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. CorlessSantiago 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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Scopus)

Abstract

Purpose: 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. Experimental Design: 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. Results: 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. Conclusions: 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.

Original languageEnglish
Pages (from-to)5334-5342
Number of pages9
JournalClinical Cancer Research
Volume27
Issue number19
DOIs
Publication statusPublished - 1 Oct 2021

Bibliographical note

Funding Information:
We appreciate funding support from the Surgical Society of the Alimentary Tract (SSAT) Mentored Research Award (S. Banerjee), NIH T32 CA121938 Cancer Therapeutics (CT2) Training Fellowship (S. Banerjee and A.K. Sharma), NIH U24 CA248457 (J.P. Mesirov), NIH U01 CA184898 (J.P. Mesirov), Lighting the Path Forward for GIST Cancer Research (J.K. Sicklick), GIST Cancer Research Fund (M.C. Heinrich and C.L. Corless), The David Foundation (J.K. Sicklick and M.C. Heinrich), VA Merit Award Grant (M.C. Heinrich, 2I01BX000338-05), NIH R01 CA226803 (J.K. Sicklick), and FDA R01 FD006334 (J.K.Sicklick and A.M. Burgoyne). We appreciate our insightful discussions with GIST patient advocates, Sarah Rothschild and Peter Knox of the GIST Life Raft Group, regarding inequities in GIST care globally. This study has been presented in part at the Connective Tissue Oncology Society (CTOS) Meeting in Tokyo, Japan, on November 15, 2019.

Funding Information:
A.K. Sharma reports grants from NIH Cancer Therapeutics (CT2) Training Fellowship during the conduct of the study. P. Snaebjornsson reports other support from MSD, Bayer, and MEDtalks outside the submitted work. S. Kato reports that he serves as a consultant for Foundation Medicine, NeoGenomics, and CureMatch; receives speaker’s fee from Roche; serves on the advisory board for Pfizer; and has research funding from ACT Genomics, Sysmex, Konica Minolta, and OmniSeq. M.C. Heinrich reports personal fees from Novartis, Deciphera, and Blueprint Medicines, as well as grants from Department of Veterans Affairs during the conduct of the study; in addition, M.C. Heinrich has a patent for Treatment of GIST issued, licensed, and with royalties paid from Novartis. S. Horgan reports personal fees from Stryker, Ethicon, and Intuitive outside the submitted work. A.M. Burgoyne reports personal fees from Deciphera, Genentech, and Exelixis outside the submitted work. N. Steeghs reports other support from multiple entities outside the submitted work. J.K. Sicklick reports other support from Amgen Pharmaceuticals and Foundation Medicine during the conduct of the study; J.K. Sicklick also reports personal fees from Deciphera, Foundation Medicine, F. Hoffman-La Roche, Merck, MJH Life Sciences, and QED Therapeutics, as well as other support from Personalis outside the submitted work. No disclosures were reported by the other authors.

Publisher Copyright:
2021 American Association for Cancer Research

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