Elsevier

Cancer Genetics

Volume 241, February 2020, Pages 61-65
Cancer Genetics

Short Communication
Pediatric gastrointestinal stromal tumor: Report of two novel patients harboring germline variants in SDHB and SDHC genes

https://doi.org/10.1016/j.cancergen.2019.12.002Get rights and content

Highlights

  • Multi-gene hereditary cancer testing detected two loss-of-function variants, in SDHB and SDHC genes in two patients with pediatric gastric GIST; one of these variants has never been reported.

  • Both variants, detected in heterozygous status in the DNA isolated from blood, were found in the tumor DNA sample with an allele burden greater than 95%, suggesting a loss-of-heterozygosity in the cancer cells.

  • The identification of constitutional SDH deficiency by the molecular test is critical to direct genetic counseling and take preventive and surveillance measures not only for patients but also for other mutation carriers in the family.

Abstract

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and rarely occur in pediatric patients. 85% of pediatric GISTs and 15% of adult GISTs lack of KIT or PDGFRA mutations. 40% of these “wild-type” GISTs present loss of function mutations in genes encoding for the subunits of the succinate dehydrogenase (SDH) complex. Germline mutations in SDH complex genes have been described in patients with the Carney–Stratakis syndrome (CSS), a rare inherited condition that predisposes to GIST and paraganglioma. We report two pediatric patients with multifocal GIST, harboring respectively a novel and a previously reported loss-of-function germline variant, in SDHC and SDHB genes.

Introduction

Gastrointestinal stromal tumors (GISTs) are the most common GI mesenchymal neoplasms [1], but rarely occur in pediatric patients, displaying a unique biology and clinical behavior [2]. Activating mutations of KIT or PDGFRA proto-oncogenes are detected in 85–90% of GISTs occurring in adult patients [3], [4], and most of these respond to tyrosine kinase inhibitors such as imatinib or sunitinib [5], [6]. However, 85% of pediatric GISTs and 10–15% of GISTs in adults lack of KIT or PDGFRA mutations [7], [8]. These tumors are termed “wild-type” GISTs and 40% of them present deficiency of succinate dehydrogenase (SDH) complex, a heterotetrametric enzyme involved in both the citric acid cycle and the electron transport chain [9]. Here, we describe two pediatric patients, with multifocal GIST, liver lesions and no history of paraganglioma (PGL), harboring respectively a novel and a previously reported loss-of-function germline variant, in SDHC and SDHB genes.

Section snippets

Patient 1

A 16-year-old boy with unremarkable medical history was referred to our Institution for an abdominal lesion discovered by ultrasound during the clinical work-up of an iron-deficiency anemia. At physical examination an epigastric mass was evident. Combined computed tomography and 18-fluoro-deoxyglucose-positron emission tomography (18FDG-PET CT) scans showed increased metabolic uptake in primary lesion arising from gastric antrum, as well as in perigastric nodes and in multiple sites of hepatic

Discussion

GISTs in pediatric and adolescent patients differ significantly in clinical, histological and genetic characteristics from those in adults with important implications for the medical management of pediatric cases. The percentage of patients younger than 21 years with GISTs is estimated to be 0.5% to 2.7% [10]. Most pediatric GISTs are located in the stomach, usually in the antrum, and show an epithelioid morphology [11]. In comparison, adult GISTs most often have a spindle cell morphology [12].

CRediT authorship contribution statement

Martina Rinelli: Conceptualization, Data curation, Formal analysis, Writing - original draft, Writing - review & editing. Emanuele Agolini: Conceptualization, Data curation, Formal analysis, Writing - original draft, Writing - review & editing. Giuseppe Maria Milano: Conceptualization, Writing - review & editing. Ida Russo: Conceptualization, Writing - review & editing. Alessandro Crocoli: Conceptualization, Writing - review & editing. Rita De Vito: Conceptualization, Data curation, Formal

Declaration of Competing Interest

The authors declare that they have no conflict of interest.

Acknowledgments

We are grateful to the participating families. We are thankful to Technogenetics for its support on NextSeq 550 (Illumina) instrument.

References (30)

  • M.C. Heinrich et al.

    Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor

    J. Clin. Oncol

    (2003)
  • M.G. Belinsky et al.

    Succinate dehydrogenase deficiency in pediatric and adult gastrointestinal stromal tumors

    Front Oncol

    (2013)
  • R.P. DeMatteo et al.

    Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival

    Ann. Surg

    (2000)
  • M. Miettinen et al.

    Gastrointestinal stromal tumors of the stomach in children and young adults: a clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases with long-term follow-up and review of the literature

    Am. J. Surg. Pathol

    (2005)
  • X. Zhao et al.

    Gastrointestinal stromal tumor

    J. Gastrointest. Oncol

    (2012)
  • 1

    Both authors contributed equally to this manuscript.

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