Location of Gastrointestinal Stromal Tumor (GIST) in the Stomach Predicts Tumor Mutation Profile and Drug Sensitivity

Ashwyn K Sharma; Jorge de la Torre; Nikki S IJzerman; Thomas L Sutton; Beiqun Zhao; Tahsin M Khan; Sudeep Banerjee; Christina Cui; Vi Nguyen; Maha Alkhuziem; Petur Snaebjornsson; Hester van Boven; Annemarie Bruining; Chih-Min Tang; Hyunho Yoon; Alexa De la Fuente; Shumei Kato; Hitendra Patel; Michael C Heinrich; Christopher L Corless; Santiago Horgan; Adam M Burgoyne; Paul Fanta; Jill P Mesirov; Andrew M Blakely; Jeremy L Davis; Skye C Mayo; Winan J van Houdt; Neeltje Steeghs; Jason K Sicklick

doi:10.1158/1078-0432.CCR-21-1221

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Location of Gastrointestinal Stromal Tumor (GIST) in the Stomach Predicts Tumor Mutation Profile and Drug Sensitivity

Ashwyn K Sharma, Jorge de la Torre, Nikki S IJzerman, Thomas L Sutton, Beiqun Zhao, Tahsin M Khan, Sudeep Banerjee, Christina Cui, Vi Nguyen, Maha Alkhuziem, …

Clinical cancer research, Vol.27(19), pp.5334-5342

10/01/2021

DOI: 10.1158/1078-0432.CCR-21-1221

PMCID: PMC8799780

PMID: 34326133

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Abstract

Gastrointestinal stromal tumors (GIST) commonly arise in different regions of the stomach and are driven by various mutations (most often in KIT, PDGFRA, and SDHx). We hypothesized that the anatomic location of gastric GIST is associated with unique genomic profiles and distinct driver mutations. We compared KIT versus non-KIT status with tumor location within the National Cancer Database (NCDB) for 2,418 patients with primary gastric GIST. Additionally, we compiled an international cohort (TransAtlantic GIST Collaborative, TAGC) of 236 patients and reviewed sequencing results, cross-sectional imaging, and operative reports. Subgroup analyses were performed for tumors located proximally versus distally. Risk factors for KIT versus non-KIT tumors were identified using multivariate regression analysis. A random forest machine learning model was then developed to determine feature importance. Within the NCDB cohort, non-KIT mutants dominated distal tumor locations (P < 0.03). Proximal GIST were almost exclusively KIT mutant (96%) in the TAGC cohort, whereas 100% of PDGFRA and SDH-mutant GIST occurred in the distal stomach. On multivariate regression analysis, tumor location was associated with KIT versus non-KIT mutations. Using random forest machine learning analysis, stomach location was the most important feature for predicting mutation status. We provide the first evidence that the mutational landscape of gastric GIST is related to tumor location. Proximal gastric GIST are overwhelmingly KIT mutant, irrespective of morphology or age, whereas distal tumors display non-KIT genomic diversity. Anatomic location of gastric GIST may therefore provide immediate guidance for clinical treatment decisions and selective confirmatory genomic testing when resources are limited.

Gastrointestinal Stromal Tumors - drug therapy

Gastrointestinal Stromal Tumors - genetics

Gastrointestinal Stromal Tumors - pathology

Humans

Mutation

Prognosis

Proto-Oncogene Proteins c-kit - genetics

Receptor, Platelet-Derived Growth Factor alpha - genetics

Stomach - pathology

Details

Title: Subtitle: Location of Gastrointestinal Stromal Tumor (GIST) in the Stomach Predicts Tumor Mutation Profile and Drug Sensitivity
Creators: Ashwyn K Sharma - University of San Diego
Jorge de la Torre - University of San Diego
Nikki S IJzerman - Oncode Institute
Thomas L Sutton - Oregon Health & Science University
Beiqun Zhao - University of California San Diego
Tahsin M Khan - Center for Cancer Research
Sudeep Banerjee - University of San Diego
Christina Cui - University of San Diego
Vi Nguyen - University of San Diego
Maha Alkhuziem - University of San Diego
Petur Snaebjornsson - Department of Pathology, Netherlands Cancer Institute, Amsterdam, the Netherlands
Hester van Boven - Dutch Cancer Society
Annemarie Bruining - Dutch Cancer Society
Chih-Min Tang - University of San Diego
Hyunho Yoon - University of San Diego
Alexa De la Fuente - Department of Surgery, Division of Surgical Oncology, University of California San Diego, San Diego, California
Shumei Kato - University of California San Diego
Hitendra Patel - University of California San Diego
Michael C Heinrich - Oregon Health & Science University
Christopher L Corless - Oregon Health & Science University
Santiago Horgan - University of San Diego
Adam M Burgoyne - University of California San Diego
Paul Fanta - University of California San Diego
Jill P Mesirov - University of San Diego
Andrew M Blakely - Center for Cancer Research
Jeremy L Davis - Center for Cancer Research
Skye C Mayo - Oregon Health & Science University
Winan J van Houdt - Dutch Cancer Society
Neeltje Steeghs - Oncode Institute
Jason K Sicklick - University of California San Diego
Resource Type: Journal article
Publication Details: Clinical cancer research, Vol.27(19), pp.5334-5342
DOI: 10.1158/1078-0432.CCR-21-1221
PMID: 34326133
PMCID: PMC8799780
NLM abbreviation: Clin Cancer Res
ISSN: 1078-0432
eISSN: 1557-3265
Grant note: R01 FD006334 / FDA HHS T32 CA121938 / NCI NIH HHS U01 CA184898 / NCI NIH HHS R01 CA226803 / NCI NIH HHS I01 BX000338 / BLRD VA U24 CA248457 / NCI NIH HHS
Language: English
Date published: 10/01/2021
Academic Unit: Surgery
Record Identifier: 9985224317502771

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