Genomic and clinical characterization of a familial GIST kindred intolerant to imatinib

K M Ingley; M Zatzman; A M Fontebasso; W Lo; V Subasri; A Goldenberg; Y Li; S Davidson; N Kanwar; L Waldman; L Brunga; Y Babichev; E G Demicco; A Gupta; M Szybowska; S Thipphavong; D Malkin; A Villani; A Shlien; R A Gladdy; R H Kim

doi:10.1038/s41525-024-00405-z

Genomic and clinical characterization of a familial GIST kindred intolerant to imatinib

NPJ Genom Med. 2024 Mar 27;9(1):24. doi: 10.1038/s41525-024-00405-z.

Authors

K M Ingley^#^{1

2

3}, M Zatzman^#^{4

5}, A M Fontebasso^{6

7}, W Lo⁴, V Subasri^{5

8}, A Goldenberg^{5

9}, Y Li¹⁰, S Davidson^{5

10}, N Kanwar¹⁰, L Waldman^{5

11}, L Brunga⁵, Y Babichev^{6

7}, E G Demicco¹², A Gupta^{1

2}, M Szybowska¹³, S Thipphavong¹⁴, D Malkin², A Villani², A Shlien^{5

10}, R A Gladdy^{15

16}, R H Kim^{17

18}

Affiliations

¹ Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada.
² Department of Pediatrics, Division of Haematology/ Oncology, The Hospital for Sick Children, Toronto, ON, Canada.
³ Department of Oncology, Royal Children's Hospital, Melbourne and Victorian Adolescent & Young Adult Cancer Service, Peter MacCallum Cancer Centre, Melbourne, Australia.
⁴ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
⁵ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON, Canada.
⁶ Division of General Surgery, Sinai Health System, Department of Surgery, University of Toronto, Toronto, ON, Canada.
⁷ Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada.
⁸ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
⁹ Department of Computer Science, University of Toronto, Toronto, ON, Canada.
¹⁰ Department of Pediatric and Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
¹¹ Department of Genetic Counselling, The Hospital for Sick Children, Toronto, ON, Canada.
¹² Department of Pathology and Laboratory Medicine, Sinai Health System, University of Toronto, Toronto, ON, Canada.
¹³ Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Fred A. Litwin Centre in Genetic Medicine, University Health Network, Toronto, ON, Canada.
¹⁴ Department of Radiology, Sinai Health System, University of Toronto, Toronto, ON, Canada.
¹⁵ Division of General Surgery, Sinai Health System, Department of Surgery, University of Toronto, Toronto, ON, Canada. rebecca.gladdy@sinaihealth.ca.
¹⁶ Department of Surgical Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada. rebecca.gladdy@sinaihealth.ca.
¹⁷ Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Fred A. Litwin Centre in Genetic Medicine, University Health Network, Toronto, ON, Canada. Raymond.kim@uhn.ca.
¹⁸ Department of Medicine, University of Toronto, Toronto, ON, Canada. Raymond.kim@uhn.ca.

^# Contributed equally.

Abstract

Familial gastrointestinal stromal tumors (GIST) are rare. We present a kindred with multiple family members affected with multifocal GIST who underwent whole genome sequencing of the germline and tumor. Affected individuals with GIST harbored a germline variant found within exon 13 of the KIT gene (c.1965T>G; p.Asn655Lys, p.N655K) and a variant in the MSR1 gene (c.877 C > T; p.Arg293*, pR293X). Multifocal GISTs in the proband and her mother were treated with preoperative imatinib, which resulted in severe intolerance. The clinical features of multifocal GIST, cutaneous mastocytosis, allergies, and gut motility disorders seen in the affected individuals may represent manifestations of the multifunctional roles of KIT in interstitial cells of Cajal or mast cells and/or may be suggestive of additional molecular pathways which can contribute to tumorigenesis.