Skip to main content

Advertisement

SpringerLink
Log in

Wild-Type Gastrointestinal Stromal Tumors—Molecular Features, Frequency, and Consequences Among the Indian Population

  • Original Article
  • Published:
Indian Journal of Surgery Aims and scope Submit manuscript

Abstract

Wild-type gastrointestinal stromal tumors (WT-GIST) are a unique and uncommon subtype of GISTs that lack activating mutations in the tyrosine kinase c-KIT or PDGFRA receptors rendering resistance to tyrosine kinase receptor inhibitors, such as imatinib. Among these WT-GISTs, a small subset is associated with loss of function of succinate dehydrogenase (SDH). It is postulated that SDH deficiency leads to activation of insulin-like growth factor 1-receptor (IGF1R) signaling which in turn results in oncogenesis. SDH-proficient WT-GISTs on the other hand are associated with other mutations such as Neurofibromatosis type-1 (NF1), BRAF, and RAS. The study compared the overall survival among the SDH-deficient vs. SDH-proficient WT-GIST groups. In the present study, 265 histologically confirmed cases of GIST accessioned over the period of 2014–2018 were analyzed for KIT, PDGFRA gene mutations by sequencing on the ABI 3500 Gene Analyzer (Applied Biosystems, Foster City, USA), and BRAFV600 gene mutation using the real-time (RT) PCR assay on ABI™ Quant Studio 12K Flex System. SDH protein expression was evaluated by immunohistochemistry using the mouse monoclonal antibody against SDHB (clone 21A11AE7; Abcam, Cambridge, MA). WT-GIST cases constituted 12.3% of the total GIST cases (30/243). Based on SDH expression, 9 cases (30%) were SDH-deficient and 18 cases (60%) were SDH-proficient. The overall survival rate of the SDH-proficient group was 67.3%, whereas the SDH-deficient group had a 100% survival rate during the study period. WT-GIST although rare is a unique entity which needs molecular characterization for better clinical management of the patients. The SDH-deficient WT-GIST group was associated with a better clinical outcome, thereby suggesting the importance of recognizing these patients in clinical practice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Huss S, Elges S, Trautmann M, Sperveslage J, Hartmann W, Wardelmann E (2015) Classification of KIT/PDGFRA wild-type gastrointestinal stromal tumors: implications for therapy. Expert Rev Anticancer Ther 15(6):623–628. https://doi.org/10.1586/14737140.2015.1032941

    Article  PubMed  CAS  Google Scholar 

  2. Gheysen M, Vander Borght S, Lehnert S, Vanslembrouck R, Vanden Bempt I, Schöffski P (2020) An unexpected response to imatinib in a “wild-type” gastrointestinal stromal tumor. Oncol Res Treat 43(9):470–473. https://doi.org/10.1159/000508536

    Article  PubMed  CAS  Google Scholar 

  3. Mou Y, Wang Q, Li B (2018) The ‘wild’-type gastrointestinal stromal tumors: heterogeneity on molecule characteristics and clinical features. Cancer Translational Med 4(3):75. https://link.gale.com/apps/doc/A578160472/AONE?u=anon~7927e67a&sid=googleScholar&xid=e1e35ee8. Accessed 7 Aug 2023

  4. Heinrich MC, Corless CL, Blanke CD, Demetri GD, Joensuu H, Roberts PJ, Eisenberg BL, von Mehren M, Fletcher CD, Sandau K, McDougall K, Ou WB, Chen CJ, Fletcher JA (2006) Molecular correlates of imatinib resistance in gastrointestinal stromal tumors. J Clin Oncol 24(29):4764–4774. https://doi.org/10.1200/JCO.2006.06.2265

    Article  PubMed  CAS  Google Scholar 

  5. Celestino R, Lima J, Faustino A, Vinagre J, Máximo V, Gouveia A, Soares P, Lopes JM (2013) Molecular alterations and expression of succinate dehydrogenase complex in wild-type KIT/PDGFRA/BRAF gastrointestinal stromal tumors. Eur J Hum Genet : EJHG 21(5):503–510. https://doi.org/10.1038/ejhg.2012.205

    Article  PubMed  CAS  Google Scholar 

  6. Ahmad F, Lad P, Bhatia S, Das BR (2015) Molecular spectrum of c-KIT and PDGFRA gene mutations in gastro intestinal stromal tumor: determination of frequency, distribution pattern and identification of novel mutations in Indian patients. Med Oncol (Northwood, London, England) 32(1):424. https://doi.org/10.1007/s12032-014-0424-7

    Article  CAS  Google Scholar 

  7. Kays JK, Sohn JD, Kim BJ, Goze K, Koniaris LG (2018) Approach to wild-type gastrointestinal stromal tumors. Transl Gastroenterol Hepatol 3(92). https://doi.org/10.21037/tgh.2018.10.13

  8. Zhang H, Liu Q (2020) Prognostic indicators for gastrointestinal stromal tumors: a review. Transl Oncol 13(10):100812. https://doi.org/10.1016/j.tranon.2020.100812

    Article  PubMed  PubMed Central  Google Scholar 

  9. Boikos SA, Stratakis CA (2014) The genetic landscape of gastrointestinal stromal tumor lacking KIT and PDGFRA mutations. Endocrine 47(2):401–408. https://doi.org/10.1007/s12020-014-0346-3

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Szucs Z, Thway K, Fisher C, Bulusu R, Constantinidou A, Benson C, van der Graaf WT, Jones RL (2017) Molecular subtypes of gastrointestinal stromal tumors and their prognostic and therapeutic implications. Future Oncol(London, England) 13(1):93–107. https://doi.org/10.2217/fon-2016-0192

    Article  CAS  Google Scholar 

  11. Boikos SA, Pappo AS, Killian JK, LaQuaglia MP, Weldon CB, George S, Trent JC, von Mehren M, Wright JA, Schiffman JD, Raygada M, Pacak K, Meltzer PS, Miettinen MM, Stratakis C, Janeway KA, Helman LJ (2016) Molecular subtypes of KIT/PDGFRA wild-type gastrointestinal stromal tumors: a report from the National Institutes of Health Gastrointestinal Stromal Tumor Clinic. JAMA Oncol 2(7):922–928. https://doi.org/10.1001/jamaoncol.2016.0256

    Article  PubMed  PubMed Central  Google Scholar 

  12. Agaimy A (2010) Gastrointestinal stromal tumors (GIST) from risk stratification systems to the new TNM proposal: more questions than answers? A review emphasizing the need for a standardized GIST reporting. Int J Clin Exp Pathol 3(5):461–471

    PubMed  PubMed Central  Google Scholar 

  13. Pai T, Bal M, Shetty O, Gurav M, Ostwal V, Ramaswamy A, Ramadwar M, Desai S (2017) Unraveling the spectrum of KIT mutations in gastrointestinal stromal tumors: an Indian tertiary cancer center experience. South Asian J Cancer 6(3):113–117. https://doi.org/10.4103/sajc.sajc_275_16

    Article  PubMed  PubMed Central  Google Scholar 

  14. Minhas S, Bhalla S, Jauhri M, Ganvir M, Aggarwal S (2019) Clinico-pathological characteristics and mutational analysis of gastrointestinal stromal tumors from India: a single institution experience. Asian Pac J Cancer Prev APJCP 20(10):3051–3055. https://doi.org/10.31557/APJCP.2019.20.10.3051

    Article  PubMed  CAS  Google Scholar 

  15. Bosman FT, Carneiro F, Hruban RH, Theise N (2010) WHO classification of tumours of the digestive system, fourth edn. IARC, France

    Google Scholar 

  16. Lasota J, Kowalik A, Wasag B, Wang ZF, Felisiak-Golabek A, Coates T, Kopczynski J, Gozdz S, Miettinen M (2014) Detection of the BRAF V600E mutation in colon carcinoma: critical evaluation of the imunohistochemical approach. Am J Surg Pathol 38(9):1235–1241. https://doi.org/10.1097/PAS.0000000000000229

    Article  PubMed  PubMed Central  Google Scholar 

  17. Jiang Z, Zhang J, Li Z, Liu Y, Wang D, Han G (2016) A meta-analysis of prognostic value of KIT mutation status in gastrointestinal stromal tumors. Onco Targets Ther 9:3387–3398. https://doi.org/10.2147/OTT.S101858

    Article  PubMed  PubMed Central  Google Scholar 

  18. Yacob M, Inian S, Sudhakar CB (2015) Gastrointestinal stromal tumours: review of 150 cases from a single centre. Indian J Surg 77(Suppl 2):505–510. https://doi.org/10.1007/s12262-013-0899-z

    Article  PubMed  Google Scholar 

  19. Cassier PA, Fumagalli E, Rutkowski P, Schöffski P, Van Glabbeke M, Debiec-Rychter M, Emile JF, Duffaud F, Martin-Broto J, Landi B, Adenis A, Bertucci F, Bompas E, Bouché O, Leyvraz S, Judson I, Verweij J, Casali P, Blay JY et al (2012) Outcome of patients with platelet-derived growth factor receptor alpha-mutated gastrointestinal stromal tumors in the tyrosine kinase inhibitor era. Clin Cancer Res : Off J American Assoc Cancer Res 18(16):4458–4464. https://doi.org/10.1158/1078-0432.CCR-11-3025

    Article  CAS  Google Scholar 

  20. Yan L, Zou L, Zhao W, Wang Y, Liu B, Yao H, Yu H (2015) Clinicopathological significance of c-KIT mutation in gastrointestinal stromal tumors: a systematic review and meta-analysis. Sci Rep 5:13718. https://doi.org/10.1038/srep13718

    Article  PubMed  PubMed Central  Google Scholar 

  21. Wang YM, Gu ML, Ji F (2015) Succinate dehydrogenase-deficient gastrointestinal stromal tumors. World J Gastroenterol 21(8):2303–2314. https://doi.org/10.3748/wjg.v21.i8.2303

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Ibrahim A, Chopra S (2020) Succinate dehydrogenase-deficient gastrointestinal stromal tumors. Arch Pathol Lab Med 144(5):655–660. https://doi.org/10.5858/arpa.2018-0370-RS

    Article  PubMed  CAS  Google Scholar 

  23. Mathias-Machado MC, de Jesus VHF, de Carvalho Oliveira LJ, Neumann M, Peixoto RD (2022) Current molecular profile of gastrointestinal stromal tumors and systemic therapeutic implications. Cancers 14(21):5330. https://doi.org/10.3390/cancers14215330

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Baa AK, Rastogi S, Fernandes S, Shrivastava S, Yadav R, Barwad A, Shamim SA, Dash NR (2023) Insights into the medical management of gastrointestinal stromal tumours: lessons learnt from a dedicated gastrointestinal stromal tumour clinic in North India. Ecancermedicalscience 17:1497. https://doi.org/10.3332/ecancer.2023.1497

    Article  PubMed  PubMed Central  Google Scholar 

  25. Wu CE, Tzen CY, Wang SY, Yeh CN (2019) Clinical diagnosis of gastrointestinal stromal tumor (GIST): from the molecular genetic point of view. Cancers 11(5):679. https://doi.org/10.3390/cancers11050679

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Molecular Pathology, Department of Pathology, Tata Memorial Hospital, Homi Bhabha National Institute, Parel, Mumbai, 400012, India

    Mamta Gurav, Prachi Bapat, Vaibhavi Vengurlekar, Karishma Vyas, Rachna Rumde, Trupti Pai, Mukta Ramadwar, Munita Bal & Omshree Shetty

  2. Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Parel, Mumbai, 400012, India

    Vikas Ostwal, Anant Ramaswamy & Akhil Kapoor

Authors
  1. Mamta Gurav
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Prachi Bapat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vikas Ostwal
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Vaibhavi Vengurlekar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Karishma Vyas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rachna Rumde
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Trupti Pai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mukta Ramadwar
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Munita Bal
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Anant Ramaswamy
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Akhil Kapoor
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Omshree Shetty
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Mamta Gurav: Conceptualization, Manuscript writing, Data analysis, Prachi Bapat: Manuscript writing, Performing the study, Data analysis, Vikas Ostwal: Editing and Reviewing manuscript, Vaibhavi Vengurlekar: Performing the study, Karishma Vyas: Performing the study, Rachna Rumde: Performing the study, Trupti Pai: Conceptualization and Reviewing manuscript, Mukta Ramadwar: Editing and Reviewing manuscript, Munita Bal: Conceptualization, Editing and Reviewing manuscript, Anant Ramaswamy: Editing and Reviewing manuscript, Akhil Kapoor: Data Analysis,Omshree Shetty: Conceptualization, Manuscript writing, Editing and Reviewing manuscript.

Corresponding author

Correspondence to Omshree Shetty.

Ethics declarations

Competing Interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM 1

(DOCX 13 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gurav, M., Bapat, P., Ostwal, V. et al. Wild-Type Gastrointestinal Stromal Tumors—Molecular Features, Frequency, and Consequences Among the Indian Population. Indian J Surg (2024). https://doi.org/10.1007/s12262-024-04023-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12262-024-04023-y

Keywords

Search

Navigation