Academic Journal
View in EDS
HTML Full Text

Utility of Clinical Next Generation Sequencing Tests in KIT/PDGFRA/SDH Wild-Type Gastrointestinal Stromal Tumors.

Bibliographic Details
Title: Utility of Clinical Next Generation Sequencing Tests in KIT/PDGFRA/SDH Wild-Type Gastrointestinal Stromal Tumors.
Authors: Denu, Ryan A., Joseph, Cissimol P., Urquiola, Elizabeth S., Byrd, Precious S., Yang, Richard K., Ratan, Ravin, Zarzour, Maria Alejandra, Conley, Anthony P., Araujo, Dejka M., Ravi, Vinod, Nassif Haddad, Elise F., Nakazawa, Michael S., Patel, Shreyaskumar, Wang, Wei-Lien, Lazar, Alexander J., Somaiah, Neeta
Source: Cancers; May2024, Vol. 16 Issue 9, p1707, 16p
Subject Terms: GASTROINTESTINAL tumors, GENOMICS, STOMACH tumors, CANCER relapse, RESEARCH funding, DESCRIPTIVE statistics, GENES, RECTUM tumors, METASTASIS, OXIDOREDUCTASES, COMBINED modality therapy, GENETIC mutation, COMPARATIVE studies, SEQUENCE analysis, DISEASE progression
Abstract: Simple Summary: Most gastrointestinal stromal tumors (GISTs) are driven by activating mutations in KIT and PDGFRA or alterations in the succinate dehydrogenase (SDH) complex. A small fraction of GISTs lack alterations in KIT, PDGFRA, and the SDH complex, so-called "triple-negative" GISTs. We assessed clinical genomic sequencing, treatment, and survival outcomes in a cohort of 20 triple-negative GISTs. Genomic alterations were most commonly seen in the RAS/RAF/MAPK pathway and the DNA damage response pathway. Compared to KIT/PDGFRA mutant GIST, limited benefit was observed with imatinib in triple-negative GIST. In-depth molecular profiling can be helpful in identifying driver mutations and guiding therapy. Objective: The vast majority of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in KIT, PDGFRA, or components of the succinate dehydrogenase (SDH) complex (SDHA, SDHB, SDHC, and SDHD genes). A small fraction of GISTs lack alterations in KIT, PDGFRA, and SDH. We aimed to further characterize the clinical and genomic characteristics of these so-called "triple-negative" GISTs. Methods: We extracted clinical and genomic data from patients seen at MD Anderson Cancer Center with a diagnosis of GIST and available clinical next generation sequencing data to identify "triple-negative" patients. Results: Of the 20 patients identified, 11 (55.0%) had gastric, 8 (40.0%) had small intestinal, and 1 (5.0%) had rectal primary sites. In total, 18 patients (90.0%) eventually developed recurrent or metastatic disease, and 8 of these presented with de novo metastatic disease. For the 13 patients with evaluable response to imatinib (e.g., neoadjuvant treatment or for recurrent/metastatic disease), the median PFS with imatinib was 4.4 months (range 0.5–191.8 months). Outcomes varied widely, as some patients rapidly developed progressive disease while others had more indolent disease. Regarding potential genomic drivers, four patients were found to have alterations in the RAS/RAF/MAPK pathway: two with a BRAF V600E mutation and two with NF1 loss-of-function (LOF) mutations (one deletion and one splice site mutation). In addition, we identified two with TP53 LOF mutations, one with NTRK3 fusion (ETV6-NTRK3), one with PTEN deletion, one with FGFR1 gain-of-function (GOF) mutation (K654E), one with CHEK2 LOF mutation (T367fs*), one with Aurora kinase A fusion (AURKA-CSTF1), and one with FANCA deletion. Patients had better responses with molecularly targeted therapies than with imatinib. Conclusions: Triple-negative GISTs comprise a diverse cohort with different driver mutations. Compared to KIT/PDGFRA-mutant GIST, limited benefit was observed with imatinib in triple-negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy. [ABSTRACT FROM AUTHOR]
Copyright of Cancers is the property of MDPI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Complementary Index
Full text is not displayed to guests.
FullText Links:
  – Type: pdflink
Text:
  Availability: 1
CustomLinks:
  – Url: https://resolver.ebsco.com/c/xy5jbn/result?sid=EBSCO:edb&genre=article&issn=20726694&ISBN=&volume=16&issue=9&date=20240501&spage=1707&pages=1707-1722&title=Cancers&atitle=Utility%20of%20Clinical%20Next%20Generation%20Sequencing%20Tests%20in%20KIT%2FPDGFRA%2FSDH%20Wild-Type%20Gastrointestinal%20Stromal%20Tumors.&aulast=Denu%2C%20Ryan%20A.&id=DOI:10.3390/cancers16091707
    Name: Full Text Finder (for New FTF UI) (s8985755)
    Category: fullText
    Text: Find It @ SCU Libraries
    MouseOverText: Find It @ SCU Libraries
Header DbId: edb
DbLabel: Complementary Index
An: 177182584
RelevancyScore: 1023
AccessLevel: 6
PubType: Academic Journal
PubTypeId: academicJournal
PreciseRelevancyScore: 1022.79138183594
IllustrationInfo
Items – Name: Title
  Label: Title
  Group: Ti
  Data: Utility of Clinical Next Generation Sequencing Tests in KIT/PDGFRA/SDH Wild-Type Gastrointestinal Stromal Tumors.
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AR" term="%22Denu%2C+Ryan+A%2E%22">Denu, Ryan A.</searchLink><br /><searchLink fieldCode="AR" term="%22Joseph%2C+Cissimol+P%2E%22">Joseph, Cissimol P.</searchLink><br /><searchLink fieldCode="AR" term="%22Urquiola%2C+Elizabeth+S%2E%22">Urquiola, Elizabeth S.</searchLink><br /><searchLink fieldCode="AR" term="%22Byrd%2C+Precious+S%2E%22">Byrd, Precious S.</searchLink><br /><searchLink fieldCode="AR" term="%22Yang%2C+Richard+K%2E%22">Yang, Richard K.</searchLink><br /><searchLink fieldCode="AR" term="%22Ratan%2C+Ravin%22">Ratan, Ravin</searchLink><br /><searchLink fieldCode="AR" term="%22Zarzour%2C+Maria+Alejandra%22">Zarzour, Maria Alejandra</searchLink><br /><searchLink fieldCode="AR" term="%22Conley%2C+Anthony+P%2E%22">Conley, Anthony P.</searchLink><br /><searchLink fieldCode="AR" term="%22Araujo%2C+Dejka+M%2E%22">Araujo, Dejka M.</searchLink><br /><searchLink fieldCode="AR" term="%22Ravi%2C+Vinod%22">Ravi, Vinod</searchLink><br /><searchLink fieldCode="AR" term="%22Nassif+Haddad%2C+Elise+F%2E%22">Nassif Haddad, Elise F.</searchLink><br /><searchLink fieldCode="AR" term="%22Nakazawa%2C+Michael+S%2E%22">Nakazawa, Michael S.</searchLink><br /><searchLink fieldCode="AR" term="%22Patel%2C+Shreyaskumar%22">Patel, Shreyaskumar</searchLink><br /><searchLink fieldCode="AR" term="%22Wang%2C+Wei-Lien%22">Wang, Wei-Lien</searchLink><br /><searchLink fieldCode="AR" term="%22Lazar%2C+Alexander+J%2E%22">Lazar, Alexander J.</searchLink><br /><searchLink fieldCode="AR" term="%22Somaiah%2C+Neeta%22">Somaiah, Neeta</searchLink>
– Name: TitleSource
  Label: Source
  Group: Src
  Data: Cancers; May2024, Vol. 16 Issue 9, p1707, 16p
– Name: Subject
  Label: Subject Terms
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22GASTROINTESTINAL+tumors%22">GASTROINTESTINAL tumors</searchLink><br /><searchLink fieldCode="DE" term="%22GENOMICS%22">GENOMICS</searchLink><br /><searchLink fieldCode="DE" term="%22STOMACH+tumors%22">STOMACH tumors</searchLink><br /><searchLink fieldCode="DE" term="%22CANCER+relapse%22">CANCER relapse</searchLink><br /><searchLink fieldCode="DE" term="%22RESEARCH+funding%22">RESEARCH funding</searchLink><br /><searchLink fieldCode="DE" term="%22DESCRIPTIVE+statistics%22">DESCRIPTIVE statistics</searchLink><br /><searchLink fieldCode="DE" term="%22GENES%22">GENES</searchLink><br /><searchLink fieldCode="DE" term="%22RECTUM+tumors%22">RECTUM tumors</searchLink><br /><searchLink fieldCode="DE" term="%22METASTASIS%22">METASTASIS</searchLink><br /><searchLink fieldCode="DE" term="%22OXIDOREDUCTASES%22">OXIDOREDUCTASES</searchLink><br /><searchLink fieldCode="DE" term="%22COMBINED+modality+therapy%22">COMBINED modality therapy</searchLink><br /><searchLink fieldCode="DE" term="%22GENETIC+mutation%22">GENETIC mutation</searchLink><br /><searchLink fieldCode="DE" term="%22COMPARATIVE+studies%22">COMPARATIVE studies</searchLink><br /><searchLink fieldCode="DE" term="%22SEQUENCE+analysis%22">SEQUENCE analysis</searchLink><br /><searchLink fieldCode="DE" term="%22DISEASE+progression%22">DISEASE progression</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Simple Summary: Most gastrointestinal stromal tumors (GISTs) are driven by activating mutations in KIT and PDGFRA or alterations in the succinate dehydrogenase (SDH) complex. A small fraction of GISTs lack alterations in KIT, PDGFRA, and the SDH complex, so-called "triple-negative" GISTs. We assessed clinical genomic sequencing, treatment, and survival outcomes in a cohort of 20 triple-negative GISTs. Genomic alterations were most commonly seen in the RAS/RAF/MAPK pathway and the DNA damage response pathway. Compared to KIT/PDGFRA mutant GIST, limited benefit was observed with imatinib in triple-negative GIST. In-depth molecular profiling can be helpful in identifying driver mutations and guiding therapy. Objective: The vast majority of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in KIT, PDGFRA, or components of the succinate dehydrogenase (SDH) complex (SDHA, SDHB, SDHC, and SDHD genes). A small fraction of GISTs lack alterations in KIT, PDGFRA, and SDH. We aimed to further characterize the clinical and genomic characteristics of these so-called "triple-negative" GISTs. Methods: We extracted clinical and genomic data from patients seen at MD Anderson Cancer Center with a diagnosis of GIST and available clinical next generation sequencing data to identify "triple-negative" patients. Results: Of the 20 patients identified, 11 (55.0%) had gastric, 8 (40.0%) had small intestinal, and 1 (5.0%) had rectal primary sites. In total, 18 patients (90.0%) eventually developed recurrent or metastatic disease, and 8 of these presented with de novo metastatic disease. For the 13 patients with evaluable response to imatinib (e.g., neoadjuvant treatment or for recurrent/metastatic disease), the median PFS with imatinib was 4.4 months (range 0.5–191.8 months). Outcomes varied widely, as some patients rapidly developed progressive disease while others had more indolent disease. Regarding potential genomic drivers, four patients were found to have alterations in the RAS/RAF/MAPK pathway: two with a BRAF V600E mutation and two with NF1 loss-of-function (LOF) mutations (one deletion and one splice site mutation). In addition, we identified two with TP53 LOF mutations, one with NTRK3 fusion (ETV6-NTRK3), one with PTEN deletion, one with FGFR1 gain-of-function (GOF) mutation (K654E), one with CHEK2 LOF mutation (T367fs*), one with Aurora kinase A fusion (AURKA-CSTF1), and one with FANCA deletion. Patients had better responses with molecularly targeted therapies than with imatinib. Conclusions: Triple-negative GISTs comprise a diverse cohort with different driver mutations. Compared to KIT/PDGFRA-mutant GIST, limited benefit was observed with imatinib in triple-negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy. [ABSTRACT FROM AUTHOR]
– Name: Abstract
  Label:
  Group: Ab
  Data: <i>Copyright of Cancers is the property of MDPI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
PLink https://login.libproxy.scu.edu/login?url=https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&scope=site&db=edb&AN=177182584
RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.3390/cancers16091707
    Languages:
      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 16
        StartPage: 1707
    Subjects:
      – SubjectFull: GASTROINTESTINAL tumors
        Type: general
      – SubjectFull: GENOMICS
        Type: general
      – SubjectFull: STOMACH tumors
        Type: general
      – SubjectFull: CANCER relapse
        Type: general
      – SubjectFull: RESEARCH funding
        Type: general
      – SubjectFull: DESCRIPTIVE statistics
        Type: general
      – SubjectFull: GENES
        Type: general
      – SubjectFull: RECTUM tumors
        Type: general
      – SubjectFull: METASTASIS
        Type: general
      – SubjectFull: OXIDOREDUCTASES
        Type: general
      – SubjectFull: COMBINED modality therapy
        Type: general
      – SubjectFull: GENETIC mutation
        Type: general
      – SubjectFull: COMPARATIVE studies
        Type: general
      – SubjectFull: SEQUENCE analysis
        Type: general
      – SubjectFull: DISEASE progression
        Type: general
    Titles:
      – TitleFull: Utility of Clinical Next Generation Sequencing Tests in KIT/PDGFRA/SDH Wild-Type Gastrointestinal Stromal Tumors.
        Type: main
  BibRelationships:
    HasContributorRelationships:
      – PersonEntity:
          Name:
            NameFull: Denu, Ryan A.
      – PersonEntity:
          Name:
            NameFull: Joseph, Cissimol P.
      – PersonEntity:
          Name:
            NameFull: Urquiola, Elizabeth S.
      – PersonEntity:
          Name:
            NameFull: Byrd, Precious S.
      – PersonEntity:
          Name:
            NameFull: Yang, Richard K.
      – PersonEntity:
          Name:
            NameFull: Ratan, Ravin
      – PersonEntity:
          Name:
            NameFull: Zarzour, Maria Alejandra
      – PersonEntity:
          Name:
            NameFull: Conley, Anthony P.
      – PersonEntity:
          Name:
            NameFull: Araujo, Dejka M.
      – PersonEntity:
          Name:
            NameFull: Ravi, Vinod
      – PersonEntity:
          Name:
            NameFull: Nassif Haddad, Elise F.
      – PersonEntity:
          Name:
            NameFull: Nakazawa, Michael S.
      – PersonEntity:
          Name:
            NameFull: Patel, Shreyaskumar
      – PersonEntity:
          Name:
            NameFull: Wang, Wei-Lien
      – PersonEntity:
          Name:
            NameFull: Lazar, Alexander J.
      – PersonEntity:
          Name:
            NameFull: Somaiah, Neeta
    IsPartOfRelationships:
      – BibEntity:
          Dates:
            – D: 01
              M: 05
              Text: May2024
              Type: published
              Y: 2024
          Identifiers:
            – Type: issn-print
              Value: 20726694
          Numbering:
            – Type: volume
              Value: 16
            – Type: issue
              Value: 9
          Titles:
            – TitleFull: Cancers
              Type: main
ResultId 1