and Bouchard-Cote, Alexandre and Aparicio, Samuel and Shah, Sohrab P
    bioRxiv 344309

  • Atrophin controls developmental signaling pathways via interactions with Trithorax-like (2017)

    Yeung, Kelvin and Boija, Ann and Karlsson, Edvin and Holmqvist, Per-Henrik and Tsatskis, Yonit and Nisoli, Ilaria and Yap, Damian B and Lorzadeh, Alireza and Moksa, Michelle and Hirst, Martin and Aparicio, Samuel and Fanto, Manolis and Stenberg, Per and Mannervik, Mattias and McNeill, Helen
    Elife 6

  • CDK12 regulates alternative last exon mRNA splicing and promotes breast cancer cell invasion (2017)

    Tien, Jerry F and Mazloomian, Alborz and Cheng, S-W Grace and Hughes, Christopher S and Chow, Christalle C T and Canapi, Leanna T and Oloumi, Arusha and Trigo-Gonzalez, Genny and Bashashati, Ali and Xu, James and Chang, Vicky C-D and Shah, Sohrab P and Aparicio, Samuel and Morin, Gregg B
    Nucleic Acids Res.

  • CX-5461 is a DNA G-quadruplex stabilizer with selective lethality in BRCA1/2 deficient tumours (2017)

    Xu, Hong and Di Antonio, Marco and McKinney, Steven and Mathew, Veena and Ho, Brandon and O'Neil, Nigel J and Santos, Nancy Dos and Silvester, Jennifer and Wei, Vivien and Garcia, Jessica and Kabeer, Farhia and Lai, Daniel and Soriano, Priscilla and Banath, Judit and Chiu, Derek S and Yap, Damian and Le, Daniel D and Ye, Frank B and Zhang, Anni and Thu, Kelsie and Soong, John and Lin, Shu-Ch
    Nat. Commun. 8 14432

  • Discovery of selective ATP-competitive eIF4A3 inhibitors (2017)

    Ito, Masahiro and Iwatani, Misa and Kamada, Yusuke and Sogabe, Satoshi and Nakao, Shoichi and Tanaka, Toshio and Kawamoto, Tomohiro and Aparicio, Samuel and Nakanishi, Atsushi and Imaeda, Yasuhiro
    Bioorg. Med. Chem. 25 (7) 2200--2209

  • Scalable whole-genome single-cell library preparation without preamplification (2017)
    Hans Zahn and Adi Steif and Emma Laks and Peter Eirew and Michael VanInsberghe and Sohrab P Shah and Samuel Aparicio and Carl L Hansen
    Nature Methods 14 (2) 167--173
  • The RNA helicase DDX39B and its paralog DDX39A regulate androgen receptor splice variant AR-V7 generation (2017)

    Nakata, Daisuke and Nakao, Shoichi and Nakayama, Kazuhide and Araki, Shinsuke and Nakayama, Yusuke and Aparicio, Samuel and Hara, Takahito and Nakanishi, Atsushi
    Biochem. Biophys. Res. Commun. 483 (1) 271--276

  • A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds (2016)

    Bruna, Alejandra and Rueda, Oscar M and Greenwood, Wendy and Batra, Ankita Sati and Callari, Maurizio and Batra, Rajbir Nath and Pogrebniak, Katherine and Sandoval, Jose and Cassidy, John W and Tufegdzic-Vidakovic, Ana and Sammut, Stephen-John and Jones, Linda and Provenzano, Elena and Baird, Richard and Eirew, Peter and Hadfield, James and Eldridge, Matthew and McLaren-Douglas, Anne and Barthor
    Cell 167 (1) 260--274.e22

  • Analysis of Normal Human Mammary Epigenomes Reveals Cell-Specific Active Enhancer States and Associated Transcription Factor Networks (2016)

    Pellacani, Davide and Bilenky, Misha and Kannan, Nagarajan and Heravi-Moussavi, Alireza and Knapp, David J H F and Gakkhar, Sitanshu and Moksa, Michelle and Carles, Annaick and Moore, Richard and Mungall, Andrew J and Marra, Marco A and Jones, Steven J M and Aparicio, Samuel and Hirst, Martin and Eaves, Connie J
    Cell Rep. 17 (8) 2060--2074

  • Clonal genotype and population structure inference from single-cell tumor sequencing (2016)

    Roth, Andrew and McPherson, Andrew and Laks, Emma and Biele, Justina and Yap, Damian and Wan, Adrian and Smith, Maia A and Nielsen, Cydney B and McAlpine, Jessica N and Aparicio, Samuel and Bouchard-Cote, Alexandre and Shah, Sohrab P
    Nat. Methods 13 (7) 573--576

  • Combined Use of Gene Expression Modeling and siRNA Screening Identifies Genes and Pathways Which Enhance the Activity of Cisplatin When Added at No Effect Levels to Non-Small Cell Lung Cancer Cells In Vitro (2016)

    Leung, Ada W Y and Hung, Stacy S and Backstrom, Ian and Ricaurte, Daniel and Kwok, Brian and Poon, Steven and McKinney, Steven and Segovia, Romulo and Rawji, Jenna and Qadir, Mohammed A and Aparicio, Samuel and Stirling, Peter C and Steidl, Christian and Bally, Marcel B
    PLoS One 11 (3) e0150675

  • Direct Transcriptional Consequences of Somatic Mutation in Breast Cancer (2016)

    Shlien, Adam and Raine, Keiran and Fuligni, Fabio and Arnold, Roland and Nik-Zainal, Serena and Dronov, Serge and Mamanova, Lira and Rosic, Andrej and Ju, Young Seok and Cooke, Susanna L and Ramakrishna, Manasa and Papaemmanuil, Elli and Davies, Helen R and Tarpey, Patrick S and Van Loo, Peter and Wedge, David C and Jones, David R and Martin, Sancha and Marshall, John and Anderson, Elizabeth a
    Cell Rep. 16 (7) 2032--2046

  • Divergent modes of clonal spread and intraperitoneal mixing in high-grade serous ovarian cancer (2016)

    McPherson, Andrew and Roth, Andrew and Laks, Emma and Masud, Tehmina and Bashashati, Ali and Zhang, Allen W and Ha, Gavin and Biele, Justina and Yap, Damian and Wan, Adrian and Prentice, Leah M and Khattra, Jaswinder and Smith, Maia A and Nielsen, Cydney B and Mullaly, Sarah C and Kalloger, Steve and Karnezis, Anthony and Shumansky, Karey and Siu, Celia and Rosner, Jamie and Chan, Hector Li a
    Nat. Genet. 48 (7) 758--767

  • Genome co-amplification upregulates a mitotic gene network activity that predicts outcome and response to mitotic protein inhibitors in breast cancer (2016)

    Hu, Zhi and Mao, Jian-Hua and Curtis, Christina and Huang, Ge and Gu, Shenda and Heiser, Laura and Lenburg, Marc E and Korkola, James E and Bayani, Nora and Samarajiwa, Shamith and Seoane, Jose A and A Dane, Mark and Esch, Amanda and Feiler, Heidi S and Wang, Nicholas J and Hardwicke, Mary Ann and Laquerre, Sylvie and Jackson, Jeff and W Wood, Kenneth and Weber, Barbara and Spellman, Paul T a
    Breast Cancer Res. 18 (1) 70

  • Patient-derived xenograft (PDX) models in basic and translational breast cancer research (2016)

    Dobrolecki, Lacey E and Airhart, Susie D and Alferez, Denis G and Aparicio, Samuel and Behbod, Fariba and Bentires-Alj, Mohamed and Brisken, Cathrin and Bult, Carol J and Cai, Shirong and Clarke, Robert B and Dowst, Heidi and Ellis, Matthew J and Gonzalez-Suarez, Eva and Iggo, Richard D and Kabos, Peter and Li, Shunqiang and Lindeman, Geoffrey J and Marangoni, Elisabetta and McCoy, Aaron and Me
    Cancer Metastasis Rev. 35 (4) 547--573

  • Robust high-performance nanoliter-volume single-cell multiple displacement amplification on planar substrates (2016)

    Leung, Kaston and Klaus, Anders and Lin, Bill K and Laks, Emma and Biele, Justina and Lai, Daniel and Bashashati, Ali and Huang, Yi-Fei and Aniba, Radhouane and Moksa, Michelle and Steif, Adi and Mes-Masson, Anne-Marie and Hirst, Martin and Shah, Sohrab P and Aparicio, Samuel and Hansen, Carl L
    Proc. Natl. Acad. Sci. U. S. A. 113 (30) 8484--8489

  • A co-culture genome-wide RNAi screen with mammary epithelial cells reveals transmembrane signals required for growth and differentiation (2015)

    Burleigh, Angela and McKinney, Steven and Brimhall, Jazmine and Yap, Damian and Eirew, Peter and Poon, Steven and Ng, Viola and Wan, Adrian and Prentice, Leah and Annab, Lois and Barrett, J Carl and Caldas, Carlos and Eaves, Connie and Aparicio, Samuel
    Breast Cancer Res. 17 4

  • A tumor DNA complex aberration index is an independent predictor of survival in breast and ovarian cancer (2015)

    Vollan, Hans Kristian Moen and Rueda, Oscar M and Chin, Suet-Feung and Curtis, Christina and Turashvili, Gulisa and Shah, Array, rde, Ole Christian and Yuan, Yinyin and Ng, Charlotte K and Dunning, Mark J and Dicks, Ed and Provenzano, Elena and Sammut, Stephen and McKinney, Steven and Ellis, Ian O and Pinder, Sarah and Purushotham, Arnie and Murphy, Leigh C and Kristensen, and Brenton, James D
    Mol. Oncol. 9 (1) 115--127

  • Barcoding reveals complex clonal dynamics of de novo transformed human mammary cells (2015)

    Nguyen, Long V and Pellacani, Davide and Lefort, Sylvain and Kannan, Nagarajan and Osako, Tomo and Makarem, Maisam and Cox, Claire L and Kennedy, William and Beer, Philip and Carles, Annaick and Moksa, Michelle and Bilenky, Misha and Balani, Sneha and Babovic, Sonja and Sun, Ivan and Rosin, Miriam and Aparicio, Samuel and Hirst, Martin and Eaves, Connie J
    Nature 528 (7581) 267--271

  • BCL11A is a triple-negative breast cancer gene with critical functions in stem and progenitor cells (2015)

    Khaled, Walid T and Choon Lee, Song and Stingl, John and Chen, Xiongfeng and Raza Ali, H and Rueda, Oscar M and Hadi, Fazal and Wang, Juexuan and Yu, Yong and Chin, Suet-Feung and Stratton, Mike and Futreal, Andy and Jenkins, Nancy A and Aparicio, Sam and Copeland, Neal G and Watson, Christine J and Caldas, Carlos and Liu, Pentao
    Nat. Commun. 6 5987

  • Dynamics of genomic clones in breast cancer patient xenografts at single-cell resolution (2015)

    Eirew, Peter and Steif, Adi and Khattra, Jaswinder and Ha, Gavin and Yap, Damian and Farahani, Hossein and Gelmon, Karen and Chia, Stephen and Mar, Colin and Wan, Adrian and Laks, Emma and Biele, Justina and Shumansky, Karey and Rosner, Jamie and McPherson, Andrew and Nielsen, Cydney and Roth, Andrew J L and Lefebvre, Calvin and Bashashati, Ali and de Souza, Camila and Siu, Celia and Aniba,
    Nature 518 (7539) 422--426

  • Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells (2015)

    Ju, Young Seok and Tubio, Jose M C and Mifsud, William and Fu, Beiyuan and Davies, Helen R and Ramakrishna, Manasa and Li, Yilong and Yates, Lucy and Gundem, Gunes and Tarpey, Patrick S and Behjati, Sam and Papaemmanuil, Elli and Martin, Sancha and Fullam, Anthony and Gerstung, Array, and Nangalia, Jyoti and Green, Anthony R and Caldas, Carlos and Borg, Ake and Tutt, Andrew and Lee, Ming Ta M
    Genome Res. 25 (6) 814--824

  • Lapatinib or Trastuzumab Plus Taxane Therapy for Human Epidermal Growth Factor Receptor 2-Positive Advanced Breast Cancer: Final Results of NCIC CTG MA.31 (2015)

    Gelmon, Karen A and Boyle, Frances M and Kaufman, Bella and Huntsman, David G and Manikhas, Alexey and Di Leo, Angelo and Martin, Miguel and Schwartzberg, Lee S and Lemieux, Julie and Aparicio, Samuel and Shepherd, Lois E and Dent, Susan and Ellard, Susan L and Tonkin, Katia and Pritchard, Kathleen I and Whelan, Timothy J and Nomikos, Dora and Nusch, Arnd and Coleman, Robert E and Mukai, Hirof
    J. Clin. Oncol. 33 (14) 1574--1583

  • Lessons learned from the application of whole-genome analysis to the treatment of patients with advanced cancers (2015)

    Laskin, Janessa and Jones, Steven and Aparicio, Samuel and Chia, Stephen and Ch'ng, Carolyn and Deyell, Rebecca and Eirew, Peter and Fok, Alexandra and Gelmon, Karen and Ho, Cheryl and Huntsman, David and Jones, Martin and Kasaian, Katayoon and Karsan, Aly and Leelakumari, Sreeja and Li, Yvonne and Lim, Howard and Ma, Yussanne and Mar, Colin and Martin, Monty and Moore, Richard and Mungall,
    Cold Spring Harb Mol Case Stud 1 (1) a000570

  • Systematic analysis of somatic mutations impacting gene expression in 12 tumour types (2015)

    Ding, Jiarui and McConechy, Melissa K and Horlings, Hugo M and Ha, Gavin and Chun Chan, Fong and Funnell, Tyler and Mullaly, Sarah C and Reimand, Juri and Bashashati, Ali and Bader, Gary D and Huntsman, David and Aparicio, Samuel and Condon, Anne and Shah, Sohrab P
    Nat. Commun. 6 8554

  • DNA barcoding reveals diverse growth kinetics of human breast tumour subclones in serially passaged xenografts (2014)

    Nguyen, Long V and Cox, Claire L and Eirew, Peter and Knapp, David J H F and Pellacani, Davide and Kannan, Nagarajan and Carles, Annaick and Moksa, Michelle and Balani, Sneha and Shah, Sohrab and Hirst, Martin and Aparicio, Samuel and Eaves, Connie J
    Nat. Commun. 5 5871

  • Genome-driven integrated classification of breast cancer validated in over 7,500 samples (2014)

    Ali, H Raza and Rueda, Oscar M and Chin, Suet-Feung and Curtis, Christina and Dunning, Mark J and Aparicio, Samuel Ajr and Caldas, Carlos
    Genome Biol. 15 (8) 431

  • Mobile DNA in cancer. Extensive transduction of nonrepetitive DNA mediated by L1 retrotransposition in cancer genomes (2014)

    Tubio, Jose M C and Li, Yilong and Ju, Young Seok and Martincorena, Inigo and Cooke, Susanna L and Tojo, Marta and Gundem, Gunes and Pipinikas, Christodoulos P and Zamora, Jorge and Raine, Keiran and Menzies, Andrew and Roman-Garcia, Pablo and Fullam, Anthony and Gerstung, Moritz and Shlien, Adam and Tarpey, Patrick S and Papaemmanuil, Elli and Knappskog, Stian and Van Loo, Peter and Ramakrishn
    Science 345 (6196) 1251343

  • TITAN: inference of copy number architectures in clonal cell populations from tumor whole-genome sequence data (2014)

    Ha, Gavin and Roth, Andrew and Khattra, Jaswinder and Ho, Julie and Yap, Damian and Prentice, Leah M and Melnyk, Nataliya and McPherson, Andrew and Bashashati, Ali and Laks, Emma and Biele, Justina and Ding, Jiarui and Le, Alan and Rosner, Jamie and Shumansky, Karey and Marra, Marco A and Gilks, C Blake and Huntsman, David G and McAlpine, Jessica N and Aparicio, Samuel and Shah, Sohrab P
    Genome Res. 24 (11) 1881--1893

  • Improving breast cancer survival analysis through competition-based multidimensional modeling (2013)

    Bilal, Erhan and Dutkowski, Janusz and Guinney, Justin and Jang, In Sock and Logsdon, Benjamin A and Pandey, Gaurav and Sauerwine, Benjamin A and Shimoni, Yishai and Moen Vollan, Hans Kristian and Mecham, Brigham H and Rueda, Oscar M and Tost, Jorg and Curtis, Christina and Alvarez, Mariano J and Kristensen, Vessela N and Aparicio, Samuel and Borresen-Dale, Anne-Lise and Caldas, Carlos and Calif
    PLoS Comput. Biol. 9 (5) e1003047

  • iReckon: simultaneous isoform discovery and abundance estimation from RNA-seq data (2013)

    Mezlini, Aziz M and Smith, Eric J M and Fiume, Marc and Buske, Orion and Savich, Gleb L and Shah, Sohrab and Aparicio, Sam and Chiang, Derek Y and Goldenberg, Anna and Brudno, Michael
    Genome Res. 23 (3) 519--529

  • Solution NMR structure and histone binding of the PHD domain of human MLL5 (2013)

    Lemak, Alexander and Yee, Adelinda and Wu, Hong and Yap, Damian and Zeng, Hong and Dombrovski, Ludmila and Houliston, Scott and Aparicio, Samuel and Arrowsmith, Cheryl H
    PLoS One 8 (10) e77020

  • The implications of clonal genome evolution for cancer medicine (2013)

    Aparicio, Samuel and Caldas, Carlos
    N. Engl. J. Med. 368 (9) 842--851

  • DriverNet: uncovering the impact of somatic driver mutations on transcriptional networks in cancer (2012)

    Bashashati, Ali and Haffari, Gholamreza and Ding, Jiarui and Ha, Gavin and Lui, Kenneth and Rosner, Jamie and Huntsman, David G and Caldas, Carlos and Aparicio, Samuel A and Shah, Sohrab P
    Genome Biol. 13 (12) R124

  • Integrative analysis of genome-wide loss of heterozygosity and monoallelic expression at nucleotide resolution reveals disrupted pathways in triple-negative breast cancer (2012)

    Ha, Gavin and Roth, Andrew and Lai, Daniel and Bashashati, Ali and Ding, Jiarui and Goya, Rodrigo and Giuliany, Ryan and Rosner, Jamie and Oloumi, Arusha and Shumansky, Karey and Chin, Suet-Feung and Turashvili, Gulisa and Hirst, Martin and Caldas, Carlos and Marra, Marco A and Aparicio, Samuel and Shah, Sohrab P
    Genome Res. 22 (10) 1995--2007

  • Mutation discovery in regions of segmental cancer genome amplifications with CoNAn-SNV: a mixture model for next generation sequencing of tumors (2012)

    Crisan, Anamaria and Goya, Rodrigo and Ha, Gavin and Ding, Jiarui and Prentice, Leah M and Oloumi, Arusha and Senz, Janine and Zeng, Thomas and Tse, Kane and Delaney, Allen and Marra, Marco A and Huntsman, David G and Hirst, Martin and Aparicio, Sam and Shah, Sohrab
    PLoS One 7 (8) e41551

  • Opening Pandora's Box--the new biology of driver mutations and clonal evolution in cancer as revealed by next generation sequencing (2012)

    Ma, Qianli C and Ennis, Catherine A and Aparicio, Samuel
    Curr. Opin. Genet. Dev. 22 (1) 3--9

  • Recurrent Somatic DICER1 Mutations in Nonepithelial Ovarian Cancers (2012)

    Heravi-Moussavi, Alireza and Anglesio, Michael S and Cheng, S-W Grace and Senz, Janine and Yang, Winnie and Prentice, Leah and Fejes, Anthony P and Chow, Christine and Tone, Alicia and Kalloger, Steve E and Hamel, Nancy and Roth, Andrew and Ha, Gavin and Wan, Adrian N C and Maines-Bandiera, Sarah and Salamanca, Clara and Pasini, Barbara and Clarke, Blaise A and Lee, Anna F and Lee, Cheng-Han a
    N. Engl. J. Med. 366 (3) 234--242

  • The clonal and mutational evolution spectrum of primary triple-negative breast cancers (2012)

    Shah, Sohrab P and Roth, Andrew and Goya, Rodrigo and Oloumi, Arusha and Ha, Gavin and Zhao, Yongjun and Turashvili, Gulisa and Ding, Jiarui and Tse, Kane and Haffari, Gholamreza and Bashashati, Ali and Prentice, Leah M and Khattra, Jaswinder and Burleigh, Angela and Yap, Damian and Bernard, Virginie and McPherson, Andrew and Shumansky, Karey and Crisan, Anamaria and Giuliany, Ryan and Heravi-
    Nature 486 (7403) 395--399

  • The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups (2012)

    Curtis, Christina and Shah, Sohrab P and Chin, Suet-Feung and Turashvili, Gulisa and Rueda, Oscar M and Dunning, Mark J and Speed, Doug and Lynch, Andy G and Samarajiwa, Shamith and Yuan, Yinyin and Graf, Stefan and Ha, Gavin and Haffari, Gholamreza and Bashashati, Ali and Russell, Roslin and McKinney, Array, and Langerod, Anita and Green, Andrew and Provenzano, Elena and Wishart, Gordon and Pinder, Sarah
    Nature 486 (7403) 346--352

  • Raman microscopy-based cytochemical investigations of potential niche-forming inhomogeneities present in human embryonic stem cell colonies (2011)

    Konorov, Stanislav O and Schulze, H Georg and Piret, James M and Aparicio, Samuel A and Turner, Robin F B and Blades, Michael W
    Appl. Spectrosc. 65 (9) 1009--1016

  • ARID1A Mutations in Endometriosis-Associated Ovarian Carcinomas (2010)

    Wiegand, Kimberly C and Shah, Sohrab P and Al-Agha, Osama M and Zhao, Yongjun and Tse, Kane and Zeng, Thomas and Senz, Janine and McConechy, Melissa K and Anglesio, Michael S and Kalloger, Steve E and Yang, Winnie and Heravi-Moussavi, Alireza and Giuliany, Ryan and Chow, Christine and Fee, John and Zayed, Abdalnasser and Prentice, Leah and Melnyk, Nataliya and Turashvili, Gulisa and Delaney, A
    N. Engl. J. Med. 363 (16) 1532--1543

  • Does massively parallel DNA resequencing signify the end of histopathology as we know it? (2010)

    Aparicio, Samuel A J R and Huntsman, David G
    J. Pathol. 220 (2) 307--315

  • SNVMix: predicting single nucleotide variants from next-generation sequencing of tumors (2010)

    Goya, Rodrigo and Sun, Mark G F and Morin, Ryan D and Leung, Gillian and Ha, Gavin and Wiegand, Kimberley C and Senz, Janine and Crisan, Anamaria and Marra, Marco A and Hirst, Martin and Huntsman, David and Murphy, Kevin P and Aparicio, Sam and Shah, Sohrab P
    Bioinformatics 26 (6) 730--736

  • Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution (2009)

    Shah, Sohrab P and Morin, Ryan D and Khattra, Jaswinder and Prentice, Leah and Pugh, Trevor and Burleigh, Angela and Delaney, Allen and Gelmon, Karen and Guliany, Ryan and Senz, Janine and Steidl, Christian and Holt, Robert A and Jones, Steven and Sun, Mark and Leung, Gillian and Moore, Richard and Severson, Tesa and Taylor, Greg A and Teschendorff, Andrew E and Tse, Kane and Turashvili, Guli
    Nature 461 (7265) 809--813

  • Mice lacking pro-opiomelanocortin are sensitive to high-fat feeding but respond normally to the acute anorectic effects of peptide-YY(3-36) (2004)

    Challis, B G and Coll, A P and Yeo, G S H and Pinnock, S B and Dickson, S L and Thresher, R R and Dixon, J and Zahn, D and Rochford, J J and White, A and Oliver, R L and Millington, G and Aparicio, S A and Colledge, W H and Russ, A P and Carlton, M B and O'Rahilly, S
    Proc. Natl. Acad. Sci. U. S. A. 101 (13) 4695--4700

  • The molecular outlook (2002)

    Caldas, Carlos and Aparicio, Samuel A J
    Nature 415 (6871) 484--485

  • MLL2, the second human homolog of the Drosophila trithorax gene, maps to 19q13.1 and is amplified in solid tumor cell lines (1999)

    Huntsman, D G and Chin, S F and Muleris, M and Batley, S J and Collins, V P and Wiedemann, L M and Aparicio, S and Caldas, C
    Oncogene 18 (56) 7975--7984

  • Characterization of the pufferfish (Fugu) genome as a compact model vertebrate genome (1993)

    Brenner, S and Elgar, G and Sandford, R and Macrae, A and Venkatesh, B and Aparicio, S
    Nature 366 (6452) 265--268

  • An ultrastructural morphometric study of membranous glomerulonephritis (1986)

    Aparicio, S R and Woolgar, A E and Aparicio, S A and Watkins, A and Davison, A M
    Nephrol. Dial. Transplant 1 (1) 22--30

 
 

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