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Pancreatic Neoplasms: HELP
Articles by Steven Gallinger
Based on 87 articles published since 2009
(Why 87 articles?)
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Between 2009 and 2019, S. Gallinger wrote the following 87 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3 · 4
1 Guideline Comparison of Practice Guidelines, BRCAPRO, and Genetic Counselor Estimates to Identify Germline BRCA1 and BRCA2 Mutations in Pancreatic Cancer. 2018

Grant, Robert C / Holter, Spring / Borgida, Ayelet / Dhani, Neesha C / Hedley, David W / Knox, Jennifer J / Akbari, Mohammad R / Zogopoulos, George / Gallinger, Steven. ·Division of Medical Oncology, University of Toronto, Toronto, Canada. robert.grant@utoronto.ca. · Ontario Institute for Cancer Research, Toronto, Canada. robert.grant@utoronto.ca. · Princess Margaret Cancer Centre-Ontario Power Generation, 700 University Avenue, Work Station 7W460, Toronto, ON, M5G 1Z5, Canada. robert.grant@utoronto.ca. · Ontario Pancreas Cancer Study, Toronto, Canada. · Division of Medical Oncology, University of Toronto, Toronto, Canada. · Wallace McCain Centre for Pancreatic Cancer, University of Toronto, Toronto, Canada. · Dalla Lana School of Public Health, University of Toronto, Toronto, Canada. · Women's College Research Institute, Toronto, Canada. · Research Institute of the McGill University Health Centre, Montreal, Canada. · Goodman Cancer Research Centre, McGill University, Montreal, Canada. · Ontario Institute for Cancer Research, Toronto, Canada. · Princess Margaret Cancer Centre-Ontario Power Generation, 700 University Avenue, Work Station 7W460, Toronto, ON, M5G 1Z5, Canada. · Division of General Surgery, University of Toronto, Toronto, Canada. ·J Genet Couns · Pubmed #29441441.

ABSTRACT: Germline BRCA1 and BRCA2 (BRCA) mutation carriers with pancreatic ductal adenocarcinoma (PDAC) may benefit from precision therapies and their relatives should undergo tailored cancer prevention. In this study, we compared strategies to identify BRCA carriers with PDAC. Incident cases of PDAC were prospectively recruited for BRCA sequencing. Probands were evaluated using the National Comprehensive Cancer Network (NCCN) and the Ontario Ministry of Health and Long-Term Care (MOHLTC) guidelines. The probability of each proband carrying a mutation was estimated by surveying genetic counselors and using BRCAPRO. BRCA mutations were detected in 22/484 (4.5%) probands. 152/484 (31.2%) and 16/484 (3.3%) probands met the NCCN and MOHLTC guidelines, respectively. The NCCN guidelines had higher sensitivity than the MOHLTC guidelines (0.864 versus 0.227, P < 0.001) but lower specificity (0.712 versus 0.976, P < 0.001). One hundred and nineteen genetic counselors completed the survey. Discrimination was similar between genetic counselors and BRCAPRO (area-under-the-curve: 0.755 and 0.775, respectively, P = 0.702). Genetic counselors generally overestimated (P = 0.008), whereas BRCAPRO severely underestimated (P < 0.001), the probability that each proband carried a mutation. Our results indicate that the NCCN guidelines and genetic counselors accurately identify BRCA mutations in PDAC, while the MOHLTC guidelines and BRCAPRO should be updated to account for the association between BRCA and PDAC.

2 Review Molecular Events in the Natural History of Pancreatic Cancer. 2017

Oldfield, Leslie E / Connor, Ashton A / Gallinger, Steven. ·PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada; Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada; Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Canada. Electronic address: steven.gallinger@uhn.on.ca. ·Trends Cancer · Pubmed #28718411.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest epithelial malignancies. Improvements in our understanding of PDAC carcinogenesis will hopefully improve its detection, management, and outcomes, as has been achieved with other malignancies. Here we review the literature on the natural history of PDAC, including its cell of origin, the initiating somatic mutational events, pathways deranged in the mature tumor, its biological heterogeneity, and the relationship of the primary tumor with metastases. We also suggest areas for further research and highlight translatable findings that are beginning to make clinical inroads.

3 Review Next generation sequencing of pancreatic ductal adenocarcinoma: right or wrong? 2017

Connor, Ashton A / Gallinger, Steven. ·a PanCuRx Translational Research Initiative , Ontario Institute for Cancer Research , Toronto , Ontario , Canada. · b Lunenfeld-Tanenbaum Research Institute , Mount Sinai Hospital , Toronto , Ontario , Canada. · c Hepatobiliary/Pancreatic Surgical Oncology Program , University Health Network , Toronto , Ontario , Canada. ·Expert Rev Gastroenterol Hepatol · Pubmed #28460572.

ABSTRACT: INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) has the highest mortality rate of all epithelial malignancies and a paradoxically rising incidence rate. Clinical translation of next generation sequencing (NGS) of tumour and germline samples may ameliorate outcomes by identifying prognostic and predictive genomic and transcriptomic features in appreciable fractions of patients, facilitating enrolment in biomarker-matched trials. Areas covered: The literature on precision oncology is reviewed. It is found that outcomes may be improved across various malignancies, and it is suggested that current issues of adequate tissue acquisition, turnaround times, analytic expertise and clinical trial accessibility may lessen as experience accrues. Also reviewed are PDAC genomic and transcriptomic NGS studies, emphasizing discoveries of promising biomarkers, though these require validation, and the fraction of patients that will benefit from these outside of the research setting is currently unknown. Expert commentary: Clinical use of NGS with PDAC should be used in investigational contexts in centers with multidisciplinary expertise in cancer sequencing and pancreatic cancer management. Biomarker directed studies will improve our understanding of actionable genomic variation in PDAC, and improve outcomes for this challenging disease.

4 Review Identifying Factors Influencing Pancreatic Cancer Management to Inform Quality Improvement Efforts and Future Research: A Scoping Systematic Review. 2016

Gagliardi, Anna R / Soong, Daniel / Gallinger, Steven. ·From the *Toronto General Hospital, University Health Network, Toronto; and †Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada. ·Pancreas · Pubmed #26752254.

ABSTRACT: Pancreatic cancer (PC) patients appear to receive suboptimal care. We conducted a systematic review to identify factors that influence PC management which are amenable to quality improvement. MEDLINE, EMBASE, and the references of eligible studies were searched from 1996 to July 2014. Two authors independently selected and reviewed eligible studies. Identified factors were mapped onto a framework of determinants of care delivery and outcomes. Methodological quality of studies was assessed using Downs and Black criteria. Most of the 33 eligible studies were population-based observational studies conducted in the United States. Patient (age, socioeconomic status, race) and institutional (case volume, academic status) factors influence care delivery and outcomes (complications, mortality, readmission, survival). Two studies implemented interventions to improve quality of care (centralization to high-volume hospitals, multidisciplinary care). One study examined system determinants (referral wait times). No studies examined the influence of guideline or provider characteristics. The overall lack of health services research in PC is striking. Factors and interventions identified here can be used to plan PC quality improvement programs. Further research is needed to explore the influence of guideline and provider factors on PC management and evaluate the impact of quality improvement interventions.

5 Review Hereditary Pancreatic Cancer Syndromes. 2015

Connor, Ashton A / Gallinger, Steven. ·Division of General Surgery, Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. · Division of General Surgery, Department of Surgery, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address: steven.gallinger@uhn.ca. ·Surg Oncol Clin N Am · Pubmed #26363539.

ABSTRACT: Despite decades of scientific and clinical research, pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy. The clinical and pathologic features of PDAC, specifically the known environmental and genetic risk factors, are reviewed here with special emphasis on the hereditary pancreatic cancer (HPC) syndromes. For these latter conditions, strategies are described for their identification, for primary and secondary prevention in unaffected carriers, and for disease management in affected carriers. Nascent steps have been made toward personalized medicine based on the rational use of screening, tumor subtyping, and targeted therapies; these have been guided by growing knowledge of HPC syndromes in PDAC.

6 Review Diagnosis and management of pancreatic cancer. 2013

Kanji, Zaheer S / Gallinger, Steven. · ·CMAJ · Pubmed #23610017.

ABSTRACT: -- No abstract --

7 Clinical Trial Mutations in the pancreatic secretory enzymes 2018

Tamura, Koji / Yu, Jun / Hata, Tatsuo / Suenaga, Masaya / Shindo, Koji / Abe, Toshiya / MacGregor-Das, Anne / Borges, Michael / Wolfgang, Christopher L / Weiss, Matthew J / He, Jin / Canto, Marcia Irene / Petersen, Gloria M / Gallinger, Steven / Syngal, Sapna / Brand, Randall E / Rustgi, Anil / Olson, Sara H / Stoffel, Elena / Cote, Michele L / Zogopoulos, George / Potash, James B / Goes, Fernando S / McCombie, Richard W / Zandi, Peter P / Pirooznia, Mehdi / Kramer, Melissa / Parla, Jennifer / Eshleman, James R / Roberts, Nicholas J / Hruban, Ralph H / Klein, Alison Patricia / Goggins, Michael. ·Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Health Sciences Research, Mayo Clinic, Rochester, MN 55905. · Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5. · Population Sciences Division, Dana-Farber Cancer Institute, Boston, MA 02215. · Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213. · Division of Gastroenterology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104. · Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104. · Pancreatic Cancer Translational Center of Excellence, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104. · Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10017. · Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109. · Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201. · The Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada H3H 2R9. · The Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada H3A 1A3. · Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, Baltimore, MD 21287. · Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724. · InGenious Targeting Laboratory, Ronkonkoma, NY 11779. · Department of Epidemiology, Bloomberg School of Public Health, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. · Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205; mgoggins@jhmi.edu. ·Proc Natl Acad Sci U S A · Pubmed #29669919.

ABSTRACT: To evaluate whether germline variants in genes encoding pancreatic secretory enzymes contribute to pancreatic cancer susceptibility, we sequenced the coding regions of

8 Clinical Trial Analysis of the intra- and intertumoral heterogeneity of hypoxia in pancreatic cancer patients receiving the nitroimidazole tracer pimonidazole. 2015

Dhani, N C / Serra, S / Pintilie, M / Schwock, J / Xu, J / Gallinger, S / Hill, R P / Hedley, D W. ·Division of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre/Ontario Cancer Institute, 610 University Avenue, Toronto, ON, Canada M5G 2M9. · Department of Laboratory Medicine and Pathobiology, University Health Network, Princess Margaret Cancer Centre/Ontario Cancer Institute, 610 University Avenue, Toronto, ON, Canada M5G 2M9. · Department of Biostatistics, University Health Network, Princess Margaret Cancer Centre/Ontario Cancer Institute, 610 University Avenue, Toronto, ON, M5G 2M9. · Applied Molecular Profiling Laboratory, University Health Network, Princess Margaret Cancer Centre/Ontario Cancer Institute, 610 University Avenue, Toronto, ON, Canada M5G 2M9. · Division of Hepato-biliary Pancreatic Surgical Oncology, University Health Network and Mount Sinai Hospital, University Health Network, Princess Margaret Cancer Centre/Ontario Cancer Institute, 610 University Avenue, Toronto, ON, Canada M5G 2M9. · Radiation Medicine Program, University Health Network, Princess Margaret Cancer Centre/Ontario Cancer Institute, 610 University Avenue, Toronto, ON, Canada M5G 2M9. ·Br J Cancer · Pubmed #26325106.

ABSTRACT: BACKGROUND: Hypoxia is thought to be an adverse feature of pancreatic cancer, but direct measurement in patients is technically challenging. To address this, we characterised the intra/interpatient heterogeneity of hypoxia in surgical specimens from patients who received the 2-nitroimidazole tracer pimonidazole pre-operatively. METHODS: Pimondazole was given intravenously 16-20 h before pancreatectomy, and the extent and intratumoral heterogeneity of hypoxia determined by image analysis applied to multiple tissue blocks stained by immunohistochemistry. Intra/interpatient heterogeneity was estimated by variance component analysis. RESULTS: Pimonidazole staining was analysed in 10 tumours. The extent of labelling varied amongst patients (0-26%), with a broader range of hypoxia in the epithelial (1-39%) compared with the stromal (1-13%) compartments. Variance component analysis demonstrated greater inter- than intrapatient variability of hypoxia, and that multiple (4-5) tumour sections are required to provide a consistent evaluation of its extent in individual tumours. CONCLUSIONS: There is significant intra- and intertumoral heterogeneity of hypoxia in pancreatic cancers, and these do not appear to be generally more hypoxic than other cancer types. This study establishes the feasibility to assess hypoxia in pancreatic cancer patients using pimonidazole, but questions the reliability of measurements made using a single tissue section.

9 Clinical Trial Induction gemcitabine plus concurrent gemcitabine and radiotherapy for locally advanced unresectable or resected pancreatic cancer. 2014

Youl, M / Hashem, S / Brade, A / Cummings, B / Dawson, L A / Gallinger, S / Hedley, D / Jiang, H / Kim, J / Krzyzanowska, M K / Ringash, J / Wong, R / Brierley, J. ·Department of Radiation Oncology, University Health Network, Princess Margaret Cancer Centre and The University of Toronto, Toronto, Ontario, Canada. · Department of Surgical Oncology, University Health Network, Princess Margaret Cancer Centre and The University of Toronto, Toronto, Ontario, Canada. · Department of Medical Oncology, University Health Network, Princess Margaret Cancer Centre and The University of Toronto, Toronto, Ontario, Canada. · Department of Biostatistics, University Health Network, Princess Margaret Cancer Centre and The University of Toronto, Toronto, Ontario, Canada. · Department of Radiation Oncology, University Health Network, Princess Margaret Cancer Centre and The University of Toronto, Toronto, Ontario, Canada. Electronic address: James.Brierley@rmp.uhn.on.ca. ·Clin Oncol (R Coll Radiol) · Pubmed #24462333.

ABSTRACT: AIMS: To determine the efficacy of induction gemcitabine followed by biweekly gemcitabine concurrent with radiotherapy for locally advanced pancreatic cancer. MATERIALS AND METHODS: Between March 2001 and August 2009, 90 patients with unresectable (78) or resected (12) pancreatic cancer were treated with a standard treatment policy of induction gemcitabine (seven doses of weekly gemcitabine at 1000 mg/m(2)) followed by concurrent radiotherapy (52.5 Gy) and biweekly gemcitabine (40 mg/m(2)). RESULTS: After induction gemcitabine, 17.8% of patients did not proceed to chemoradiotherapy, due to either disease progression, performance status deterioration or gemcitabine toxicity. Of the patients who received chemoradiotherapy, 68.9% completed the course of 52.5 Gy, whereas 79.7% received more than 45 Gy. Chemoradiotherapy was stopped early due to treatment toxicity in 22.9% of patients. On intention to treat analysis, the median overall survival was 12.7 months in the locally advanced group and 18.2 months in the resected group. On multivariate analysis for the unresectable patients, a larger gross tumour volume was a significant poor prognostic factor for overall survival and local progression-free survival. CONCLUSION: This large series confirms, in a standard practice setting, similar efficacy and tolerability of treatment as previously reported in our phase I-II study. The benefit to patients with a gross tumour volume >48 cm(3) may be limited.

10 Clinical Trial Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. 2010

Neoptolemos, John P / Stocken, Deborah D / Bassi, Claudio / Ghaneh, Paula / Cunningham, David / Goldstein, David / Padbury, Robert / Moore, Malcolm J / Gallinger, Steven / Mariette, Christophe / Wente, Moritz N / Izbicki, Jakob R / Friess, Helmut / Lerch, Markus M / Dervenis, Christos / Oláh, Attila / Butturini, Giovanni / Doi, Ryuichiro / Lind, Pehr A / Smith, David / Valle, Juan W / Palmer, Daniel H / Buckels, John A / Thompson, Joyce / McKay, Colin J / Rawcliffe, Charlotte L / Büchler, Markus W / Anonymous9620671. ·Liverpool Cancer Research UK Cancer Trials Unit, Cancer Research UK Centre, University of Liverpool, Fifth Floor, UCD Bldg, Daulby Street, Liverpool, L69 3GA, United Kingdom. j.p.neoptolemos@liverpool.ac.uk ·JAMA · Pubmed #20823433.

ABSTRACT: CONTEXT: Adjuvant fluorouracil has been shown to be of benefit for patients with resected pancreatic cancer. Gemcitabine is known to be the most effective agent in advanced disease as well as an effective agent in patients with resected pancreatic cancer. OBJECTIVE: To determine whether fluorouracil or gemcitabine is superior in terms of overall survival as adjuvant treatment following resection of pancreatic cancer. DESIGN, SETTING, AND PATIENTS: The European Study Group for Pancreatic Cancer (ESPAC)-3 trial, an open-label, phase 3, randomized controlled trial conducted in 159 pancreatic cancer centers in Europe, Australasia, Japan, and Canada. Included in ESPAC-3 version 2 were 1088 patients with pancreatic ductal adenocarcinoma who had undergone cancer resection; patients were randomized between July 2000 and January 2007 and underwent at least 2 years of follow-up. INTERVENTIONS: Patients received either fluorouracil plus folinic acid (folinic acid, 20 mg/m(2), intravenous bolus injection, followed by fluorouracil, 425 mg/m(2) intravenous bolus injection given 1-5 days every 28 days) (n = 551) or gemcitabine (1000 mg/m(2) intravenous infusion once a week for 3 of every 4 weeks) (n = 537) for 6 months. MAIN OUTCOME MEASURES: Primary outcome measure was overall survival; secondary measures were toxicity, progression-free survival, and quality of life. RESULTS: Final analysis was carried out on an intention-to-treat basis after a median of 34.2 (interquartile range, 27.1-43.4) months' follow-up after 753 deaths (69%). Median survival was 23.0 (95% confidence interval [CI], 21.1-25.0) months for patients treated with fluorouracil plus folinic acid and 23.6 (95% CI, 21.4-26.4) months for those treated with gemcitabine (chi(1)(2) = 0.7; P = .39; hazard ratio, 0.94 [95% CI, 0.81-1.08]). Seventy-seven patients (14%) receiving fluorouracil plus folinic acid had 97 treatment-related serious adverse events, compared with 40 patients (7.5%) receiving gemcitabine, who had 52 events (P < .001). There were no significant differences in either progression-free survival or global quality-of-life scores between the treatment groups. CONCLUSION: Compared with the use of fluorouracil plus folinic acid, gemcitabine did not result in improved overall survival in patients with completely resected pancreatic cancer. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00058201.

11 Article None 2019

Jones, Martin R / Williamson, Laura M / Topham, James T / Lee, Michael K C / Goytain, Angela / Ho, Julie / Denroche, Robert E / Jang, GunHo / Pleasance, Erin / Shen, Yaoquing / Karasinska, Joanna M / McGhie, John P / Gill, Sharlene / Lim, Howard J / Moore, Malcolm J / Wong, Hui-Li / Ng, Tony / Yip, Stephen / Zhang, Wei / Sadeghi, Sara / Reisle, Carolyn / Mungall, Andrew J / Mungall, Karen L / Moore, Richard A / Ma, Yussanne / Knox, Jennifer J / Gallinger, Steven / Laskin, Janessa / Marra, Marco A / Schaeffer, David F / Jones, Steven J M / Renouf, Daniel J. ·BC Cancer, Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada. · Pancreas Centre British Columbia, Vancouver, Canada. · BC Cancer, Division of Medical Oncology, Vancouver, British Columbia, Canada. · Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, British Columbia, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. · Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. · Department of Molecular Biology and Biochemistry, Simon Fraser University, Vancouver, British Columbia, Canada. · Pancreas Centre British Columbia, Vancouver, Canada. drenouf@bccancer.bc.ca. ·Clin Cancer Res · Pubmed #31068372.

ABSTRACT: PURPOSE: Gene fusions involving neuregulin 1 ( EXPERIMENTAL DESIGN: Forty-seven patients with pancreatic ductal adenocarcinoma received comprehensive whole-genome and transcriptome sequencing and analysis. Two patients with gene fusions involving RESULTS: Three of 47 (6%) patients with advanced pancreatic ductal adenocarcinoma were identified as CONCLUSIONS: This work adds to a growing body of evidence that

12 Article Management and surveillance of non-functional pancreatic neuroendocrine tumours: Retrospective review. 2019

Yohanathan, Lavanya / Dossa, Fahima / St Germain, Amelie Tremblay / Golbafian, Faegheh / Moulton, Carol-Anne / McGilvray, Ian D / Greig, Paul D / Serra, Stefano / Wei, Alice C / Jhaveri, Kartik S / Gallinger, Steve / Cleary, Sean P. ·Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, MN, USA. · Division of General Surgery, University of Toronto, Toronto, ON, Canada. · Department of Surgery, Hotel-Dieu De Levis, Levis, QC, Canada. · Department of Family Medicine, London, ON, Canada. · Division of General Surgery, University of Toronto, Toronto, ON, Canada; Department of Surgery, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada. · Department of Pathology, University Health Network/University of Toronto, Canada. · Department of Surgery, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada. · Joint Department of Medical Imaging, University Health Network, Mount Sinai Hospital and Women's College Hospital, University of Toronto, Toronto, ON, Canada. · Division of General Surgery, University of Toronto, Toronto, ON, Canada; Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, MN, USA; Department of Surgery, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada. Electronic address: cleary.sean@mayo.edu. ·Pancreatology · Pubmed #30803874.

ABSTRACT: BACKGROUND: /Objective. To determine the outcomes of a non-operative management approach for sporadic, small, non-functional pancreatic neuroendocrine tumours. METHODS: A retrospective chart review of patients with non-functional pancreatic neuroendocrine tumours initially managed non-operatively at a single institution was performed. Patients were identified through a search of radiologic reports, and individuals with ≥2 cross-sectional imaging studies performed >6 months apart from Jan. 1, 2000 to Dec. 31, 2013 were included. Data on tumour size, radiologic characteristics at diagnosis, interval radiologic growth, and surgical outcomes were recorded. RESULTS: Over the thirteen-year study period, 95 patients met inclusion criteria and were followed radiologically for a median of 36 months (18-69 months). Median initial tumour size on first imaging was 14.0 mm (IQR 10-19 mm). Median overall tumour growth rate was 0.03 mm/month (IQR: 0.00-0.14 mm/month). There was no significant relationship between initial tumour size and growth rate for tumours ≤ 2 cm or for lesions between 2 and 4 cm. Thirteen (14%) patients initially managed non-operatively underwent resection during the follow-up period. Reasons for surgery included interval tumour growth, patient anxiety or preference, or diagnostic uncertainty. Median time to surgery was 14 months (IQR 8-19 months). No patients progressed beyond resectability or developed metastatic disease during the observation period. CONCLUSION: For patients with sporadic, small, non-functional pancreatic neuroendocrine tumours, radiologic surveillance appears to be a safe initial approach to management.

13 Article Whole genomes define concordance of matched primary, xenograft, and organoid models of pancreas cancer. 2019

Gendoo, Deena M A / Denroche, Robert E / Zhang, Amy / Radulovich, Nikolina / Jang, Gun Ho / Lemire, Mathieu / Fischer, Sandra / Chadwick, Dianne / Lungu, Ilinca M / Ibrahimov, Emin / Cao, Ping-Jiang / Stein, Lincoln D / Wilson, Julie M / Bartlett, John M S / Tsao, Ming-Sound / Dhani, Neesha / Hedley, David / Gallinger, Steven / Haibe-Kains, Benjamin. ·Centre for Computational Biology, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom. · School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom. · PanCuRx Translational Research Initiative, Ontario Institute of Cancer Research (OICR), Toronto, Ontario, Canada. · Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Princess Margaret Living Biobank Core, University Health Network, Toronto, Ontario, Canada. · Department of Statistical Science, University of Toronto, Toronto, Ontario, Canada. · Department of Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada. · UHN Program in BioSpecimen Sciences, Department of Pathology, University Health Network, Toronto, Ontario, Canada. · Transformative Pathology, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. · Molecular Genetics Department, University of Toronto, Toronto, Ontario, Canada. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. · Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. · Vector Institute, Toronto, Ontario, Canada. ·PLoS Comput Biol · Pubmed #30629588.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) has the worst prognosis among solid malignancies and improved therapeutic strategies are needed to improve outcomes. Patient-derived xenografts (PDX) and patient-derived organoids (PDO) serve as promising tools to identify new drugs with therapeutic potential in PDAC. For these preclinical disease models to be effective, they should both recapitulate the molecular heterogeneity of PDAC and validate patient-specific therapeutic sensitivities. To date however, deep characterization of the molecular heterogeneity of PDAC PDX and PDO models and comparison with matched human tumour remains largely unaddressed at the whole genome level. We conducted a comprehensive assessment of the genetic landscape of 16 whole-genome pairs of tumours and matched PDX, from primary PDAC and liver metastasis, including a unique cohort of 5 'trios' of matched primary tumour, PDX, and PDO. We developed a pipeline to score concordance between PDAC models and their paired human tumours for genomic events, including mutations, structural variations, and copy number variations. Tumour-model comparisons of mutations displayed single-gene concordance across major PDAC driver genes, but relatively poor agreement across the greater mutational load. Genome-wide and chromosome-centric analysis of structural variation (SV) events highlights previously unrecognized concordance across chromosomes that demonstrate clustered SV events. We found that polyploidy presented a major challenge when assessing copy number changes; however, ploidy-corrected copy number states suggest good agreement between donor-model pairs. Collectively, our investigations highlight that while PDXs and PDOs may serve as tractable and transplantable systems for probing the molecular properties of PDAC, these models may best serve selective analyses across different levels of genomic complexity.

14 Article Sensitive tumour detection and classification using plasma cell-free DNA methylomes. 2018

Shen, Shu Yi / Singhania, Rajat / Fehringer, Gordon / Chakravarthy, Ankur / Roehrl, Michael H A / Chadwick, Dianne / Zuzarte, Philip C / Borgida, Ayelet / Wang, Ting Ting / Li, Tiantian / Kis, Olena / Zhao, Zhen / Spreafico, Anna / Medina, Tiago da Silva / Wang, Yadon / Roulois, David / Ettayebi, Ilias / Chen, Zhuo / Chow, Signy / Murphy, Tracy / Arruda, Andrea / O'Kane, Grainne M / Liu, Jessica / Mansour, Mark / McPherson, John D / O'Brien, Catherine / Leighl, Natasha / Bedard, Philippe L / Fleshner, Neil / Liu, Geoffrey / Minden, Mark D / Gallinger, Steven / Goldenberg, Anna / Pugh, Trevor J / Hoffman, Michael M / Bratman, Scott V / Hung, Rayjean J / De Carvalho, Daniel D. ·Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. · Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada. · Memorial Sloan Kettering Cancer Center, New York, NY, USA. · Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. · Genome Technologies, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · UMR_S 1236, Univ Rennes 1, Inserm, Etablissement Français du sang Bretagne, Rennes, France. · Department of Biochemistry and Molecular Medicine, UC Davis Comprehensive Cancer Center, Sacramento, CA, USA. · Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. · Fred Litwin Centre for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Department of Surgery, Toronto General Hospital, Toronto, Ontario, Canada. · Department of Computer Science, University of Toronto, Toronto, Ontario, Canada. · Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada. rayjean.hung@lunenfeld.ca. · Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. rayjean.hung@lunenfeld.ca. · Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. ddecarv@uhnresearch.ca. · Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. ddecarv@uhnresearch.ca. ·Nature · Pubmed #30429608.

ABSTRACT: The use of liquid biopsies for cancer detection and management is rapidly gaining prominence

15 Article Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer. 2018

Klein, Alison P / Wolpin, Brian M / Risch, Harvey A / Stolzenberg-Solomon, Rachael Z / Mocci, Evelina / Zhang, Mingfeng / Canzian, Federico / Childs, Erica J / Hoskins, Jason W / Jermusyk, Ashley / Zhong, Jun / Chen, Fei / Albanes, Demetrius / Andreotti, Gabriella / Arslan, Alan A / Babic, Ana / Bamlet, William R / Beane-Freeman, Laura / Berndt, Sonja I / Blackford, Amanda / Borges, Michael / Borgida, Ayelet / Bracci, Paige M / Brais, Lauren / Brennan, Paul / Brenner, Hermann / Bueno-de-Mesquita, Bas / Buring, Julie / Campa, Daniele / Capurso, Gabriele / Cavestro, Giulia Martina / Chaffee, Kari G / Chung, Charles C / Cleary, Sean / Cotterchio, Michelle / Dijk, Frederike / Duell, Eric J / Foretova, Lenka / Fuchs, Charles / Funel, Niccola / Gallinger, Steven / M Gaziano, J Michael / Gazouli, Maria / Giles, Graham G / Giovannucci, Edward / Goggins, Michael / Goodman, Gary E / Goodman, Phyllis J / Hackert, Thilo / Haiman, Christopher / Hartge, Patricia / Hasan, Manal / Hegyi, Peter / Helzlsouer, Kathy J / Herman, Joseph / Holcatova, Ivana / Holly, Elizabeth A / Hoover, Robert / Hung, Rayjean J / Jacobs, Eric J / Jamroziak, Krzysztof / Janout, Vladimir / Kaaks, Rudolf / Khaw, Kay-Tee / Klein, Eric A / Kogevinas, Manolis / Kooperberg, Charles / Kulke, Matthew H / Kupcinskas, Juozas / Kurtz, Robert J / Laheru, Daniel / Landi, Stefano / Lawlor, Rita T / Lee, I-Min / LeMarchand, Loic / Lu, Lingeng / Malats, Núria / Mambrini, Andrea / Mannisto, Satu / Milne, Roger L / Mohelníková-Duchoňová, Beatrice / Neale, Rachel E / Neoptolemos, John P / Oberg, Ann L / Olson, Sara H / Orlow, Irene / Pasquali, Claudio / Patel, Alpa V / Peters, Ulrike / Pezzilli, Raffaele / Porta, Miquel / Real, Francisco X / Rothman, Nathaniel / Scelo, Ghislaine / Sesso, Howard D / Severi, Gianluca / Shu, Xiao-Ou / Silverman, Debra / Smith, Jill P / Soucek, Pavel / Sund, Malin / Talar-Wojnarowska, Renata / Tavano, Francesca / Thornquist, Mark D / Tobias, Geoffrey S / Van Den Eeden, Stephen K / Vashist, Yogesh / Visvanathan, Kala / Vodicka, Pavel / Wactawski-Wende, Jean / Wang, Zhaoming / Wentzensen, Nicolas / White, Emily / Yu, Herbert / Yu, Kai / Zeleniuch-Jacquotte, Anne / Zheng, Wei / Kraft, Peter / Li, Donghui / Chanock, Stephen / Obazee, Ofure / Petersen, Gloria M / Amundadottir, Laufey T. ·Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, 21231, USA. aklein1@jhmi.edu. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA. aklein1@jhmi.edu. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. · Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, 06520, USA. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. · Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, 21231, USA. · Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. · Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY, 10016, USA. · Department of Population Health, New York University School of Medicine, New York, NY, 10016, USA. · Department of Environmental Medicine, New York University School of Medicine, New York, NY, 10016, USA. · Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA. · Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, M5G 1×5, Canada. · Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, 94158, USA. · International Agency for Research on Cancer (IARC), 69372, Lyon, France. · Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. · Division of Preventive Oncology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. · National Center for Tumor Diseases (NCT), 69120, Heidelberg, Germany. · Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), 3720 BA, Bilthoven, The Netherlands. · Department of Gastroenterology and Hepatology, University Medical Centre, 3584 CX, Utrecht, The Netherlands. · Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, SW7 2AZ, UK. · Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia. · Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, 02215, USA. · Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA. · Department of Biology, University of Pisa, 56126, Pisa, Italy. · Digestive and Liver Disease Unit, 'Sapienza' University of Rome, 00185, Rome, Italy. · Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy. · Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA. · Cancer Care Ontario, University of Toronto, Toronto, Ontario, M5G 2L7, Canada. · Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, M5T 3M7, Canada. · Department of Pathology, Academic Medical Center, University of Amsterdam, 1007 MB, Amsterdam, The Netherlands. · Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), Barcelona, 08908, Spain. · Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, 65653, Brno, Czech Republic. · Yale Cancer Center, New Haven, CT, 06510, USA. · Department of Translational Research and The New Technologies in Medicine and Surgery, University of Pisa, 56126, Pisa, Italy. · Division of Aging, Brigham and Women's Hospital, Boston, MA, 02115, USA. · Boston VA Healthcare System, Boston, MA, 02132, USA. · Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, 106 79, Athens, Greece. · Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, VIC, 3004, Australia. · Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, 3010, Australia. · Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, 3004, Australia. · Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. · SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. · Department of General Surgery, University Hospital Heidelberg, 69120, Heidelberg, Germany. · Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90032, USA. · Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, 77230, USA. · First Department of Medicine, University of Szeged, 6725, Szeged, Hungary. · Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. · Department of Radiation Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, 21231, USA. · Institute of Public Health and Preventive Medicine, Charles University, 2nd Faculty of Medicine, 150 06, Prague 5, Czech Republic. · Epidemiology Research Program, American Cancer Society, Atlanta, GA, 30303, USA. · Department of Hematology, Institute of Hematology and Transfusion Medicine, 02-776, Warsaw, Poland. · Department of Epidemiology and Public Health, Faculty of Medicine, University of Ostrava, 701 03, Ostrava, Czech Republic. · Faculty of Medicine, University of Olomouc, 771 47, Olomouc, Czech Republic. · Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. · School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0SP, UK. · Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, 44195, USA. · ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), 08003, Barcelona, Spain. · CIBER Epidemiología y Salud Pública (CIBERESP), 08003, Barcelona, Spain. · Hospital del Mar Institute of Medical Research (IMIM), Universitat Autònoma de Barcelona, 08003, Barcelona, Spain. · Universitat Pompeu Fabra (UPF), 08002, Barcelona, Spain. · Department of Gastroenterology, Lithuanian University of Health Sciences, 44307, Kaunas, Lithuania. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. · ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, 37134, Verona, Italy. · Department of Epidemiology, Harvard School of Public Health, Boston, MA, 02115, USA. · Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, 96813, USA. · Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO), 28029, Madrid, Spain. · CIBERONC, 28029, Madrid, Spain. · Oncology Department, ASL1 Massa Carrara, Carrara, 54033, Italy. · Department of Public Health Solutions, National Institute for Health and Welfare, 00271, Helsinki, Finland. · Department of Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital, 775 20, Olomouc, Czech Republic. · Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, 4029, Australia. · Department of General Surgery, University of Heidelburg, Heidelberg, Germany. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. · Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padua, 35124, Padua, Italy. · Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, 40138, Bologna, Italy. · Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, 28029, Madrid, Spain. · Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08002, Barcelona, Spain. · Centre de Recherche en Épidémiologie et Santé des Populations (CESP, Inserm U1018), Facultés de Medicine, Université Paris-Saclay, UPS, UVSQ, Gustave Roussy, 94800, Villejuif, France. · Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. · Department of Medicine, Georgetown University, Washington, 20057, USA. · Laboratory for Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, 323 00, Pilsen, Czech Republic. · Department of Surgical and Perioperative Sciences, Umeå University, 901 85, Umeå, Sweden. · Department of Digestive Tract Diseases, Medical University of Łodz, 90-647, Łodz, Poland. · Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", 71013, San Giovanni Rotondo, FG, Italy. · Division of Research, Kaiser Permanente Northern California, Oakland, CA, 94612, USA. · Department of General, Visceral and Thoracic Surgery, University Hamburg-Eppendorf, 20246, Hamburg, Germany. · Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA. · Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 142 20, Prague 4, Czech Republic. · Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, NY, 14214, USA. · Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. · Department of Epidemiology, University of Washington, Seattle, WA, 98195, USA. · Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA. · Department of Biostatistics, Harvard School of Public Health, Boston, MA, 02115, USA. · Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. · Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. amundadottirl@mail.nih.gov. ·Nat Commun · Pubmed #29422604.

ABSTRACT: In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10

16 Article Recapitulating the clinical scenario of BRCA-associated pancreatic cancer in pre-clinical models. 2018

Golan, Talia / Stossel, Chani / Atias, Dikla / Buzhor, Ella / Halperin, Sharon / Cohen, Keren / Raitses-Gurevich, Maria / Glick, Yulia / Raskin, Stephen / Yehuda, Daniel / Feldman, Anna / Schvimer, Michael / Friedman, Eitan / Karni, Rotem / Wilson, Julie M / Denroche, Robert E / Lungu, Ilinca / Bartlett, John M S / Mbabaali, Faridah / Gallinger, Steven / Berger, Raanan. ·Oncology Institute, Sheba Medical Center, Tel Hashomer, Israel. · Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. · Radiology Institute, Sheba Medical Center, Tel Hashomer, Israel. · Pathology Department, Sheba Medical Center, Tel Hashomer, Israel. · Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Tel-Hashomer, Israel. · Department of Biochemistry and Molecular Biology, IMRIC, Hebrew University - Hadassah Medical School, Jerusalem, Israel. · Ontario Institute for Cancer Research, Toronto, Canada. · Department of Surgery, University Health Network, Toronto, Canada. ·Int J Cancer · Pubmed #29396858.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. BRCA-associated PDAC comprises a clinically relevant subtype. A portion of these patients are highly susceptible to DNA damaging therapeutics, however, responses are heterogeneous and clinical resistance evolves. We have developed unique patient-derived xenograft (PDX) models from metastatic lesions of germline BRCA-mutated patients obtained at distinct time points; before treatment and at progression. Thus, closely mimicking clinical scenarios, to further investigate treatment naïve and resistant patients. DNA was isolated from six BRCA-mutated PDXs and classified by whole-genome sequencing to stable-genome or homologous recombination deficient (HRD)-genome. The sensitivity to DNA-damaging agents was evaluated in vivo in three BRCA-associated PDAC PDXs models: (1) HRD-genome naïve to treatments; (2) stable-genome naïve to treatment; (3) HRD-genome resistant to treatment. Correlation between disease course at tissue acquisition and response to PARP inhibitor (PARPi)/platinum was demonstrated in PDXs in vivo. Only the HRD-genome PDX, naïve to treatment, was sensitive to PARP inhibitor/cisplatin treatments. Our results demonstrate heterogeneous responses to DNA damaging agents/PARPi in BRCA-associated PDX thus reflecting the wide clinical spectrum. An HRD-genome PDX generated from a naïve to treatment biopsy was sensitive to platinum/PARPi whereas no benefit was observed in treating a HRD-genome PDXs generated from a patient that had acquired resistance nor stable-genome PDXs.

17 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.

18 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:

19 Article Exome-Wide Association Study of Pancreatic Cancer Risk. 2018

Grant, Robert C / Denroche, Robert E / Borgida, Ayelet / Virtanen, Carl / Cook, Natalie / Smith, Alyssa L / Connor, Ashton A / Wilson, Julie M / Peterson, Gloria / Roberts, Nicholas J / Klein, Alison P / Grimmond, Sean M / Biankin, Andrew / Cleary, Sean / Moore, Malcolm / Lemire, Mathieu / Zogopoulos, George / Stein, Lincoln / Gallinger, Steven. ·Ontario Institute for Cancer Research, Toronto, Canada. · Ontario Pancreas Cancer Study, Toronto, Canada. · Princess Margaret Genomics Centre, Toronto, Canada. · Research Institute of the McGill University Health Centre, Montreal, Canada. · Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. · Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Melbourne, Australia. · Wohl Cancer Research Centre, Institute of, Cancer Sciences, University of Glasgow, Glasgow, United Kingdom; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom; South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, Australia. · Ontario Institute for Cancer Research, Toronto, Canada; Ontario Pancreas Cancer Study, Toronto, Canada. · Ontario Institute for Cancer Research, Toronto, Canada; Ontario Pancreas Cancer Study, Toronto, Canada. Electronic address: steven.gallinger@uhn.ca. ·Gastroenterology · Pubmed #29074453.

ABSTRACT: We conducted a case-control exome-wide association study to discover germline variants in coding regions that affect risk for pancreatic cancer, combining data from 5 studies. We analyzed exome and genome sequencing data from 437 patients with pancreatic cancer (cases) and 1922 individuals not known to have cancer (controls). In the primary analysis, BRCA2 had the strongest enrichment for rare inactivating variants (17/437 cases vs 3/1922 controls) (P = 3.27x10

20 Article CT texture features are associated with overall survival in pancreatic ductal adenocarcinoma - a quantitative analysis. 2017

Eilaghi, Armin / Baig, Sameer / Zhang, Yucheng / Zhang, Junjie / Karanicolas, Paul / Gallinger, Steven / Khalvati, Farzad / Haider, Masoom A. ·Department of Medical Imaging and Sunnybrook Research Institute, Sunnybrook Health Sciences Center, University of Toronto, 2075 Bayview Ave., Room Rm AG 46, Toronto, M4N 3 M5, ON, Canada. · Mechanical Engineering Department, Australian College of Kuwait, Kuwait City, Kuwait. · Department of Surgery, Sunnybrook Health Sciences Center, University of Toronto, Toronto, ON, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON, Canada. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada. · Hepatobiliary/pancreatic Surgical Oncology Program, University Health Network, Toronto, ON, Canada. · Department of Medical Imaging and Sunnybrook Research Institute, Sunnybrook Health Sciences Center, University of Toronto, 2075 Bayview Ave., Room Rm AG 46, Toronto, M4N 3 M5, ON, Canada. masoom.haider@sunnybrook.ca. ·BMC Med Imaging · Pubmed #28629416.

ABSTRACT: BACKGROUND: To assess whether CT-derived texture features predict survival in patients undergoing resection for pancreatic ductal adenocarcinoma (PDAC). METHODS: Thirty patients with pre-operative CT from 2007 to 2012 for PDAC were included. Tumor size and five texture features namely uniformity, entropy, dissimilarity, correlation, and inverse difference normalized were calculated. Mann-Whitney rank sum test was used to compare tumor with normal pancreas. Receiver operating characteristics (ROC) analysis, Cox regression and Kaplan-Meier tests were used to assess association of texture features with overall survival (OS). RESULTS: Uniformity (p < 0.001), entropy (p = 0.009), correlation (p < 0.001), and mean intensity (p < 0.001) were significantly different in tumor regions compared to normal pancreas. Tumor dissimilarity (p = 0.045) and inverse difference normalized (p = 0.046) were associated with OS whereas tumor intensity (p = 0.366), tumor size (p = 0.611) and other textural features including uniformity (p = 0.334), entropy (p = 0.330) and correlation (p = 0.068) were not associated with OS. CONCLUSION: CT-derived PDAC texture features of dissimilarity and inverse difference normalized are promising prognostic imaging biomarkers of OS for patients undergoing curative intent surgical resection.

21 Article Pancreatic cancer ascites xenograft-an expeditious model mirroring advanced therapeutic resistant disease. 2017

Golan, Talia / Stossel, Chani / Schvimer, Michael / Atias, Dikla / Halperin, Sharon / Buzhor, Ella / Raitses-Gurevich, Maria / Cohen, Keren / Pri-Chen, Sara / Wilson, Julie / Denroche, Robert E / Lungu, Ilinca / Bartlett, John M S / Mbabaali, Faridah / Yarden, Yosef / Nataraj, Nishanth Belugali / Gallinger, Steven / Berger, Raanan. ·Pancreatic Cancer Translational Research Laboratory, Oncology Institute, Sheba Medical Center, Tel Hashomer, Israel. · Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. · Pathology Department, Sheba Medical Center, Tel Hashomer, Israel. · Microsurgery Laboratory, Eye Institute, Sheba Medical Center, Tel Hashomer, Israel. · Ontario Institute for Cancer Research, Toronto, Canada. · Department of Surgery, University Health Network, Toronto, Canada. · Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel. · Oncology Institute, Sheba Medical Center, Tel Hashomer, Israel. ·Oncotarget · Pubmed #28489577.

ABSTRACT: Pancreatic ductal adenocarcinoma has limited treatment options. There is an urgent need for developing appropriate pre-clinical models recapitulating metastatic disease, the most common clinical scenario at presentation. Ascites accumulation occurs in up to 20-30% of patients with pancreatic cancer; this milieu represents a highly cellular research resource of metastatic peritoneal spread. In this study, we utilized pancreatic ascites/pleural effusion cancer cells to establish patient derived xenografts.Ascites/pleural effusion-patient derived xenografts were established from twelve independent cases. Xenografts were serially passed in nude mice and tissue bio-specimen banking has been established. Histopathology of emergent tumors demonstrates poorly to moderately differentiated, glandular and mucin producing tumors, mirroring morphology of primary pancreatic cancer tumors. Whole genome sequencing of six patient derived xenografts samples demonstrates common mutations and structural variations similar to those reported in primary pancreatic cancer. Xenograft tumors were dissociated to single-cells and in-vitro drug sensitivity screen assays demonstrated chemo-resistance, correlating with patient clinical scenarios, thus serving as a platform for clinically relevant translational research.Therefore, establishment of this novel ascites/pleural effusion patient derived xenograft model, with extensive histopathology and genomic characterization, opens an opportunity for the study of advanced aggressive pancreatic cancer. Characterization of metastatic disease and mechanisms of resistance to therapeutics may lead to the development of novel drug combinations.

22 Article Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma. 2017

Feigin, Michael E / Garvin, Tyler / Bailey, Peter / Waddell, Nicola / Chang, David K / Kelley, David R / Shuai, Shimin / Gallinger, Steven / McPherson, John D / Grimmond, Sean M / Khurana, Ekta / Stein, Lincoln D / Biankin, Andrew V / Schatz, Michael C / Tuveson, David A. ·Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA. · Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York, USA. · Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, UK. · QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. · The Kinghorn Cancer Centre, Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. · Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales, Australia. · Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. · Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Division of General Surgery, Toronto General Hospital, Toronto, Ontario, Canada. · Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Sandra and Edward Meyer Cancer Center, Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, USA. · Informatics and Biocomputing, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, Scotland, UK. · Department of Computer Science, Johns Hopkins University, Baltimore, Maryland, USA. · Department of Biology, Johns Hopkins University, Baltimore, Maryland, USA. · Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA. ·Nat Genet · Pubmed #28481342.

ABSTRACT: The contributions of coding mutations to tumorigenesis are relatively well known; however, little is known about somatic alterations in noncoding DNA. Here we describe GECCO (Genomic Enrichment Computational Clustering Operation) to analyze somatic noncoding alterations in 308 pancreatic ductal adenocarcinomas (PDAs) and identify commonly mutated regulatory regions. We find recurrent noncoding mutations to be enriched in PDA pathways, including axon guidance and cell adhesion, and newly identified processes, including transcription and homeobox genes. We identified mutations in protein binding sites correlating with differential expression of proximal genes and experimentally validated effects of mutations on expression. We developed an expression modulation score that quantifies the strength of gene regulation imposed by each class of regulatory elements, and found the strongest elements were most frequently mutated, suggesting a selective advantage. Our detailed single-cancer analysis of noncoding alterations identifies regulatory mutations as candidates for diagnostic and prognostic markers, and suggests new mechanisms for tumor evolution.

23 Article Overall survival and clinical characteristics of BRCA mutation carriers with stage I/II pancreatic cancer. 2017

Golan, Talia / Sella, Tal / O'Reilly, Eileen M / Katz, Matthew H G / Epelbaum, Ron / Kelsen, David P / Borgida, Ayelet / Maynard, Hannah / Kindler, Hedy / Friedmen, Eitan / Javle, Milind / Gallinger, Steven. ·Department of Oncology, Sheba Medical Center, Ramat Gan 52621, Israel. · Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel. · Department of Medicine, Memorial Sloan Kettering Cancer Center New York, New York, NY 10065, USA. · Weill Cornell Medical College New York, New York, NY 10065, USA. · Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. · Department of Oncology, Rambam Health Care Campus, Haifa 3109601, Israel. · The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3109601, Israel. · Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada. · Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA. · The Susanne Levy Gertner Oncogenetics Unit, Sheba Medical Center, Ramat Gan 52621, Israel. · Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA. ·Br J Cancer · Pubmed #28183138.

ABSTRACT: BACKGROUND: BRCA1/BRCA2 germ line (GL) mutation carriers with pancreatic adenocarcinoma (PDAC) may have distinct outcomes. We recently described an apparent more favourable prognosis of surgically resected BRCA-associated PDAC patients in a single-arm, uncontrolled, retrospective study. However, the prognostic impact of GL BRCA1/2 mutations in surgically resected PDAC has not been compared with a matched control population. METHODS: A larger multi-centre, case-control retrospective analysis was performed. Cases were patients with surgically resected, BRCA1/2-associated PDAC from 2004 to 2013. Controls included surgically resected PDAC cases treated during the same time period that were either BRCA non-carriers, or had no family history of breast, ovarian or pancreatic cancers. Cases and controls were matched by: age at diagnosis (within ±5-year period) and institution. Demographics, clinical history, overall survival (OS) and disease-free survival (DFS) were abstracted from patient records. Statistical comparisons were assessed using χ RESULTS: Twenty-five patients with BRCA1-(n=4) or BRCA2 (N=21)-associated resectable PDAC were identified. Mean age was 55.7 years (range, 34-78 years), 48% (n=12) were females and 76% (n=19) were Jewish. Cases were compared (1 : 2) with 49 resectable PDAC controls, and were balanced for age, ethnicity and other relevant clinical and pathological features. BRCA-associated PDAC patients received neoadjuvant, or adjuvant platinum-based treatment more frequently than controls (7 out of 8 vs 6 out of 14) and (7 out of 21 vs 3 out of 44), respectively. No significant difference in median OS (37.06 vs 38.77 months, P=0.838) and in DFS (14.3 vs 12.0 months, P=0.303) could be demonstrated between cases and controls. A trend to increased DFS was observed among BRCA-positive cases treated with neoadjuvant/adjuvant platinum-containing regimens (n=10) compared with similarly treated controls (n=7) (39.1 vs 12.4 months, P=0.255). CONCLUSIONS: In this retrospective analysis, the prognosis of surgically resectable BRCA-associated PDAC is no different than that of sporadic PDAC from the same institution. The role of platinum-based adjuvant therapy in this setting requires prospective investigation.

24 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.

25 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.

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