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         headline:Metastatic tumor evolution and organoid modeling implicate TGFBR2as a cancer driver in diffuse gastric cancer
         description:Gastric cancer is the second-leading cause of global cancer deaths, with metastatic disease representing the primary cause of mortality. To identify candidate drivers involved in oncogenesis and tumor evolution, we conduct an extensive genome sequencing analysis of metastatic progression in a diffuse gastric cancer. This involves a comparison between a primary tumor from a hereditary diffuse gastric cancer syndrome proband and its recurrence as an ovarian metastasis. Both the primary tumor and ovarian metastasis have common biallelic loss-of-function of both the CDH1 and TP53 tumor suppressors, indicating a common genetic origin. While the primary tumor exhibits amplification of the Fibroblast growth factor receptor 2 (FGFR2) gene, the metastasis notably lacks FGFR2 amplification but rather possesses unique biallelic alterations of Transforming growth factor-beta receptor 2 (TGFBR2), indicating the divergent in vivo evolution of a TGFBR2-mutant metastatic clonal population in this patient. As TGFBR2 mutations have not previously been functionally validated in gastric cancer, we modeled the metastatic potential of TGFBR2 loss in a murine three-dimensional primary gastric organoid culture. The Tgfbr2 shRNA knockdown within Cdh1 -/- ; Tp53 -/- organoids generates invasion in vitro and robust metastatic tumorigenicity in vivo, confirming Tgfbr2 metastasis suppressor activity. We document the metastatic differentiation and genetic heterogeneity of diffuse gastric cancer and reveal the potential metastatic role of TGFBR2 loss-of-function. In support of this study, we apply a murine primary organoid culture method capable of recapitulating in vivo metastatic gastric cancer. Overall, we describe an integrated approach to identify and functionally validate putative cancer drivers involved in metastasis.
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            Allelic Imbalance
            Ovarian Metastasis
            Diffuse Gastric Cancer
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            Animal Genetics and Genomics
            Human Genetics
            Plant Genetics and Genomics
            Microbial Genetics and Genomics
            Bioinformatics
            Evolutionary Biology
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      headline:Metastatic tumor evolution and organoid modeling implicate TGFBR2as a cancer driver in diffuse gastric cancer
      description:Gastric cancer is the second-leading cause of global cancer deaths, with metastatic disease representing the primary cause of mortality. To identify candidate drivers involved in oncogenesis and tumor evolution, we conduct an extensive genome sequencing analysis of metastatic progression in a diffuse gastric cancer. This involves a comparison between a primary tumor from a hereditary diffuse gastric cancer syndrome proband and its recurrence as an ovarian metastasis. Both the primary tumor and ovarian metastasis have common biallelic loss-of-function of both the CDH1 and TP53 tumor suppressors, indicating a common genetic origin. While the primary tumor exhibits amplification of the Fibroblast growth factor receptor 2 (FGFR2) gene, the metastasis notably lacks FGFR2 amplification but rather possesses unique biallelic alterations of Transforming growth factor-beta receptor 2 (TGFBR2), indicating the divergent in vivo evolution of a TGFBR2-mutant metastatic clonal population in this patient. As TGFBR2 mutations have not previously been functionally validated in gastric cancer, we modeled the metastatic potential of TGFBR2 loss in a murine three-dimensional primary gastric organoid culture. The Tgfbr2 shRNA knockdown within Cdh1 -/- ; Tp53 -/- organoids generates invasion in vitro and robust metastatic tumorigenicity in vivo, confirming Tgfbr2 metastasis suppressor activity. We document the metastatic differentiation and genetic heterogeneity of diffuse gastric cancer and reveal the potential metastatic role of TGFBR2 loss-of-function. In support of this study, we apply a murine primary organoid culture method capable of recapitulating in vivo metastatic gastric cancer. Overall, we describe an integrated approach to identify and functionally validate putative cancer drivers involved in metastasis.
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      dateModified:2014-08-27T00:00:00Z
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         Allelic Imbalance
         Ovarian Metastasis
         Diffuse Gastric Cancer
         Hereditary Diffuse Gastric Cancer
         Animal Genetics and Genomics
         Human Genetics
         Plant Genetics and Genomics
         Microbial Genetics and Genomics
         Bioinformatics
         Evolutionary Biology
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      name:Laura Miotke
      affiliation:
            name:Stanford University School of Medicine, CCSR 1115
            address:
               name:Division of Oncology, Department of Medicine, Stanford University School of Medicine, CCSR 1115, Stanford, USA
               type:PostalAddress
            type:Organization
      name:Erik S Hopmans
      affiliation:
            name:Stanford University
            address:
               name:Stanford Genome Technology Center, Stanford University, Palo Alto, USA
               type:PostalAddress
            type:Organization
      name:Hua Xu
      affiliation:
            name:Stanford University
            address:
               name:Stanford Genome Technology Center, Stanford University, Palo Alto, USA
               type:PostalAddress
            type:Organization
      name:Reetesh K Pai
      affiliation:
            name:University of Pittsburgh Medical Center
            address:
               name:Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, USA
               type:PostalAddress
            type:Organization
      name:Curt Palm
      affiliation:
            name:Stanford University
            address:
               name:Stanford Genome Technology Center, Stanford University, Palo Alto, USA
               type:PostalAddress
            type:Organization
      name:John F Regan
      affiliation:
            name:Bio-Rad, Inc
            address:
               name:Bio-Rad, Inc, Pleasanton, USA
               type:PostalAddress
            type:Organization
      name:Hao Chen
      affiliation:
            name:Stanford University
            address:
               name:Department of Statistics, Stanford University, Stanford, USA
               type:PostalAddress
            type:Organization
      name:Patrick Flaherty
      affiliation:
            name:Stanford University
            address:
               name:Stanford Genome Technology Center, Stanford University, Palo Alto, USA
               type:PostalAddress
            type:Organization
      name:Akifumi Ootani
      affiliation:
            name:Stanford University School of Medicine, CCSR 1155
            address:
               name:Division of Hematology, Department of Medicine, Stanford University School of Medicine, CCSR 1155, Stanford, USA
               type:PostalAddress
            type:Organization
      name:Nancy R Zhang
      affiliation:
            name:University of Pennsylvania
            address:
               name:Department of Statistics, The Wharton School, University of Pennsylvania, Philadelphia, USA
               type:PostalAddress
            type:Organization
      name:James M Ford
      affiliation:
            name:Stanford University School of Medicine, CCSR 1115
            address:
               name:Division of Oncology, Department of Medicine, Stanford University School of Medicine, CCSR 1115, Stanford, USA
               type:PostalAddress
            type:Organization
      name:Calvin J Kuo
      affiliation:
            name:Stanford University School of Medicine, CCSR 1155
            address:
               name:Division of Hematology, Department of Medicine, Stanford University School of Medicine, CCSR 1155, Stanford, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
      name:Hanlee P Ji
      affiliation:
            name:Stanford University School of Medicine, CCSR 1115
            address:
               name:Division of Oncology, Department of Medicine, Stanford University School of Medicine, CCSR 1115, Stanford, USA
               type:PostalAddress
            type:Organization
            name:Stanford University
            address:
               name:Stanford Genome Technology Center, Stanford University, Palo Alto, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Division of Oncology, Department of Medicine, Stanford University School of Medicine, CCSR 1115, Stanford, USA
      name:Stanford Genome Technology Center, Stanford University, Palo Alto, USA
      name:Stanford Genome Technology Center, Stanford University, Palo Alto, USA
      name:Division of Oncology, Department of Medicine, Stanford University School of Medicine, CCSR 1115, Stanford, USA
      name:Stanford Genome Technology Center, Stanford University, Palo Alto, USA
      name:Division of Oncology, Department of Medicine, Stanford University School of Medicine, CCSR 1115, Stanford, USA
      name:Stanford Genome Technology Center, Stanford University, Palo Alto, USA
      name:Stanford Genome Technology Center, Stanford University, Palo Alto, USA
      name:Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, USA
      name:Stanford Genome Technology Center, Stanford University, Palo Alto, USA
      name:Bio-Rad, Inc, Pleasanton, USA
      name:Department of Statistics, Stanford University, Stanford, USA
      name:Stanford Genome Technology Center, Stanford University, Palo Alto, USA
      name:Division of Hematology, Department of Medicine, Stanford University School of Medicine, CCSR 1155, Stanford, USA
      name:Department of Statistics, The Wharton School, University of Pennsylvania, Philadelphia, USA
      name:Division of Oncology, Department of Medicine, Stanford University School of Medicine, CCSR 1115, Stanford, USA
      name:Division of Hematology, Department of Medicine, Stanford University School of Medicine, CCSR 1155, Stanford, USA
      name:Division of Oncology, Department of Medicine, Stanford University School of Medicine, CCSR 1115, Stanford, USA
      name:Stanford Genome Technology Center, Stanford University, Palo Alto, USA

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