Daniel Sinnett , Ph.D.
    Daniel Sinnett
    Research Axis
    Immune Diseases and Cancer Axis
    Research Theme
    Cancers: mechanisms, new therapeutic approaches and disease outcomes
    CHUSJ - Centre de Recherche

    514-345-4931, ext. 2990



    • Full Time Professor, Department of Pediatrics, University of Montreal
    • Accredited Professor, Department of Biochemistry and Molecular Medicine, University of Montreal
    • Scientific, Robert Cedergren Centre, Bioinformatics and Genomics Research Centre, University of Montreal
    • Director, Newtwork of Applied Genetic Medicine, Fonds de recherche du Québec - Santé (FRQS)


    • Postdoctoral Fellow, Harvard Medical School, Children’s Hospital, Boston, USA, 1991-1994
    • Ph.D., Biochemistry, University of Montreal, 1987-1991

    Research Interests

    The Role of the transcription factor ETV6 in Childhood Leukemia

    Oncogenesis is a multi-stage process involving genetic alterations in a number of oncogenes and tumour suppressor genes. Over the years, we and others have identified and characterized allelic losses in leukemic cells from childhood Acute lymphoblastic leukemia (ALL) patients. Creation of the ETV6-AML1 fusion gene and complete inactivation of ETV6 following a secondary deletion event, is a situation that is unique to childhood ALL. However the t(12;21) translocation is not sufficient to trigger leukemogenesis, therefore it is possible that loss of the non-translocated ETV6 allele could represent a key initiating event in the leukemic process, probably through disruption of the downstream regulatory network. ETV6 is a member of the ETS family of transcription factors, and functions as a transcriptional repressor during normal hematopoiesis. Our work has focused on dissecting the role of ETV6 and of the underlying mechanisms leading to leukemogenesis. Given that we know little about the genes targeted by this transcriptional repressor, the main goal of this project is to build the gene regulatory network associated with expression of ETV6. We have proposed a global approach in which we integrate data generated through DNA, RNA and protein studies to identify proteins that interact with ETV6 and genes that are targeted by ETV6 to further elucidate the mechanism through which disruption of this tumour-suppressor promotes the leukemic process. These findings will then be used to develop more appropriate and more efficient diagnostic and treatment tools for childhood ALL patients.

    Genetic and genomic determinants of childhood leukemia

    Acute lymphoblastic leukemia (ALL) is the most frequent cancer and the leading cause of death due to disease among children aged 18 or younger. Despite what is known about the leukemic process, there remains much to be learned about the molecular causes of this disease. Few studies have thoroughly investigated the role of inherited genetic variation in influencing a child's risk of ALL. We and others have shown that childhood ALL might originate through the collective contribution of DNA variants in genes controlling the efficiency of carcinogen metabolism, the capacity of maintaining DNA integrity and the response to oxidative stress. More recently, two GWAS have provided the first genome-wide glimpse into the role of inherited alleles in ALL pathogenesis and identified common germline variants associated with the pathogenesis and heterogeneity of pediatric ALL. Still few bona fide genetic risk factors for ALL have been identified and therefore the genetic contribution to childhood ALL remains largely unexplained. It is likely that this complex disease is caused by a combination of both common and rare variants. In fact, a more realistic disease model is that functional variants involved in childhood ALL onset have a wide spectrum of allele frequencies that range from common to not-so-common to rare and that the landscape of genetic variation contributing to ALL includes structural variation, epigenetic changes, and even parentally-mediated genetic effects. The advent of next-generation sequencing and sophisticated bioinformatic tools, combined with the availability of unique well-characterized cohorts of ALL patients is providing us with unprecedented views of the genetic landscape of childhood ALL, allowing us to simultaneously detect common and rare inherited (germline) genetic changes as well as leukemia-specific (somatic) mutations in childhood ALL genomes. Our main goal is to identify the full complement of genetic and epigenetic variation in childhood ALL genomes. Using cutting-edge technologies, we are performing deep-resequencing of over 800 genomes from matched normal-tumour patient samples, as well as mothers and fathers of leukemia patients. In parallele we are also generating transcriptomic data (RNA-seq), genome-wide genotyping data, as well as array-based methylation profiling, in order to build a comprehensive catalogue of genomic (sequence and structural) as well as epigenomic variants involved in childhood ALL. In response to the important challenge of integrating these various sources of information, and identifying true causal events involved in driving leukemogenesis, we are developing new bioinformatics tools. These findings will ultimately lead to development of powerful research and clinical tools that could improve detection, diagnosis and treatment of childhood leukemia.

    Investigating the Genetic determinants of Long Term Side Effects of Treatment in Childhood Leukemia Survivors

    The primary factor that led to advances in childhood ALL survival is the introduction of multi-agent treatment regimens based on predicted risk of relapse using clinical- and laboratory-based outcome variables (risk-adapted therapy). However, there is a price to pay for this therapeutic success. Although 85% of ALL cases are cured with modern therapy, the exposure to chemotherapeutic agents and/or irradiation during a vulnerable period of development has been associated with high frequency of late-occurring health problems in more than two-thirds of the survivors. There is substantial variability regarding the occurrence and severity of the therapy-related morbidities in ALL survivors and importantly, the underlying causes of these long-term effects remain unclear. Early-detection biomarkers which would identify population at risk are currently lacking. We gathered a multidisciplinary team of clinical and basic scientists to comprehensively investigate and identify biomarkers of the most common therapy-related late effects in childhood ALL survivors, including neurocognitive effects, metabolic syndrome, cardiotoxicity and bone morbidity. To better understand the mechanisms through which these adverse long-term effects might arise in childhood ALL survivors we propose a study to identify the genetic variations in childhood ALL patients and a set of biologically and clinically relevant biomarkers on long-term treatment effects. We also want to assess the impact of candidate genetic and biological biomarkers on long-term treatment in childhood ALL survivors. These findings will lead to the development of new strategies and clinical tools that will prevent and/or reduce the occurrence of late-onset treatment related toxicities, and ultimately improve detection, diagnosis and treatment of childhood leukemia.

    Awards and Distinctions

    • National Scientist, Fonds de la recherche en santé du Québec (FRSQ), 2006-2011
    • Lauréat du programme de reconnaissance, Prix recherche, CHU Sainte-Justine, 2009
    • Senior Scientist Scholar, FRSQ, 2002-2006
    • Prix d’accomplissement, Recherche Biomédicale, Faculté de Médecine/ Association des diplômés, Université de Montréal, 2005
    • Prix du jeune chercheur André Dupont, 2004
    • Prix Mérite du Conseil québécois de lutte contre le cancer, 2003
    • Chairholder, François-Karl Viau Research Chair in Pediatric, 2002
    • Junior 2 Scientist Scholar, FRSQ, 1998-2002
    • Prix d’Excellence, Fondation de la recherche sur les maladies infantiles, 1999
    • Junior 1 Scientist Scholar, FRSQ, 1994-1998
    • Postdoctoral Fellowship, Canadian Institutes of Health Research, 1991-1994


    • B. Ge, D. K. Pokholok, E. Grundberg,  T. Kwan, L. Morcos, J. Le,  D.J. Verlaan, V. Koka, K.C.L. Lam, V. Gagné, J. Dias, R. Hoberman, A. Montpetit, M.M. Joly, E. J. Harvey, D. Sinnett, P. Beaulieu*, R. Hamon*, A. Graziani, K. Dewar, E. Harmsen, J. Majewski, A.K. Naumova,  M. Blanchette, H.H.H. Göring, K.L. Gunderson, T. Pastinen (2009). Global patterns of cis-variation in human cells revealed by high-density allelic expression analysis. Nature Genetics  Nov;41(11):1216-22.
    • Sherborne A, Hosking FJ, Prasad RB, Kumar R, Koehler R, Vijayakrishnan J, Papaemmanuil E, Bartram CR, Stanulla M, Schrappe M, Gast A, Sheridan E, Taylor M, Kinsey SE, Lightfoot T, Roman E, Irving JAE, Allan JM, Moorman AV, Harrison CJ, Tomlinson IP, Szalai C, Semsei AF, Erdelyi DJ, Krajinovic M, Sinnett D, Healy J, Neira AG, Hemminki K, Greaves M, Houlston RS (2010). Variation at 9p21.3 (CKN2A) influences childhood acute lymphoblastic leukemia risk. Nat Genet. Jun;42(6):492-4.
    • Busche S, Ge B, Vidal R, Spinella J-F, Saillour V, Richer C, Healy J, Chen S-H, Droit A, Sinnett D#, Pastinen T. (2013) Integration of high-resolution methylome and transcriptome analyses to dissect epigenomic changes in childhood acute lymphoblastic leukemia. Cancer Research, May 35(4) e157-162. #corresponding author.
    • Spinella J-F, Cassart P, Richer C, Saillour V, Ouimet M, Langlois S, St-Onge P, Sontag T, Healy J, Minden M, Sinnett D (2016) The genomic characterization of pediatric T-cell acute lymphoblastic leukemia reveals novel recurrent driver mutations.  Oncotarget 2016 Sep 1. doi: 10.18632/oncotarget.11796
    • Marcoux S, Drouin S, Laverdière C, Alos N, Andelfinger GU, Bertout L, Curnier D, Friedrich MG, Kritikou EA, Levy E, Lippé S, Marcil V, Raboisson M-J, Rauch F, Robaey P, Séguin C, Sultan S, Krajinovic M, Sinnett D.  (2016)The PETALE Study: Late Adverse Effects and Biomarkers in Childhood Acute Lymphoblastic Leukemia Survivors.  Pediatric Blood & Cancer Dec 4. doi: 10.1002/pbc.26361  (PETALE-CIHR team leader)

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