Tom 7, Nr 5 (2022)
Artykuł przeglądowy
Opublikowany online: 2022-10-19

dostęp otwarty

Wyświetlenia strony 3497
Wyświetlenia/pobrania artykułu 122
Pobierz cytowanie

Eksport do Mediów Społecznościowych

Eksport do Mediów Społecznościowych

SDH-deficient gastrointestinal stromal tumours

Piotr Rutkowski1, Katarzyna Seliga2, Maria Dębiec-Rychter3
Biuletyn Polskiego Towarzystwa Onkologicznego Nowotwory 2022;7(5):373-380.


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.

Artykuł dostępny w formacie PDF

Pokaż PDF (angielski) Pobierz plik PDF


  1. Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer. 2011; 11(12): 865–878.
  2. Rutkowski P, Przybył J, Wozniak A, et al. Targeted Therapy in Gastrointestinal Stromal Tumors. Current Clinical Pathology. 2015: 163–196.
  3. Blay JY, Kang YK, Nishida T, et al. Gastrointestinal stromal tumours. Nat Rev Dis Primers. 2021; 7(1): 22.
  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.
  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.
  6. Schaefer IM, Mariño-Enríquez A, Fletcher JA. What is New in Gastrointestinal Stromal Tumor? Adv Anat Pathol. 2017; 24(5): 259–267.
  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.
  8. Ibrahim A, Chopra S. Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumors. Arch Pathol Lab Med. 2020; 144(5): 655–660.
  9. Brčić I, Argyropoulos A, Liegl-Atzwanger B. Update on Molecular Genetics of Gastrointestinal Stromal Tumors. Diagnostics (Basel). 2021; 11(2).
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  23. Gill AJ. Succinate dehydrogenase (SDH)-deficient neoplasia. Histopathology. 2018; 72(1): 106–116.
  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.
  25. Sun F, Huo X, Zhai Y, et al. Crystal structure of mitochondrial respiratory membrane protein complex II. Cell. 2005; 121(7): 1043–1057.
  26. Huang S, Millar AH. Succinate dehydrogenase: the complex roles of a simple enzyme. Curr Opin Plant Biol. 2013; 16(3): 344–349.
  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.
  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.
  29. Settas N, Faucz FR, Stratakis CA. Succinate dehydrogenase (SDH) deficiency, Carney triad and the epigenome. Mol Cell Endocrinol. 2018; 469: 107–111.
  30. Gill AJ. Succinate dehydrogenase (SDH) and mitochondrial driven neoplasia. Pathology. 2012; 44(4): 285–292.
  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.
  32. Belinsky MG, Rink L, von Mehren M. Succinate dehydrogenase deficiency in pediatric and adult gastrointestinal stromal tumors. Front Oncol. 2013; 3: 117.
  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.
  34. Miettinen M, Lasota J. Succinate dehydrogenase deficient gastrointestinal stromal tumors (GISTs) - a review. Int J Biochem Cell Biol. 2014; 53: 514–519.
  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.
  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.
  37. Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol. 2006; 23(2): 70–83.
  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.
  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.
  40. Nannini M, Rizzo A, Indio V, et al. Targeted therapy in deficient GIST. Ther Adv Med Oncol. 2021; 13: 17588359211023278.
  41. Pantaleo MA, Urbini M, Schipani A, et al. Germline Variants in Adult Patients With -Mutant Gastrointestinal Stromal Tumor. Front Oncol. 2021; 11: 778461.
  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.
  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.
  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.
  45. NCCN Clinical Practice Guidelines in O ncology (NCCN Guidelines ®) Gastrointestinal Stromal Tumors (GISTs) Version 1.2022. (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.
  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.
  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.
  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.
  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.
  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.
  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.
  53. Mei L, Smith SC, Faber AC, et al. Gastrointestinal Stromal Tumors: The GIST of Precision Medicine. Trends Cancer. 2018; 4(1): 74–91.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  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.
  66. Indio V, Schipani A, Nannini M, et al. Gene Expression Landscape of SDH-Deficient Gastrointestinal Stromal Tumors. J Clin Med. 2021; 10(5).
  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).
  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.
  69. Ravegnini G, Ricci R. Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumors: Small Steps Toward Personalized Medicine? Epigenet Insights. 2019; 12: 2516865719842534.
  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. (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.
  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.
  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.
  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.
  75. Dudzisz-Śledź M, Rutkowski P. Advances in the management of gastrointestinal stromal tumors (GISTs). Nowotwory. Journal of Oncology. 2020; 70(6): 280–287.

Biuletyn Polskiego Towarzystwa Onkologicznego Nowotwory