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Pancreatic Neoplasms: HELP
Articles by Faiyaz Notta
Based on 8 articles published since 2010
(Why 8 articles?)
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Between 2010 and 2020, Faiyaz Notta wrote the following 8 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review A genetic roadmap of pancreatic cancer: still evolving. 2017

Notta, Faiyaz / Hahn, Stephan A / Real, Francisco X. ·Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. · Department of Medical Biophysics, University of Toronto, Toronto, Canada. · Department of Molecular Gastrointestinal Oncology, Ruhr-University Bochum, Bochum, Germany. · Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. · Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain. · CIBERONC, Madrid, Spain. ·Gut · Pubmed #28993418.

ABSTRACT: A diagnosis of pancreatic ductal adenocarcinoma (PDA) is often fatal. PDA is widely recognised as one of the 'incurable cancers' because therapies against this tumour type are generally ineffective. The fatal nature of this tumour is due to its aggressive clinical course. Pancreatic cancer commonly presents at the metastatic stage; even in cases where tumours are localised to the pancreas at diagnosis, metastatic seeds have often been invariably been spawned off, frustrating surgical attempts to cure the cancer. The key principles of pancreatic cancer mutational development were outlined nearly two decades ago using the genetics of precursor lesions to position the various stages of tumour progression. Since then, there has been a cavalcade of new data. How these recent studies impact the classical perceptions of pancreatic cancer development is a work in progress. Given that significant improvements in patient outcomes are not in sight for this disease, it is likely that broadening the current perspectives and acquiring deeper biological insights into the morphogenetic route of tumour development will be needed to foster new strategies for more effective cancer control.

2 Article Integration of Genomic and Transcriptional Features in Pancreatic Cancer Reveals Increased Cell Cycle Progression in Metastases. 2019

Connor, Ashton A / Denroche, Robert E / Jang, Gun Ho / Lemire, Mathieu / Zhang, Amy / Chan-Seng-Yue, Michelle / Wilson, Gavin / Grant, Robert C / Merico, Daniele / Lungu, Ilinca / Bartlett, John M S / Chadwick, Dianne / Liang, Sheng-Ben / Eagles, Jenna / Mbabaali, Faridah / Miller, Jessica K / Krzyzanowski, Paul / Armstrong, Heather / Luo, Xuemei / Jorgensen, Lars G T / Romero, Joan M / Bavi, Prashant / Fischer, Sandra E / Serra, Stefano / Hafezi-Bakhtiari, Sara / Caglar, Derin / Roehrl, Michael H A / Cleary, Sean / Hollingsworth, Michael A / Petersen, Gloria M / Thayer, Sarah / Law, Calvin H L / Nanji, Sulaiman / Golan, Talia / Smith, Alyssa L / Borgida, Ayelet / Dodd, Anna / Hedley, David / Wouters, Bradly G / O'Kane, Grainne M / Wilson, Julie M / Zogopoulos, George / Notta, Faiyaz / Knox, Jennifer J / Gallinger, Steven. ·PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada. · Deep Genomics, Inc., Toronto, ON M5G 1L7, Canada; The Centre for Applied Genomics (TCAG), The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada. · Diagnostic Development, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada. · UHN Biobank, University Health Network, Toronto, ON M5G 2M9, Canada. · Genomics, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada. · Genome Sequence Informatics, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, ON M5G 2M9, Canada. · Department of Pathology, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, ON M5G 2M9, Canada. · Department of Pathology, University Health Network, Toronto, ON M5G 2M9, Canada. · Department of Pathology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada. · UHN Biobank, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Pathology, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada; Department of Pathology, Memorial Sloan Kettering Cancer Centre, New York, NY 10065, USA. · Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA. · University of Nebraska Medical Centre, Omaha, NE 68198, USA. · Mayo Clinic College of Medicine, Rochester, MN 55905, USA. · University of Nebraska Medical Centre, Omaha, NE 68198, USA; Massachusetts General Hospital, Boston, MA 02114, USA. · Department of Surgery, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada. · Department of Surgery, Kingston General Hospital, Kingston, ON K7L 2V7, Canada. · Pancreatic Cancer Translational Research Laboratory, Oncology Institute, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. · Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada. · Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada. · Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada. · Division of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada. · Division of Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada. · Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; Goodman Cancer Research Centre, Montreal, QC H3A 1A3, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Division of Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada; Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, ON M5G 2M9, Canada; Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada. Electronic address: steven.gallinger@uhn.ca. ·Cancer Cell · Pubmed #30686769.

ABSTRACT: We integrated clinical, genomic, and transcriptomic data from 224 primaries and 95 metastases from 289 patients to characterize progression of pancreatic ductal adenocarcinoma (PDAC). Driver gene alterations and mutational and expression-based signatures were preserved, with truncations, inversions, and translocations most conserved. Cell cycle progression (CCP) increased with sequential inactivation of tumor suppressors, yet remained higher in metastases, perhaps driven by cell cycle regulatory gene variants. Half of the cases were hypoxic by expression markers, overlapping with molecular subtypes. Paired tumor heterogeneity showed cancer cell migration by Halstedian progression. Multiple PDACs arising synchronously and metachronously in the same pancreas were actually intra-parenchymal metastases, not independent primary tumors. Established clinical co-variates dominated survival analyses, although CCP and hypoxia may inform clinical practice.

3 Article Organoid Profiling Identifies Common Responders to Chemotherapy in Pancreatic Cancer. 2018

Tiriac, Hervé / Belleau, Pascal / Engle, Dannielle D / Plenker, Dennis / Deschênes, Astrid / Somerville, Tim D D / Froeling, Fieke E M / Burkhart, Richard A / Denroche, Robert E / Jang, Gun-Ho / Miyabayashi, Koji / Young, C Megan / Patel, Hardik / Ma, Michelle / LaComb, Joseph F / Palmaira, Randze Lerie D / Javed, Ammar A / Huynh, Jasmine C / Johnson, Molly / Arora, Kanika / Robine, Nicolas / Shah, Minita / Sanghvi, Rashesh / Goetz, Austin B / Lowder, Cinthya Y / Martello, Laura / Driehuis, Else / LeComte, Nicolas / Askan, Gokce / Iacobuzio-Donahue, Christine A / Clevers, Hans / Wood, Laura D / Hruban, Ralph H / Thompson, Elizabeth / Aguirre, Andrew J / Wolpin, Brian M / Sasson, Aaron / Kim, Joseph / Wu, Maoxin / Bucobo, Juan Carlos / Allen, Peter / Sejpal, Divyesh V / Nealon, William / Sullivan, James D / Winter, Jordan M / Gimotty, Phyllis A / Grem, Jean L / DiMaio, Dominick J / Buscaglia, Jonathan M / Grandgenett, Paul M / Brody, Jonathan R / Hollingsworth, Michael A / O'Kane, Grainne M / Notta, Faiyaz / Kim, Edward / Crawford, James M / Devoe, Craig / Ocean, Allyson / Wolfgang, Christopher L / Yu, Kenneth H / Li, Ellen / Vakoc, Christopher R / Hubert, Benjamin / Fischer, Sandra E / Wilson, Julie M / Moffitt, Richard / Knox, Jennifer / Krasnitz, Alexander / Gallinger, Steven / Tuveson, David A. ·Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. · Johns Hopkins University, Division of Hepatobiliary and Pancreatic Surgery, Baltimore, Maryland. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Swiss Federal Institute of Technology Lausanne (EPFL), School of Life Sciences, Swiss Institute for Experimental Cancer Research (ISREC), Laboratory of Tumor Heterogeneity and Stemness in Cancer, Lausanne, Switzerland. · Department of Medicine, Stony Brook University, Stony Brook, New York. · Memorial Sloan Kettering Cancer Center, New York, New York. · University of California, Davis, Comprehensive Cancer Center, Division of Hematology and Oncology, Sacramento, California. · New York Genome Center, New York, New York. · Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania. · SUNY Downstate Medical Center, Department of Medicine, New York, New York. · Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), Utrecht, the Netherlands. · University Medical Center (UMC), Utrecht, the Netherlands. · Princess Maxime Center (PMC), Utrecht, the Netherlands. · Department of Pathology, Johns Hopkins University, Baltimore, Maryland. · Dana-Farber Cancer Institute, Broad Institute, Boston, Massachusetts. · Department of Surgery, Stony Brook University, Stony Brook, New York. · Department of Pathology, Stony Brook University, Stony Brook, New York. · Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Division of Gastroenterology, Hempstead, New York. · Department of Surgery, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York. · Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania. · Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska. · Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska. · University of Nebraska Medical Center, Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffet Cancer Center, Omaha, Nebraska. · Wallace McCain Centre for Pancreatic Cancer, Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada. · Department of Pathology and Laboratory Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York. · Division of Medical Oncology, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York. · Weill Cornell Medical College, New York, New York. · Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada. · Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. · Department of Biomedical Informatics, Stony Brook University, Stony Brook, New York. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. dtuveson@cshl.edu steven.gallinger@uhn.ca. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. dtuveson@cshl.edu steven.gallinger@uhn.ca. ·Cancer Discov · Pubmed #29853643.

ABSTRACT: Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection.

4 Article Mutations in Mitochondrial DNA From Pancreatic Ductal Adenocarcinomas Associate With Survival Times of Patients and Accumulate as Tumors Progress. 2018

Hopkins, Julia F / Denroche, Robert E / Aguiar, Jennifer A / Notta, Faiyaz / Connor, Ashton A / Wilson, Julie M / Stein, Lincoln D / Gallinger, Steven / Boutros, Paul C. ·Informatics Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. Electronic address: Julia.Hopkins@oicr.on.ca. · Informatics Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Informatics Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Informatics Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · Informatics Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada. Electronic address: Paul.Boutros@oicr.on.ca. ·Gastroenterology · Pubmed #29378198.

ABSTRACT: Somatic mutations have been found in the mitochondria in different types of cancer cells, but it is not clear whether these affect tumorigenesis or tumor progression. We analyzed mitochondrial genomes of 268 early-stage, resected pancreatic ductal adenocarcinoma tissues and paired non-tumor tissues. We defined a mitochondrial somatic mutation (mtSNV) as a position where the difference in heteroplasmy fraction between tumor and normal sample was ≥0.2. Our analysis identified 304 mtSNVs, with at least 1 mtSNV in 61% (164 of 268) of tumor samples. The noncoding control region had the greatest proportion of mtSNVs (60 of 304 mutations); this region contains sites that regulate mitochondrial DNA transcription and replication. Frequently mutated genes included ND5, RNR2, and CO1, plus 29 mutations in transfer RNA genes. mtSNVs in 2 separate mitochondrial genes (ND4 and ND6) were associated with shorter overall survival time. This association appeared to depend on the level of mtSNV heteroplasmy. Non-random co-occurrence between mtSNVs and mutations in nuclear genes indicates interactions between nuclear and mitochondrial DNA. In an analysis of primary tumors and metastases from 6 patients, we found tumors to accumulate mitochondrial mutational mutations as they progress.

5 Article Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer: Early Results from the COMPASS Trial. 2018

Aung, Kyaw L / Fischer, Sandra E / Denroche, Robert E / Jang, Gun-Ho / Dodd, Anna / Creighton, Sean / Southwood, Bernadette / Liang, Sheng-Ben / Chadwick, Dianne / Zhang, Amy / O'Kane, Grainne M / Albaba, Hamzeh / Moura, Shari / Grant, Robert C / Miller, Jessica K / Mbabaali, Faridah / Pasternack, Danielle / Lungu, Ilinca M / Bartlett, John M S / Ghai, Sangeet / Lemire, Mathieu / Holter, Spring / Connor, Ashton A / Moffitt, Richard A / Yeh, Jen Jen / Timms, Lee / Krzyzanowski, Paul M / Dhani, Neesha / Hedley, David / Notta, Faiyaz / Wilson, Julie M / Moore, Malcolm J / Gallinger, Steven / Knox, Jennifer J. ·Wallace McCain Centre for Pancreatic Cancer, Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada. · Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada. · Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario, Institute for Cancer Research, Toronto, Ontario, Canada. · UHN Biobank, University Health Network, Toronto, Ontario, Canada. · Genomics, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Diagnostic Development, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Joint Department of Medical Imaging, University Health Network, University of Toronto, Toronto, Ontario, Canada. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina. · Department of Biomedical Informatics, Stony Brook University, Stony Brook, New York. · Department of Surgery, University of North Carolina, Chapel Hill, North Carolina. · British Columbia Cancer Agency, Vancouver, British Columbia, Canada. · Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · Wallace McCain Centre for Pancreatic Cancer, Department of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada. Jennifer.Knox@uhn.ca. ·Clin Cancer Res · Pubmed #29288237.

ABSTRACT:

6 Article Association of Distinct Mutational Signatures With Correlates of Increased Immune Activity in Pancreatic Ductal Adenocarcinoma. 2017

Connor, Ashton A / Denroche, Robert E / Jang, Gun Ho / Timms, Lee / Kalimuthu, Sangeetha N / Selander, Iris / McPherson, Treasa / Wilson, Gavin W / Chan-Seng-Yue, Michelle A / Borozan, Ivan / Ferretti, Vincent / Grant, Robert C / Lungu, Ilinca M / Costello, Eithne / Greenhalf, William / Palmer, Daniel / Ghaneh, Paula / Neoptolemos, John P / Buchler, Markus / Petersen, Gloria / Thayer, Sarah / Hollingsworth, Michael A / Sherker, Alana / Durocher, Daniel / Dhani, Neesha / Hedley, David / Serra, Stefano / Pollett, Aaron / Roehrl, Michael H A / Bavi, Prashant / Bartlett, John M S / Cleary, Sean / Wilson, Julie M / Alexandrov, Ludmil B / Moore, Malcolm / Wouters, Bradly G / McPherson, John D / Notta, Faiyaz / Stein, Lincoln D / Gallinger, Steven. ·PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada2Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada3Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada4Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada4Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada5Department of Statistical Science, University of Toronto, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada6Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada2Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Transformative Pathology, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · University of Liverpool, Liverpool, England. · Heidelberg University Hospital, Heidelberg, Germany. · Mayo Clinic, Rochester, Minnesota. · Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts. · University of Nebraska Medical Centre, Omaha, Nebraska. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada13Molecular Genetics Department, University of Toronto, Toronto, Ontario, Canada. · Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. · Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada15Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada15Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada16Department of Pathology, University Health Network, Toronto, Ontario, Canada17Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada18BioSpecimen Sciences Program, University Health Network, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada3Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, New Mexico20Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico. · Department of Pathology, University Health Network, Toronto, Ontario, Canada. · Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada17Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. · Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada13Molecular Genetics Department, University of Toronto, Toronto, Ontario, Canada. ·JAMA Oncol · Pubmed #27768182.

ABSTRACT: Importance: Outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) remain poor. Advances in next-generation sequencing provide a route to therapeutic approaches, and integrating DNA and RNA analysis with clinicopathologic data may be a crucial step toward personalized treatment strategies for this disease. Objective: To classify PDAC according to distinct mutational processes, and explore their clinical significance. Design, Setting, and Participants: We performed a retrospective cohort study of resected PDAC, using cases collected between 2008 and 2015 as part of the International Cancer Genome Consortium. The discovery cohort comprised 160 PDAC cases from 154 patients (148 primary; 12 metastases) that underwent tumor enrichment prior to whole-genome and RNA sequencing. The replication cohort comprised 95 primary PDAC cases that underwent whole-genome sequencing and expression microarray on bulk biospecimens. Main Outcomes and Measures: Somatic mutations accumulate from sequence-specific processes creating signatures detectable by DNA sequencing. Using nonnegative matrix factorization, we measured the contribution of each signature to carcinogenesis, and used hierarchical clustering to subtype each cohort. We examined expression of antitumor immunity genes across subtypes to uncover biomarkers predictive of response to systemic therapies. Results: The discovery cohort was 53% male (n = 79) and had a median age of 67 (interquartile range, 58-74) years. The replication cohort was 50% male (n = 48) and had a median age of 68 (interquartile range, 60-75) years. Five predominant mutational subtypes were identified that clustered PDAC into 4 major subtypes: age related, double-strand break repair, mismatch repair, and 1 with unknown etiology (signature 8). These were replicated and validated. Signatures were faithfully propagated from primaries to matched metastases, implying their stability during carcinogenesis. Twelve of 27 (45%) double-strand break repair cases lacked germline or somatic events in canonical homologous recombination genes-BRCA1, BRCA2, or PALB2. Double-strand break repair and mismatch repair subtypes were associated with increased expression of antitumor immunity, including activation of CD8-positive T lymphocytes (GZMA and PRF1) and overexpression of regulatory molecules (cytotoxic T-lymphocyte antigen 4, programmed cell death 1, and indolamine 2,3-dioxygenase 1), corresponding to higher frequency of somatic mutations and tumor-specific neoantigens. Conclusions and Relevance: Signature-based subtyping may guide personalized therapy of PDAC in the context of biomarker-driven prospective trials.

7 Article Senescent Carcinoma-Associated Fibroblasts Upregulate IL8 to Enhance Prometastatic Phenotypes. 2017

Wang, Tao / Notta, Faiyaz / Navab, Roya / Joseph, Joella / Ibrahimov, Emin / Xu, Jing / Zhu, Chang-Qi / Borgida, Ayelet / Gallinger, Steven / Tsao, Ming-Sound. ·Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. · Department of Pathology, University Health Network, Toronto, Canada. · Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada. · Ontario Institute for Cancer Research, Toronto, Canada. · Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Canada. · Department of General Surgery, University Health Network, Toronto, Canada. · Department of Surgery, University of Toronto, Toronto, Canada. · Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. ming.tsao@uhn.ca. ·Mol Cancer Res · Pubmed #27678171.

ABSTRACT: Carcinoma-associated fibroblasts (CAF) represent a significant component of pancreatic cancer stroma and are biologically implicated in tumor progression. However, evidence of both cancer-promoting and -restraining properties amongst CAFs suggests the possibility of multiple phenotypic subtypes. Here, it is demonstrated that senescent CAFs promote pancreatic cancer invasion and metastasis compared with nonsenescent control CAFs using in vitro Transwell invasion models and in vivo xenograft mouse models. Screening by gene expression microarray and cytokine ELISA assays revealed IL8 to be upregulated in senescent CAFs. Experimental modulation through IL8 overexpression or receptor inhibition implicates the IL8 pathway as a mediator of the proinvasive effects of senescent CAFs. In a cohort of human pancreatic cancer cases, more abundant stromal senescence as indicated by p16 immunohistochemistry correlated with decreased survival in patients with early-stage disease. These data support senescent fibroblasts as a pathologically and clinically relevant feature of pancreatic cancer. The inhibition of senescent stroma-cancer signaling pathways has the potential to restrain pancreatic cancer progression. IMPLICATIONS: Findings show that senescent cancer-associated fibroblasts secret excess IL8 to promote pancreatic cancer invasion and metastasis; thus, senescent CAFs represent a phenotypic subtype, challenging conventional assumptions that CAFs are a homogeneous population. Mol Cancer Res; 15(1); 3-14. ©2016 AACR.

8 Article A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. 2016

Notta, Faiyaz / Chan-Seng-Yue, Michelle / Lemire, Mathieu / Li, Yilong / Wilson, Gavin W / Connor, Ashton A / Denroche, Robert E / Liang, Sheng-Ben / Brown, Andrew M K / Kim, Jaeseung C / Wang, Tao / Simpson, Jared T / Beck, Timothy / Borgida, Ayelet / Buchner, Nicholas / Chadwick, Dianne / Hafezi-Bakhtiari, Sara / Dick, John E / Heisler, Lawrence / Hollingsworth, Michael A / Ibrahimov, Emin / Jang, Gun Ho / Johns, Jeremy / Jorgensen, Lars G T / Law, Calvin / Ludkovski, Olga / Lungu, Ilinca / Ng, Karen / Pasternack, Danielle / Petersen, Gloria M / Shlush, Liran I / Timms, Lee / Tsao, Ming-Sound / Wilson, Julie M / Yung, Christina K / Zogopoulos, George / Bartlett, John M S / Alexandrov, Ludmil B / Real, Francisco X / Cleary, Sean P / Roehrl, Michael H / McPherson, John D / Stein, Lincoln D / Hudson, Thomas J / Campbell, Peter J / Gallinger, Steven. ·Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada. · Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK. · UHN Program in BioSpecimen Sciences, Department of Pathology, University Health Network, Toronto, Ontario M5G 2C4, Canada. · Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada. · Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. · Department of Computer Science, University of Toronto, Toronto, Ontario M5S 3G4, Canada. · Eppley Institute for Research in Cancer, Nebraska Medical Center, Omaha, Nebraska 68198, USA. · Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. · Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada. · Division of Surgical Oncology, Sunnybrook Health Sciences Centre, Odette Cancer Centre, Toronto, Ontario M4N 3M5, Canada. · Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA. · Research Institute of the McGill University Health Centre, Montreal, Québec, Canada, H3H 2L9. · Theoretical Biology and Biophysics (T-6) and Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, USA, 87545. · Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. · Department of Surgery, University Health Network, Toronto, Ontario M5G 2C4, Canada. · Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK. ·Nature · Pubmed #27732578.

ABSTRACT: Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the classically held view of stepwise cancer development. The current model of tumorigenesis, based on analyses of precursor lesions, termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: first, that pancreatic cancer develops through a particular sequence of genetic alterations (KRAS, followed by CDKN2A, then TP53 and SMAD4); and second, that the evolutionary trajectory of pancreatic cancer progression is gradual because each alteration is acquired independently. A shortcoming of this model is that clonally expanded precursor lesions do not always belong to the tumour lineage, indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing model of tumorigenesis has contributed to the clinical notion that pancreatic cancer evolves slowly and presents at a late stage. However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes, despite efforts aimed at early detection, suggest that pancreatic cancer progression is not gradual. Here, using newly developed informatics tools, we tracked changes in DNA copy number and their associated rearrangements in tumour-enriched genomes and found that pancreatic cancer tumorigenesis is neither gradual nor follows the accepted mutation order. Two-thirds of tumours harbour complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory. In a subset of cases, the consequence of such errors is the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that are likely to set-off invasive cancer growth. These findings challenge the current progression model of pancreatic cancer and provide insights into the mutational processes that give rise to these aggressive tumours.