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Vol 72, No 5 (2022)
Review paper
Published online: 2022-10-19
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SDH-deficient gastrointestinal stromal tumours

Piotr Rutkowski1, Katarzyna Seliga2, Maria Dębiec-Rychter3
DOI: 10.5603/NJO.2022.0052
·
Nowotwory. Journal of Oncology 2022;72(5):326-333.
Affiliations
  1. Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
  2. Molecular and Translational Oncology Department, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland
  3. Department of Human Genetics, KU Leuven and University Hospitals Leuven, Leuven, Belgium

open access

Vol 72, No 5 (2022)
Rare neoplasms in oncology
Published online: 2022-10-19

Abstract

Gastrointestinal stromal tumours (GIST) comprise a heterogeneous group of the most common mesenchymal neoplasms of the gastrointestinal tract. The majority of GIST are induced by activating, mutually exclusive mutations of two genes – KIT and PDGFRA (platelet-derived growth factor receptor-alpha). However, approximately 10–15% of GISTs lack oncogenic KIT or PDGFRA mutations and these tumours are often called “wild type” (WT) GISTs. The SDH-deficient GISTs form a distinctive subset of tumours accounting for 20–40% of KIT/PDGFRA WT GIST, which results from the loss of function mutations in the genes encoding the SDH enzyme complex. The true frequency of SDH-deficient GISTs was reported to be approximately 7.4 to 7.7%. These tumours usually occur in the stomach (most commonly in the antrum) and have a spectrum of beha­viour from indolent to progressive. In most cases the molecular mechanism behind the SDH-deficient GISTs is connected to germline mutations. SDHA germline mutations occur in approximately 30% of the SDH-deficient GIST, those in SDHB, SDHC, and SDHD appear in 20–30% of patients.

The SDH-mutated GISTs do not respond well to the commonly used targeted therapy, with no objective tumour response to imatinib. Taking into account the biological features of SDH-deficient GIST, new therapies of potential in­terest comprise PI3K/AKT/mTOR inhibitors, heat-shock protein inhibitors, HIF1-α targeting agents, epigenetic modifiers and demethylating agents. However, further research is necessary in these fields.

Abstract

Gastrointestinal stromal tumours (GIST) comprise a heterogeneous group of the most common mesenchymal neoplasms of the gastrointestinal tract. The majority of GIST are induced by activating, mutually exclusive mutations of two genes – KIT and PDGFRA (platelet-derived growth factor receptor-alpha). However, approximately 10–15% of GISTs lack oncogenic KIT or PDGFRA mutations and these tumours are often called “wild type” (WT) GISTs. The SDH-deficient GISTs form a distinctive subset of tumours accounting for 20–40% of KIT/PDGFRA WT GIST, which results from the loss of function mutations in the genes encoding the SDH enzyme complex. The true frequency of SDH-deficient GISTs was reported to be approximately 7.4 to 7.7%. These tumours usually occur in the stomach (most commonly in the antrum) and have a spectrum of beha­viour from indolent to progressive. In most cases the molecular mechanism behind the SDH-deficient GISTs is connected to germline mutations. SDHA germline mutations occur in approximately 30% of the SDH-deficient GIST, those in SDHB, SDHC, and SDHD appear in 20–30% of patients.

The SDH-mutated GISTs do not respond well to the commonly used targeted therapy, with no objective tumour response to imatinib. Taking into account the biological features of SDH-deficient GIST, new therapies of potential in­terest comprise PI3K/AKT/mTOR inhibitors, heat-shock protein inhibitors, HIF1-α targeting agents, epigenetic modifiers and demethylating agents. However, further research is necessary in these fields.

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Keywords

gastrointestinal stromal tumour; SDH-deficient GIST; Carney Triad; Carney-Stratakis syndrome; TKI; SDHA/SDHB/SDHC/SDHD mutations; targeted therapy; imatinib; regorafenib

About this article
Title

SDH-deficient gastrointestinal stromal tumours

Journal

Nowotwory. Journal of Oncology

Issue

Vol 72, No 5 (2022)

Article type

Review paper

Pages

326-333

Published online

2022-10-19

Page views

3619

Article views/downloads

543

DOI

10.5603/NJO.2022.0052

Bibliographic record

Nowotwory. Journal of Oncology 2022;72(5):326-333.

Keywords

gastrointestinal stromal tumour
SDH-deficient GIST
Carney Triad
Carney-Stratakis syndrome
TKI
SDHA/SDHB/SDHC/SDHD mutations
targeted therapy
imatinib
regorafenib

Authors

Piotr Rutkowski
Katarzyna Seliga
Maria Dębiec-Rychter

References (75)
  1. Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer. 2011; 11(12): 865–878.
    CrossRefPubMed
  2. Rutkowski P, Przybył J, Wozniak A, et al. Targeted Therapy in Gastrointestinal Stromal Tumors. Current Clinical Pathology. 2015: 163–196.
    CrossRef
  3. Blay JY, Kang YK, Nishida T, et al. Gastrointestinal stromal tumours. Nat Rev Dis Primers. 2021; 7(1): 22.
    CrossRefPubMed
  4. Boikos SA, Pappo AS, Killian JK, et al. Molecular Subtypes of KIT/PDGFRA Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Gastrointestinal Stromal Tumor Clinic. JAMA Oncol. 2016; 2(7): 922–928.
    CrossRefPubMed
  5. Janeway KA, Kim SuY, Lodish M, et al. NIH Pediatric and Wild-Type GIST Clinic. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci U S A. 2011; 108(1): 314–318.
    CrossRefPubMed
  6. Schaefer IM, Mariño-Enríquez A, Fletcher JA. What is New in Gastrointestinal Stromal Tumor? Adv Anat Pathol. 2017; 24(5): 259–267.
    CrossRefPubMed
  7. Wang JH, Lasota J, Miettinen M. Succinate Dehydrogenase Subunit B (SDHB) Is Expressed in Neurofibromatosis 1-Associated Gastrointestinal Stromal Tumors (Gists): Implications for the SDHB Expression Based Classification of Gists. J Cancer. 2011; 2: 90–93.
    CrossRefPubMed
  8. Ibrahim A, Chopra S. Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumors. Arch Pathol Lab Med. 2020; 144(5): 655–660.
    CrossRefPubMed
  9. Brčić I, Argyropoulos A, Liegl-Atzwanger B. Update on Molecular Genetics of Gastrointestinal Stromal Tumors. Diagnostics (Basel). 2021; 11(2).
    CrossRefPubMed
  10. Maertens O, Prenen H, Debiec-Rychter M, et al. Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients. Hum Mol Genet. 2006; 15(6): 1015–1023.
    CrossRefPubMed
  11. Miettinen M, Fetsch JF, Sobin LH, et al. Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases. Am J Surg Pathol. 2006; 30(1): 90–96.
    CrossRefPubMed
  12. Hostein I, Faur N, Primois C, et al. BRAF mutation status in gastrointestinal stromal tumors. Am J Clin Pathol. 2010; 133(1): 141–148.
    CrossRefPubMed
  13. Shi E, Chmielecki J, Tang CM, et al. FGFR1 and NTRK3 actionable alterations in "Wild-Type" gastrointestinal stromal tumors. J Transl Med. 2016; 14(1): 339.
    CrossRefPubMed
  14. Lasota J, Felisiak-Golabek A, Wasag B, et al. Frequency and clinicopathologic profile of PIK3CA mutant GISTs: molecular genetic study of 529 cases. Mod Pathol. 2016; 29(3): 275–282.
    CrossRefPubMed
  15. Klug LR, Khosroyani HM, Kent JD, et al. New treatment strategies for advanced-stage gastrointestinal stromal tumours. Nat Rev Clin Oncol. 2022; 19(5): 328–341.
    CrossRefPubMed
  16. Tarn C, Rink L, Merkel E, et al. Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors. Proc Natl Acad Sci U S A. 2008; 105(24): 8387–8392.
    CrossRefPubMed
  17. Miettinen M, Wang ZF, Sarlomo-Rikala M, et al. Succinate dehydrogenase-deficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age. Am J Surg Pathol. 2011; 35(11): 1712–1721.
    CrossRefPubMed
  18. Liu W, Zeng X, Wu X, et al. Clinicopathologic study of succinate-dehydrogenase-deficient gastrointestinal stromal tumors: A single-institutional experience in China. Medicine (Baltimore). 2017; 96(32): e7668.
    CrossRefPubMed
  19. Carney JA, Stratakis CA. Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from the Carney triad. Am J Med Genet. 2002; 108(2): 132–139.
    CrossRefPubMed
  20. Prakash S, Sarran L, Socci N, et al. Gastrointestinal stromal tumors in children and young adults: a clinicopathologic, molecular, and genomic study of 15 cases and review of the literature. J Pediatr Hematol Oncol. 2005; 27(4): 179–187.
    CrossRefPubMed
  21. Pantaleo MA, Lolli C, Nannini M, et al. Good survival outcome of metastatic SDH-deficient gastrointestinal stromal tumors harboring SDHA mutations. Genet Med. 2015; 17(5): 391–395.
    CrossRefPubMed
  22. Mason EF, Hornick JL. Conventional Risk Stratification Fails to Predict Progression of Succinate Dehydrogenase-deficient Gastrointestinal Stromal Tumors: A Clinicopathologic Study of 76 Cases. Am J Surg Pathol. 2016; 40(12): 1616–1621.
    CrossRefPubMed
  23. Gill AJ. Succinate dehydrogenase (SDH)-deficient neoplasia. Histopathology. 2018; 72(1): 106–116.
    CrossRefPubMed
  24. Pitsava G, Settas N, Faucz FR, et al. Carney Triad, Carney-Stratakis Syndrome, 3PAS and Other Tumors Due to SDH Deficiency. Front Endocrinol (Lausanne). 2021; 12: 680609.
    CrossRefPubMed
  25. Sun F, Huo X, Zhai Y, et al. Crystal structure of mitochondrial respiratory membrane protein complex II. Cell. 2005; 121(7): 1043–1057.
    CrossRefPubMed
  26. Huang S, Millar AH. Succinate dehydrogenase: the complex roles of a simple enzyme. Curr Opin Plant Biol. 2013; 16(3): 344–349.
    CrossRefPubMed
  27. Haller F, Moskalev EA, Faucz FR, et al. Aberrant DNA hypermethylation of SDHC: a novel mechanism of tumor development in Carney triad. Endocr Relat Cancer. 2014; 21(4): 567–577.
    CrossRefPubMed
  28. Killian JK, Kim SuY, Miettinen M, et al. Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor. Cancer Discov. 2013; 3(6): 648–657.
    CrossRefPubMed
  29. Settas N, Faucz FR, Stratakis CA. Succinate dehydrogenase (SDH) deficiency, Carney triad and the epigenome. Mol Cell Endocrinol. 2018; 469: 107–111.
    CrossRefPubMed
  30. Gill AJ. Succinate dehydrogenase (SDH) and mitochondrial driven neoplasia. Pathology. 2012; 44(4): 285–292.
    CrossRefPubMed
  31. Yebra M, Bhargava S, Kumar A, et al. Establishment of Patient-Derived Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumor Models for Predicting Therapeutic Response. Clin Cancer Res. 2022; 28(1): 187–200.
    CrossRefPubMed
  32. Belinsky MG, Rink L, von Mehren M. Succinate dehydrogenase deficiency in pediatric and adult gastrointestinal stromal tumors. Front Oncol. 2013; 3: 117.
    CrossRefPubMed
  33. Miettinen M, Killian JK, Wang ZF, et al. Immunohistochemical loss of succinate dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA germline mutation. Am J Surg Pathol. 2013; 37(2): 234–240.
    CrossRefPubMed
  34. Miettinen M, Lasota J. Succinate dehydrogenase deficient gastrointestinal stromal tumors (GISTs) - a review. Int J Biochem Cell Biol. 2014; 53: 514–519.
    CrossRefPubMed
  35. Lv BB, Li JM, Yao ZG, et al. Succinate dehydrogenase deficient gastrointestinal stromal tumor in a three month old boy with a fatal clinical course: a case report and review of literature. Diagn Pathol. 2021; 16(1): 14.
    CrossRefPubMed
  36. MacFarlane J, Seong KC, Bisambar C, et al. A review of the tumour spectrum of germline succinate dehydrogenase gene mutations: Beyond phaeochromocytoma and paraganglioma. Clin Endocrinol (Oxf). 2020; 93(5): 528–538.
    CrossRefPubMed
  37. Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol. 2006; 23(2): 70–83.
    CrossRefPubMed
  38. Pantaleo MA, Astolfi A, Indio V, et al. SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing. J Natl Cancer Inst. 2011; 103(12): 983–987.
    CrossRefPubMed
  39. Pantaleo MA, Astolfi A, Urbini M, et al. GIST Study Group. Analysis of all subunits, SDHA, SDHB, SDHC, SDHD, of the succinate dehydrogenase complex in KIT/PDGFRA wild-type GIST. Eur J Hum Genet. 2014; 22(1): 32–39.
    CrossRefPubMed
  40. Nannini M, Rizzo A, Indio V, et al. Targeted therapy in deficient GIST. Ther Adv Med Oncol. 2021; 13: 17588359211023278.
    CrossRefPubMed
  41. Pantaleo MA, Urbini M, Schipani A, et al. Germline Variants in Adult Patients With -Mutant Gastrointestinal Stromal Tumor. Front Oncol. 2021; 11: 778461.
    CrossRefPubMed
  42. Wagner AJ, Remillard SP, Zhang YX, et al. Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors. Mod Pathol. 2013; 26(2): 289–294.
    CrossRefPubMed
  43. Casey RT, Ten Hoopen R, Ochoa E, et al. SDHC epi-mutation testing in gastrointestinal stromal tumours and related tumours in clinical practice. Sci Rep. 2019; 9(1): 10244.
    CrossRefPubMed
  44. Weldon CB, Madenci AL, Boikos SA, et al. Surgical Management of Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Pediatric and Wildtype GIST Clinic. J Clin Oncol. 2017; 35(5): 523–528.
    CrossRefPubMed
  45. NCCN Clinical Practice Guidelines in O ncology (NCCN Guidelines ®) Gastrointestinal Stromal Tumors (GISTs) Version 1.2022. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1507 (01.08.2022).
  46. Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002; 347(7): 472–480.
    CrossRefPubMed
  47. Rutkowski P, Ziętek M, Cybulska-Stopa B, et al. The analysis of 3-year adjuvant therapy with imatinib in patients with high-risk molecular profiled gastrointestinal stromal tumors (GIST) treated in routine practice. Eur J Surg Oncol. 2021; 47(5): 1191–1195.
    CrossRefPubMed
  48. Reichardt P, Kang YK, Rutkowski P, et al. Clinical outcomes of patients with advanced gastrointestinal stromal tumors: safety and efficacy in a worldwide treatment-use trial of sunitinib. Cancer. 2015; 121(9): 1405–1413.
    CrossRefPubMed
  49. Demetri G, Reichardt P, Kang YK, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013; 381(9863): 295–302.
    CrossRef
  50. Blay JY, Serrano C, Heinrich M, et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2020; 21(7): 923–934.
    CrossRef
  51. Murray M, Hatcher H, Jessop F, et al. Treatment of wild-type gastrointestinal stromal tumor (WT-GIST) with imatinib and sunitinib. Pediatr Blood Cancer. 2008; 50(2): 386–388.
    CrossRefPubMed
  52. Neppala P, Banerjee S, Fanta PT, et al. Current management of succinate dehydrogenase-deficient gastrointestinal stromal tumors. Cancer Metastasis Rev. 2019; 38(3): 525–535.
    CrossRefPubMed
  53. Mei L, Smith SC, Faber AC, et al. Gastrointestinal Stromal Tumors: The GIST of Precision Medicine. Trends Cancer. 2018; 4(1): 74–91.
    CrossRefPubMed
  54. Debiec-Rychter M, Sciot R, Le Cesne A, et al. EORTC Soft Tissue and Bone Sarcoma Group, Italian Sarcoma Group, Australasian GastroIntestinal Trials Group. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer. 2006; 42(8): 1093–1103.
    CrossRefPubMed
  55. Ganjoo KN, Villalobos VM, Kamaya A, et al. A multicenter phase II study of pazopanib in patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib. Ann Oncol. 2014; 25(1): 236–240.
    CrossRefPubMed
  56. Corless CL, Ballman KV, Antonescu CR, et al. Pathologic and molecular features correlate with long-term outcome after adjuvant therapy of resected primary GI stromal tumor: the ACOSOG Z9001 trial. J Clin Oncol. 2014; 32(15): 1563–1570.
    CrossRefPubMed
  57. Joensuu H, Eriksson M, Sundby Hall K, et al. Adjuvant Imatinib for High-Risk GI Stromal Tumor: Analysis of a Randomized Trial. J Clin Oncol. 2016; 34(3): 244–250.
    CrossRefPubMed
  58. Rutkowski P, Magnan H, Chou AJ, et al. Treatment of gastrointestinal stromal tumours in paediatric and young adult patients with sunitinib: a multicentre case series. BMC Cancer. 2017; 17(1): 717.
    CrossRefPubMed
  59. Janeway KA, Albritton KH, Van Den Abbeele AD, et al. Sunitinib treatment in pediatric patients with advanced GIST following failure of imatinib. Pediatr Blood Cancer. 2009; 52(7): 767–771.
    CrossRefPubMed
  60. Ben-Ami E, Barysauskas CM, von Mehren M, et al. Long-term follow-up results of the multicenter phase II trial of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of standard tyrosine kinase inhibitor therapy. Ann Oncol. 2016; 27(9): 1794–1799.
    CrossRefPubMed
  61. Janeway KA, Zhu MJ, Barretina J, et al. Strong expression of IGF1R in pediatric gastrointestinal stromal tumors without IGF1R genomic amplification. Int J Cancer. 2010; 127(11): 2718–2722.
    CrossRefPubMed
  62. Mahadevan D, Sutton GR, Arteta-Bulos R, et al. Phase 1b study of safety, tolerability and efficacy of R1507, a monoclonal antibody to IGF-1R in combination with multiple standard oncology regimens in patients with advanced solid malignancies. Cancer Chemother Pharmacol. 2014; 73(3): 467–473.
    CrossRefPubMed
  63. Mehren Mv, George S, Heinrich M, et al. Results of SARC 022, a phase II multicenter study of linsitinib in pediatric and adult wild-type (WT) gastrointestinal stromal tumors (GIST). J Clin Oncol. 2014; 32(15_suppl): 10507–10507.
    CrossRef
  64. Flavahan WA, Drier Y, Johnstone SE, et al. Altered chromosomal topology drives oncogenic programs in SDH-deficient GISTs. Nature. 2019; 575(7781): 229–233.
    CrossRefPubMed
  65. Ricci R, Martini M, Ravegnini G, et al. Preferential MGMT methylation could predispose a subset of KIT/PDGFRA-WT GISTs, including SDH-deficient ones, to respond to alkylating agents. Clin Epigenetics. 2019; 11(1): 2.
    CrossRefPubMed
  66. Indio V, Schipani A, Nannini M, et al. Gene Expression Landscape of SDH-Deficient Gastrointestinal Stromal Tumors. J Clin Med. 2021; 10(5).
    CrossRefPubMed
  67. Astolfi A, Pantaleo MA, Indio V, et al. The Emerging Role of the FGF/FGFR Pathway in Gastrointestinal Stromal Tumor. Int J Mol Sci. 2020; 21(9).
    CrossRefPubMed
  68. Lou L, Zhang W, Li J, et al. Abnormal MGMT Promoter Methylation in Gastrointestinal Stromal Tumors: Genetic Susceptibility and Association with Clinical Outcome. Cancer Manag Res. 2020; 12: 9941–9952.
    CrossRefPubMed
  69. Ravegnini G, Ricci R. Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumors: Small Steps Toward Personalized Medicine? Epigenet Insights. 2019; 12: 2516865719842534.
    CrossRefPubMed
  70. Yebra M, Bhargava S, Kumar A, et al. Human succinate dehydrogenase-deficient gastrointestinal stromal tumors are seinsitive to temozolomide via induction of ER stress and DNA damage: 10. https://www.ctos.org/Portals/0/PDF/2020%20CTOS%20Prelim%20Program_FINAL.pdf (01.08.2022).
  71. Trent JC, Beach J, Burgess MA, et al. A two-arm phase II study of temozolomide in patients with advanced gastrointestinal stromal tumors and other soft tissue sarcomas. Cancer. 2003; 98(12): 2693–2699.
    CrossRefPubMed
  72. Garcia del Muro X, Lopez-Pousa A, Martin J, et al. Spanish Group for Research on Sarcomas. A phase II trial of temozolomide as a 6-week, continuous, oral schedule in patients with advanced soft tissue sarcoma: a study by the Spanish Group for Research on Sarcomas. Cancer. 2005; 104(8): 1706–1712.
    CrossRefPubMed
  73. Hadoux J, Favier J, Scoazec JY, et al. SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma. Int J Cancer. 2014; 135(11): 2711–2720.
    CrossRefPubMed
  74. Glod J, Arnaldez FI, Wiener L, et al. A Phase II Trial of Vandetanib in Children and Adults with Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumor. Clin Cancer Res. 2019; 25(21): 6302–6308.
    CrossRefPubMed
  75. Dudzisz-Śledź M, Rutkowski P. Advances in the management of gastrointestinal stromal tumors (GISTs). Nowotwory. Journal of Oncology. 2020; 70(6): 280–287.
    CrossRef

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