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Grant Details

Grant Number: 5R21CA192072-02 Interpret this number
Primary Investigator: Sicklick, Jason
Organization: University Of California, San Diego
Project Title: Defining the Germline Genomic Landscape of a Novel Gist Multi-Tumor Syndrome
Fiscal Year: 2017
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Abstract

? DESCRIPTION (provided by applicant): Gastrointestinal Stromal Tumor (GIST) is the most common sarcoma in the U.S. Sporadic GIST is often caused by somatic mutations in KIT, PDGFR?, or BRAF genes, while hereditary GIST syndromes are caused by germline KIT, NF-1, or succinate dehydrogenase (SDH) mutations. Our epidemiologic data under peer review suggests that 17.1% of "sporadic" GIST patients develop ?1 additional malignancies not associated with familial GIST syndromes, including Non-Hodgkin's lymphoma, carcinoid tumors, and melanoma, as well as colorectal, esophageal, pancreatic, hepatobiliary, non-small cell lung, prostate, and renal cell cancers. This raises the question as to whether a subset of "sporadic" GIST patients have an unacknowledged multi-tumor syndrome(s) caused by yet to be determined heritable genomic alteration(s). We hypothesize the existence of GIST multiple tumor syndrome(s) (GMTS) with distinct tumor phenotype(s) from those previously identified in known familial GIST syndromes that result from the inheritance of one or more deleterious germline mutation(s). Our overall objective is to determine the heritable genomic cause(s) that may lead to the concomitant development of GIST and additional malignancies that we have identified as having higher incidences/prevalence within the GIST patient population. In Aim 1, we will sequence the germline whole exome of 50 unrelated individuals with "sporadic" GIST and one or more additional malignancies. We will select: 1) ?10 patients with at least two additional malignancies; 2) 10 patients that are 40-50 years of age with one or more additional malignancies; and 3) patients with a strong family history of cancer with one or more additional malignancies. Next generation sequencing and variant selection will be performed in order to characterize the genomic germline landscape of these patients. We will then perform Sanger sequencing in order to validate any critical/pathogenic mutations identified by whole exome sequencing. Once we have identified a set of critical mutations/genes/pathways, we will perform focused, independent Sanger sequencing in the germline DNA of a cohort of sporadic GIST patients without GMTS (N=50) in order to validate our findings as unique to GMTS patients. In Aim 2, we will sequence these patients' respective GIST for somatic KIT, PDGFR?, and BRAF mutations in order to determine if one or more somatic mutations are unique in this patient population or correlate with germline genomic findings, and therefore may serve as a potential somatic biomarker of GMTS in "sporadic" GIST patients. Concomitant with these analyses, we will analyze the demographics and tumor-specific details for each patient studied. If germline mutations are identified as putative disease drivers, our proposal has the potential for rapid translational application to the clinic as the characterization of novel hereditary cancer syndrome(s) would have implications for: 1) altered cancer screening recommendations; 2) prevention strategies; 3) familial genetic counseling and screening; and 4) developing anti-cancer therapies against unappreciated targets in these diseases.

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Publications

Lymphadenectomy For Adrenocortical Carcinoma: Is There A Therapeutic Benefit?
Authors: Gerry J.M. , Tran T.B. , Postlewait L.M. , Maithel S.K. , Prescott J.D. , Wang T.S. , Glenn J.A. , Phay J.E. , Keplinger K. , Fields R.C. , et al. .
Source: Annals Of Surgical Oncology, 2016 Dec; 23(Suppl 5), p. 708-713.
PMID: 27590329
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Clinical Score Predicting Long-term Survival After Repeat Resection For Recurrent Adrenocortical Carcinoma
Authors: Tran T.B. , Maithel S.K. , Pawlik T.M. , Wang T.S. , Hatzaras I. , Phay J.E. , Fields R.C. , Weber S.M. , Sicklick J.K. , Yopp A.C. , et al. .
Source: Journal Of The American College Of Surgeons, 2016 Dec; 223(6), p. 794-803.
PMID: 27618748
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Actual 10-year Survivors Following Resection Of Adrenocortical Carcinoma
Authors: Tran T.B. , Postlewait L.M. , Maithel S.K. , Prescott J.D. , Wang T.S. , Glenn J. , Phay J.E. , Keplinger K. , Fields R.C. , Jin L.X. , et al. .
Source: Journal Of Surgical Oncology, 2016 Dec; 114(8), p. 971-976.
PMID: 27633419
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Single Agent And Synergistic Activity Of The "first-in-class" Dual Pi3k/brd4 Inhibitor Sf1126 With Sorafenib In Hepatocellular Carcinoma
Authors: Singh A.R. , Joshi S. , Burgoyne A.M. , Sicklick J.K. , Ikeda S. , Kono Y. , Garlich J.R. , Morales G.A. , Durden D.L. .
Source: Molecular Cancer Therapeutics, 2016 Nov; 15(11), p. 2553-2562.
PMID: 27496136
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Image-based Detection And Targeting Of Therapy Resistance In Pancreatic Adenocarcinoma
Authors: Fox R.G. , Lytle N.K. , Jaquish D.V. , Park F.D. , Ito T. , Bajaj J. , Koechlein C.S. , Zimdahl B. , Yano M. , Kopp J.L. , et al. .
Source: Nature, 2016-06-16 00:00:00.0; 534(7607), p. 407-11.
PMID: 27281208
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Outcomes After Resection Of Cortisol-secreting Adrenocortical Carcinoma
Authors: Margonis G.A. , Kim Y. , Tran T.B. , Postlewait L.M. , Maithel S.K. , Wang T.S. , Glenn J.A. , Hatzaras I. , Shenoy R. , Phay J.E. , et al. .
Source: American Journal Of Surgery, 2016 Jun; 211(6), p. 1106-13.
PMID: 26810939
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Population-based Epidemiology And Mortality Of Small Malignant Gastrointestinal Stromal Tumors In The Usa
Authors: Coe T.M. , Fero K.E. , Fanta P.T. , Mallory R.J. , Tang C.M. , Murphy J.D. , Sicklick J.K. .
Source: Journal Of Gastrointestinal Surgery : Official Journal Of The Society For Surgery Of The Alimentary Tract, 2016 Jun; 20(6), p. 1132-40.
PMID: 27025710
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Nomograms To Predict Recurrence-free And Overall Survival After Curative Resection Of Adrenocortical Carcinoma
Authors: Kim Y. , Margonis G.A. , Prescott J.D. , Tran T.B. , Postlewait L.M. , Maithel S.K. , Wang T.S. , Evans D.B. , Hatzaras I. , Shenoy R. , et al. .
Source: Jama Surgery, 2016 Apr; 151(4), p. 365-73.
PMID: 26676603
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Outcomes Of Adjuvant Mitotane After Resection Of Adrenocortical Carcinoma: A 13-institution Study By The Us Adrenocortical Carcinoma Group
Authors: Postlewait L.M. , Ethun C.G. , Tran T.B. , Prescott J.D. , Pawlik T.M. , Wang T.S. , Glenn J. , Hatzaras I. , Shenoy R. , Phay J.E. , et al. .
Source: Journal Of The American College Of Surgeons, 2016 Apr; 222(4), p. 480-90.
PMID: 26775162
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Incidence Of Perioperative Complications Following Resection Of Adrenocortical Carcinoma And Its Association With Long-term Survival
Authors: Margonis G.A. , Amini N. , Kim Y. , Tran T.B. , Postlewait L.M. , Maithel S.K. , Wang T.S. , Evans D.B. , Hatzaras I. , Shenoy R. , et al. .
Source: World Journal Of Surgery, 2016 Mar; 40(3), p. 706-14.
PMID: 26546184
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Single-incision laparoscopic surgery through an ostomy site: a natural approach by an unnatural orifice.
Authors: Lopez N.E. , Peterson C.Y. , Ramamoorthy S.L. , McLemore E.C. , Sedrak M.F. , Lowy A.M. , Horgan S. , Talamini M.A. , Sicklick J.K. .
Source: Surgical Laparoscopy, Endoscopy & Percutaneous Techniques, 2015 Feb; 25(1), p. 74-8.
PMID: 24743670
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The glypican 3 hepatocellular carcinoma marker regulates human hepatic stellate cells via Hedgehog signaling.
Authors: Magistri P. , Leonard S.Y. , Tang C.M. , Chan J.C. , Lee T.E. , Sicklick J.K. .
Source: The Journal Of Surgical Research, 2014 Apr; 187(2), p. 377-85.
EPub date: 2013-12-17 00:00:00.0.
PMID: 24439425
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Resection of the liver and inferior vena cava for hepatic malignancy.
Authors: Hemming A.W. , Mekeel K.L. , Zendejas I. , Kim R.D. , Sicklick J.K. , Reed A.I. .
Source: Journal Of The American College Of Surgeons, 2013 Jul; 217(1), p. 115-24; discussion 124-5.
EPub date: 2013-02-01 00:00:00.0.
PMID: 23376028
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Correcting the misnomers of epithelial-mesenchymal relations.
Authors: Sicklick J.K. .
Source: The Journal Of Surgical Research, 2013-06-01 00:00:00.0; 182(1), p. 36-9.
EPub date: 2012-03-18 00:00:00.0.
PMID: 22480829
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Management of abdominal malignancies: updates from the International Association of Surgeons, Gastroenterologists and Oncologists.
Authors: Bouvet M. , Sicklick J.K. .
Source: Expert Review Of Anticancer Therapy, 2013 Apr; 13(4), p. 395-7.
PMID: 23560834
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Have we hit an invisible barrier for preventing postoperative urinary tract infections?
Authors: Sicklick J.K. .
Source: Archives Of Surgery (chicago, Ill. : 1960), 2012 Oct; 147(10), p. 953-4.
PMID: 23070410
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Gastric Cancer
Authors: Lawson,J.D. , Sicklick,J.K. , Fanta,P.T. .
Source: Current Problems In Cancer, 2011 May-Jun; 35(3), p. 97-127.
PMID: 21635986
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Genomics Of Gallbladder Cancer: The Case For Biomarker-driven Clinical Trial Design
Authors: Sicklick J.K. , Fanta P.T. , Shimabukuro K. , Kurzrock R. .
Source: Cancer Metastasis Reviews, 2016 06; 35(2), p. 263-75.
PMID: 26857926
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Management of Recurrent Retroperitoneal Sarcoma (RPS) in the Adult: A Consensus Approach from the Trans-Atlantic RPS Working Group.
Authors: Trans-Atlantic RPS Working Group .
Source: Annals Of Surgical Oncology, 2016 10; 23(11), p. 3531-3540.
EPub date: 2016-08-01 00:00:00.0.
PMID: 27480354
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Exome-wide analysis of bi-allelic alterations identifies a Lynch phenotype in The Cancer Genome Atlas.
Authors: Buckley A.R. , Ideker T. , Carter H. , Harismendy O. , Schork N.J. .
Source: Genome Medicine, 2018-09-14 00:00:00.0; 10(1), p. 69.
EPub date: 2018-09-14 00:00:00.0.
PMID: 30217226
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Tumor Symbiosis: Gastrointestinal Stromal Tumor as a Host for Primary Peritoneal Mesothelioma.
Authors: de la Torre J. , Banerjee S. , Baumgartner J. , Lin G.Y. , Burgoyne A.M. , Kirane A. , Sicklick J. .
Source: Journal Of Gastrointestinal Surgery : Official Journal Of The Society For Surgery Of The Alimentary Tract, 2018-08-21 00:00:00.0; , .
EPub date: 2018-08-21 00:00:00.0.
PMID: 30132292
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Next-Generation Sequencing of Circulating Tumor DNA Reveals Frequent Alterations in Advanced Hepatocellular Carcinoma.
Authors: Ikeda S. , Tsigelny I.F. , Skjevik .A. , Kono Y. , Mendler M. , Kuo A. , Sicklick J.K. , Heestand G. , Banks K.C. , Talasaz A. , et al. .
Source: The Oncologist, 2018 May; 23(5), p. 586-593.
EPub date: 2018-02-27 00:00:00.0.
PMID: 29487225
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Academic Surgical Oncologists' Productivity Correlates with Gender, Grant Funding, and Institutional NCI Comprehensive Cancer Center Affiliation.
Authors: Nguyen V. , Marmor R.A. , Ramamoorthy S.L. , Blair S.L. , Clary B.M. , Sicklick J.K. .
Source: Annals Of Surgical Oncology, 2018-03-29 00:00:00.0; , .
EPub date: 2018-03-29 00:00:00.0.
PMID: 29600347
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Fusion in Gastrointestinal Stromal Tumor Guides Adjuvant Treatment Decision-Making During Pregnancy.
Authors: Charo L.M. , Burgoyne A.M. , Fanta P.T. , Patel H. , Chmielecki J. , Sicklick J.K. , McHale M.T. .
Source: Journal Of The National Comprehensive Cancer Network : Jnccn, 2018 Mar; 16(3), p. 238-242.
PMID: 29523662
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SSAT State-of-the-Art Conference: Current Surgical Management of Gastric Tumors.
Authors: Norton J.A. , Kim T. , Kim J. , McCarter M.D. , Kelly K.J. , Wong J. , Sicklick J.K. .
Source: Journal Of Gastrointestinal Surgery : Official Journal Of The Society For Surgery Of The Alimentary Tract, 2017-08-14 00:00:00.0; , .
EPub date: 2017-08-14 00:00:00.0.
PMID: 28808875
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Biochemical, Molecular, and Clinical Characterization of Succinate Dehydrogenase Subunit A Variants of Unknown Significance.
Authors: Bannon A.E. , Kent J.D. , Forquer I. , Town A. , Klug L.R. , McCann K.E. , Beadling C. , Harismendy O. , Sicklick J.K. , Corless C.L. , et al. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2017-07-19 00:00:00.0; , .
EPub date: 2017-07-19 00:00:00.0.
PMID: 28724664
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MOLECULAR PATHWAYS: TARGETING THE MICROENVIRONMENT OF LIVER METASTASES.
Authors: Milette S. , Sicklick J.K. , Lowy A.M. , Brodt P. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2017-06-14 00:00:00.0; , .
EPub date: 2017-06-14 00:00:00.0.
PMID: 28615370
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Erratum to: Management of Recurrent Retroperitoneal Sarcoma (RPS) in the Adult: A Consensus Approach from the Trans-Atlantic RPS Working Group.
Authors: Trans-Atlantic RPS Working Group .
Source: Annals Of Surgical Oncology, 2017-05-11 00:00:00.0; , .
EPub date: 2017-05-11 00:00:00.0.
PMID: 28497197
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Surgical Management of Adolescents and Young Adults With Gastrointestinal Stromal Tumors: A US Population-Based Analysis.
Authors: Fero K.E. , Coe T.M. , Fanta P.T. , Tang C.M. , Murphy J.D. , Sicklick J.K. .
Source: Jama Surgery, 2017-05-01 00:00:00.0; 152(5), p. 443-451.
PMID: 28114506
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The Call of "The Wild"-Type GIST: It's Time for Domestication.
Authors: Alkhuziem M. , Burgoyne A.M. , Fanta P.T. , Tang C.M. , Sicklick J.K. .
Source: Journal Of The National Comprehensive Cancer Network : Jnccn, 2017 May; 15(5), p. 551-554.
PMID: 28476734
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NCCN Guidelines Insights: Hepatobiliary Cancers, Version 1.2017.
Authors: Benson A.B. , D'Angelica M.I. , Abbott D.E. , Abrams T.A. , Alberts S.R. , Saenz D.A. , Are C. , Brown D.B. , Chang D.T. , Covey A.M. , et al. .
Source: Journal Of The National Comprehensive Cancer Network : Jnccn, 2017 May; 15(5), p. 563-573.
PMID: 28476736
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Curative Surgical Resection Of Adrenocortical Carcinoma: Determining Long-term Outcome Based On Conditional Disease-free Probability
Authors: Kim Y. , Margonis G.A. , Prescott J.D. , Tran T.B. , Postlewait L.M. , Maithel S.K. , Wang T.S. , Glenn J.A. , Hatzaras I. , Shenoy R. , et al. .
Source: Annals Of Surgery, 2017 Jan; 265(1), p. 197-204.
PMID: 28009746
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and Notch Pathway Mutations.
Authors: Burgoyne A.M. , De Siena M. , Alkhuziem M. , Tang C.M. , Medina B. , Fanta P.T. , Belinsky M.G. , von Mehren M. , Thorson J.A. , Madlensky L. , et al. .
Source: Jco Precision Oncology, 2017; 2017, .
EPub date: 2017-08-15 00:00:00.0.
PMID: 29938249
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Fgfr1 And Ntrk3 Actionable Alterations In "wild-type" Gastrointestinal Stromal Tumors
Authors: Shi E. , Chmielecki J. , Tang C.M. , Wang K. , Heinrich M.C. , Kang G. , Corless C.L. , Hong D. , Fero K.E. , Murphy J.D. , et al. .
Source: Journal Of Translational Medicine, 2016-12-14 00:00:00.0; 14(1), p. 339.
PMID: 27974047
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Hedgehog Pathway Dysregulation Contributes To The Pathogenesis Of Human Gastrointestinal Stromal Tumors Via Gli-mediated Activation Of Kit Expression
Authors: Tang C.M. , Lee T.E. , Syed S.A. , Burgoyne A.M. , Leonard S.Y. , Gao F. , Chan J.C. , Shi E. , Chmielecki J. , Morosini D. , et al. .
Source: Oncotarget, 2016-10-25 00:00:00.0; , .
PMID: 27793025
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Minimally Invasive Resection Of Adrenocortical Carcinoma: A Multi-institutional Study Of 201 Patients
Authors: Lee C.W. , Salem A.I. , Schneider D.F. , Leverson G.E. , Tran T.B. , Poultsides G.A. , Postlewait L.M. , Maithel S.K. , Wang T.S. , Hatzaras I. , et al. .
Source: Journal Of Gastrointestinal Surgery : Official Journal Of The Society For Surgery Of The Alimentary Tract, 2016-10-21 00:00:00.0; , .
PMID: 27770290
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The Use of Solicited Publishing by Academic Surgeons.
Authors: Nguyen V. , Marmor R.A. , Ramamoorthy S.L. , Costantini T.W. , Baumgartner J.M. , Berumen J. , Jacobsen G.R. , Sicklick J.K. .
Source: Surgery, 2018 08; 164(2), p. 212-218.
EPub date: 2018-05-01 00:00:00.0.
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