Advertisement

Cancer and Metastasis Reviews

, Volume 38, Issue 3, pp 525–535 | Cite as

Current management of succinate dehydrogenase–deficient gastrointestinal stromal tumors

  • Pushpa Neppala
  • Sudeep Banerjee
  • Paul T. Fanta
  • Mayra Yerba
  • Kevin A. Porras
  • Adam M. BurgoyneEmail author
  • Jason K. SicklickEmail author
Clinical
  • 96 Downloads

Abstract

Gastrointestinal stromal tumors (GISTs) are increasingly recognized as having diverse biology. With the development of tyrosine kinase inhibitors molecularly matched to oncogenic KIT and PDGFRA mutations, GISTs have become a quintessential model for precision oncology. However, about 5–10% of GIST lack these driver mutations and are deficient in succinate dehydrogenase (SDH), an enzyme that converts succinate to fumarate. SDH deficiency leads to accumulation of succinate, an oncometabolite that promotes tumorigenesis. SDH-deficient GISTs are clinically unique in that they generally affect younger patients and are associated with GIST-paraganglioma hereditary syndrome, also known as Carney-Stratakis Syndrome. SDH-deficient GISTs are generally resistant to tyrosine-kinase inhibitors, the standard treatment for advanced or metastatic GIST. Thus, surgical resection is the mainstay of treatment for localized disease, but recurrence is common. Clinical trials are currently underway investigating systemic agents for treatment of advanced SDH-deficient GIST. However, further studies are warranted to improve our understanding of SDH-deficient GIST disease biology, natural history, surgical approaches, and novel therapeutics.

Keywords:

Gastrointestinal stromal tumors GIST Succinate dehydrogenase Tyrosine kinase inhibitors SDH 

Notes

Contributors

Pushpa Neppala: Study design, data analysis, article drafting, and critical review of the manuscript.

Sudeep Banerjee: Data analysis, article drafting, and critical review of the manuscript.

Paul T. Fanta: Critical review of the manuscript.

Mayra Yerba: Data analysis, article drafting, and critical review of the manuscript.

Kevin A. Porras: Article drafting.

Adam M. Burgoyne: Data analysis, article drafting, and critical review of the manuscript.

Jason K. Sicklick: Study design, data analysis, article drafting, and critical review of the manuscript.

All authors had approved the final article.

Funding information

This work was supported by the Society for Surgery of the Alimentary Tract (SSAT) Mentored Research Award (S.B), UC San Diego GIST Research Fund (J.K.S.), NIH K08CA168999 (J.K.S.), NIH R21CA192072 (J.K.S.), and NIH R01CA226803 (J.K.S.).

Compliance with ethical standards

Conflict of interest

Jason Sicklick receives research funds from Foundation Medicine, Amgen Pharmaceuticals, and Novartis Pharmaceuticals, as well as consultant fees from Deciphera Pharmaceuticals, Loxo, and Grand Rounds. Adam Burgoyne receives consultant fees from Exelixis and Eisai. All other authors have no relationships to disclose.

Informed consent

Not applicable.

References

  1. 1.
    Ma, G. L., Murphy, J. D., Martinez, M. E., & Sicklick, J. K. (2015). Epidemiology of gastrointestinal stromal tumors in the era of histology codes: results of a population-based study. Cancer Epidemiol Biomarkers Prev, 24(1), 298–302.  https://doi.org/10.1158/1055-9965.EPI-14-1002.CrossRefPubMedGoogle Scholar
  2. 2.
    Kindblomd, L.-G., Remotti, H. E., Aldenborn, F., & Meis-Kindblom, J. M. (1998). Gastrointestinal pacemaker cell tumor (GIPACT) gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. American Journal of Pathology, 152(5).Google Scholar
  3. 3.
    Miettinen, M., Monihan, J. M., Sarlomo-Rikala, M., Kovatich, A. J., Carr, N. J., Emory, T. S., et al. (1999). Gastrointestinal stromal tumors/smooth muscle tumors (GISTs) primary in the omentum and mesentery: clinicopathologic and immunohistochemical study of 26 cases. The American Journal of Surgical Pathology, 23(9), 1109.CrossRefGoogle Scholar
  4. 4.
    Miettinen, M., Sarlomo-Rikala, M., Sobin, L. H., & Lasota, J. (2000). Esophageal stromal tumors: a clinicopathologic, immunohistochemical, and molecular genetic study of 17 cases and comparison with esophageal leiomyomas and leiomyosarcomas. The American Journal of Surgical Pathology, 24(2), 211–222.CrossRefGoogle Scholar
  5. 5.
    Miettinen, M., Sobin, L. H., & Lasota, J. (2005). Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. The American Journal of Surgical Pathology, 29(1), 52–68.  https://doi.org/10.1097/01.pas.0000146010.92933.de.CrossRefPubMedGoogle Scholar
  6. 6.
    Erlandson, R. A., Klimstra, D. S., & Woodruff, J. M. (2009). Subclassification of gastrointestinal stromal tumors based on evaluation by electron microscopy and immunohistochemistry. Ultrastructural Pathology, 20(4), 373–393.  https://doi.org/10.3109/01913129609016340.CrossRefGoogle Scholar
  7. 7.
    Miettinen, M. (1988). Gastrointestinal stromal tumors. An immunohistochemical study of cellular differentiation. American Journal of Clinical Pathology, 89(5), 601–610.CrossRefGoogle Scholar
  8. 8.
    Miettinen, M., & Lasota, J. (2001). Gastrointestinal stromal tumors - definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Archiv, 438(1), 1–12.  https://doi.org/10.1007/s004280000338.CrossRefPubMedGoogle Scholar
  9. 9.
    Dematteo, R. P., Heinrick, M. C., El-Rifai, W.-e., & Demetri, G. (2002). Clinical management of gastrointestinal stromal tumors: before and after STI-571. Human Pathology, 33(5), 478–483.  https://doi.org/10.1053/hupa.2002.124123.CrossRefGoogle Scholar
  10. 10.
    Hirota, S., Isozaki, K., Moriyama, Y., Hashimoto, K., Nishida, T., Ishiguro, S., Kawano, K., Hanada, M., Kurata, A., Takeda, M., Muhammad Tunio, G., Matsuzawa, Y., Kanakura, Y., Shinomura, Y., & Kitamura, Y. (1998). Gain-of-function mutations of c-kit n human gastrointestinal stromal tumors. Science, 279(5350), 577–580.  https://doi.org/10.1126/science.279.5350.577.CrossRefPubMedGoogle Scholar
  11. 11.
    Heinrich, M. C., Corless, C. L., Duensing, A., McGreevey, L., Chen, C.-J., Joseph, N., Singer, S., Griffith, D. J., Haley, A., Town, A., Demetri, G. D., Fletcher, C. D., & Fletcher, J. A. (2003). PDGFRA activating mutations in gastrointestinal stromal tumors. Science, 299(5607), 708–710.  https://doi.org/10.1126/science.1079666.CrossRefPubMedGoogle Scholar
  12. 12.
    Shi, E., Chmielecki, J., Tang, C. M., Wang, K., Heinrich, M. C., Kang, G., Corless, C. L., Hong, D., Fero, K. E., Murphy, J. D., Fanta, P. T., Ali, S. M., de Siena, M., Burgoyne, A. M., Movva, S., Madlensky, L., Heestand, G. M., Trent, J. C., Kurzrock, R., Morosini, D., Ross, J. S., Harismendy, O., & Sicklick, J. K. (2016). FGFR1 and NTRK3 actionable alterations in “Wild-Type” gastrointestinal stromal tumors. Journal of Translational Medicine, 14(1), 339.  https://doi.org/10.1186/s12967-016-1075-6.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Corless, C. L., Barnett, C. M., & Heinrich, M. C. (2011). Gastrointestinal stromal tumours: origin and molecular oncology. Nature Reviews Cancer, 11(12), 865–878.  https://doi.org/10.1038/nrc3143.CrossRefPubMedGoogle Scholar
  14. 14.
    Agaram, N. P., Wong, G. C., Guo, T., Maki, R. G., Singer, S., Dematteo, R. P., Besmer, P., & Antonescu, C. R. (2008). Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer, 47(10), 853–859.  https://doi.org/10.1002/gcc.20589.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Brenca, M., Rossi, S., Polano, M., Gasparotto, D., Zanatta, L., Racanelli, D., Valori, L., Lamon, S., Dei Tos, A. P., & Maestro, R. (2016). Transcriptome sequencing identifies ETV6-NTRK3 as a gene fusion involved in GIST. Journal of Pathology, 238(4), 543–549.  https://doi.org/10.1002/path.4677.CrossRefPubMedGoogle Scholar
  16. 16.
    Miranda, C., Nucifora, M., Molinari, F., Conca, E., Anania, M. C., Bordoni, A., Saletti, P., Mazzucchelli, L., Pilotti, S., Pierotti, M. A., Tamborini, E., Greco, A., & Frattini, M. (2012). KRAS and BRAF mutations predict primary resistance to imatinib in gastrointestinal stromal tumors. Clinical Cancer Research, 18(6), 1769–1776.  https://doi.org/10.1158/1078-0432.CCR-11-2230.CrossRefPubMedGoogle Scholar
  17. 17.
    Alkhuziem, M., Burgoyne, A. M., Fanta, P. T., Tang, C.-M., & Sicklick, J. K. (2017). The call of “The Wild”-type GIST: It’s time for domestication. Journal of the National Comprehensive Cancer Network, 15(5), 551–554.  https://doi.org/10.6004/jnccn.2017.0057.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Janeway, K. A., Kim, S. Y., Lodish, M., Nose, V., Rustin, P., Gaal, J., et al. (2011). Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proceedings of the National Academy of Sciences of the United States of America, 108(1), 314–318.  https://doi.org/10.1073/pnas.1009199108.CrossRefPubMedGoogle Scholar
  19. 19.
    Miettinen, M., Wang, Z. F., Sarlomo-Rikala, M., Osuch, C., Rutkowski, P., & Lasota, J. (2011). Succinate dehydrogenase-deficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age. The American Journal of Surgical Pathology, 35(11), 1712–1721.  https://doi.org/10.1097/PAS.0b013e3182260752.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Pasini, B., McWhinney, S. R., Bei, T., Matyakhina, L., Stergiopoulos, S., Muchow, M., et al. (2008). Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. European Journal of Human Genetics, 16(1), 79–88.  https://doi.org/10.1038/sj.ejhg.5201904.CrossRefPubMedGoogle Scholar
  21. 21.
    Boikos, S. A., Pappo, A. S., Killian, J., et al. (2016). Molecular subtypes of KIT/PDGFRa wild-type gastrointestinal stromal tumors: a report from the National Institutes of Health gastrointestinal stromal tumor clinic. JAMA Oncology, 2(7), 922–928.  https://doi.org/10.1001/jamaoncol.2016.0256.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Mullassery, D., & Weldon, C. B. (2016). Pediatric/“Wildtype” gastrointestinal stromal tumors. Seminars in Pediatric Surgery, 25(5), 305–310.  https://doi.org/10.1053/j.sempedsurg.2016.09.004.CrossRefPubMedGoogle Scholar
  23. 23.
    Wang, Y. M., Gu, M. L., & Ji, F. (2015). Succinate dehydrogenase-deficient gastrointestinal stromal tumors. World Journal of Gastroenterology, 21(8), 2303–2314.  https://doi.org/10.3748/wjg.v21.i8.2303.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Miettinen, M., & Lasota, J. (2014). Succinate dehydrogenase deficient gastrointestinal stromal tumors (GISTs) - a review. The International Journal of Biochemistry & Cell Biology, 53, 514–519.  https://doi.org/10.1016/j.biocel.2014.05.033.CrossRefGoogle Scholar
  25. 25.
    Gottlieb, E., & Tomlinson, I. P. M. (2005). Mitochondrial tumour suppressors: a genetic and biochemical update. [Review Article]. Nature Reviews Cancer, 5, 857.  https://doi.org/10.1038/nrc1737.CrossRefPubMedGoogle Scholar
  26. 26.
    Rutter, J., Winge, D. R., & Schiffman, J. D. (2010). Succinate dehydrogenase - assembly, regulation and role in human disease. Mitochondrion, 10(4), 393–401.  https://doi.org/10.1016/j.mito.2010.03.001.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Lussey-Lepoutre, C., Hollinshead, K. E. R., Ludwig, C., Menara, M., Morin, A., Castro-Vega, L.-J., et al. (2015). Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism. Nature communications, 6, 8784–8784.  https://doi.org/10.1038/ncomms9784.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Cardaci, S., Zheng, L., MacKay, G., van den Broek, N. J. F., MacKenzie, E. D., Nixon, C., et al. (2015). Pyruvate carboxylation enables growth of SDH-deficient cells by supporting aspartate biosynthesis. Nature cell biology, 17(10), 1317–1326.  https://doi.org/10.1038/ncb3233.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Soderberg, K. L., Ditta, G. S., & Scheffler, I. E. (1977). Mammalian cells with defective mitochondrial functions: a Chinese hamster mutant cell line lacking succinate dehydrogenase activity. Cell, 10(4), 697–702.  https://doi.org/10.1016/0092-8674(77)90103-9.CrossRefPubMedGoogle Scholar
  30. 30.
    Baysal, B. E., Ferrell, R. E., Willett-Brozick, J. E., Lawrence, E. C., Myssiorek, D., Bosch, A., van der Mey, A., Taschner, P. E., Rubinstein, W. S., Myers, E. N., Richard 3rd, C. W., Cornelisse, C. J., Devilee, P., & Devlin, B. (2000). Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science, 287(5454), 848–851.  https://doi.org/10.1126/science.287.5454.848.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Astuti, D., Latif, F., Dallol, A., Dahia, P. L., Douglas, F., George, E., Sköldberg, F., Husebye, E. S., Eng, C., & Maher, E. R. (2001). Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. American Journal of Human Genetics, 69(1), 49–54.  https://doi.org/10.1086/321282.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Bardella, C., Pollard, P. J., & Tomlinson, I. (2011). SDH mutations in cancer. Biochimica et Biophysica Acta, 1807(11), 1432–1443.  https://doi.org/10.1016/j.bbabio.2011.07.003.CrossRefPubMedGoogle Scholar
  33. 33.
    Burnichon, N., Vescovo, L., Amar, L., Libe, R., de Reynies, A., Venisse, A., et al. (2011). Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma. Human Molecular Genetics, 20(20), 3974–3985.  https://doi.org/10.1093/hmg/ddr324.CrossRefPubMedGoogle Scholar
  34. 34.
    Ricketts, C., Woodward, E. R., Killick, P., Morris, M. R., Astuti, D., Latif, F., & Maher, E. R. (2008). Germline SDHB mutations and familial renal cell carcinoma. Journal of the National Cancer Institute, 100(17), 1260–1262.  https://doi.org/10.1093/jnci/djn254.CrossRefPubMedGoogle Scholar
  35. 35.
    Iommarini, L., Porcelli, A. M., Gasparre, G., & Kurelac, I. (2017). Non-canonical mechanisms regulating hypoxia-inducible factor 1 alpha in cancer. Frontiers in Oncology, 7, 286.  https://doi.org/10.3389/fonc.2017.00286.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Fuhler, G. M., Eppinga, H., & Peppelenbosch, M. P. (2017). Fumarates and cancer. Trends in Molecular Medicine, 23(1), 3–5.  https://doi.org/10.1016/j.molmed.2016.12.001.CrossRefPubMedGoogle Scholar
  37. 37.
    Frezza, C., Pollard, P. J., & Gottlieb, E. (2011). Inborn and acquired metabolic defects in cancer. Journal of Molecular Medicine, 89(3), 213–220.  https://doi.org/10.1007/s00109-011-0728-4.CrossRefPubMedGoogle Scholar
  38. 38.
    Ruas, J. L., & Poellinger, L. (2005). Hypoxia-dependent activation of HIF into a transcriptional regulator. Seminars in Cell and Developmental Biology, 16(4-5), 514–522.  https://doi.org/10.1016/j.semcdb.2005.04.001.CrossRefPubMedGoogle Scholar
  39. 39.
    Selak, M. A., Armour, S. M., MacKenzie, E. D., Boulahbel, H., Watson, D. G., Mansfield, K. D., et al. (2005). Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell, 7.  https://doi.org/10.1016/j.ccr.2004.11.022.CrossRefGoogle Scholar
  40. 40.
    MacKenzie, E. D., Selak, M. A., Tennant, D. A., Payne, L. J., Crosby, S., Frederiksen, C. M., et al. (2007). Cell-permeating alpha-ketoglutarate derivatives alleviate pseudohypoxia in succinate dehydrogenase-deficient cells. Molecular and Cellular Biology, 27(9), 3282–3289.  https://doi.org/10.1128/MCB.01927-06.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Guerra, F., Guaragnella, N., Arbini, A. A., Bucci, C., Giannattasio, S., & Moro, L. (2017). Mitochondrial dysfunction: a novel potential driver of epithelial-to-mesenchymal transition in cancer. Frontiers in Oncology, 7, 295–295.  https://doi.org/10.3389/fonc.2017.00295.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Aspuria, P.-J. P., Lunt, S. Y., Väremo, L., Vergnes, L., Gozo, M., Beach, J. A., et al. (2014). Succinate dehydrogenase inhibition leads to epithelial-mesenchymal transition and reprogrammed carbon metabolism. Cancer & Metabolism, 2(1), 21.  https://doi.org/10.1186/2049-3002-2-21.CrossRefGoogle Scholar
  43. 43.
    Yang, L., Moss, T., Mangala, L. S., Marini, J., Zhao, H., Wahlig, S., Armaiz-Pena, G., Jiang, D., Achreja, A., Win, J., Roopaimoole, R., Rodriguez-Aguayo, C., Mercado-Uribe, I., Lopez-Berestein, G., Liu, J., Tsukamoto, T., Sood, A. K., Ram, P. T., & Nagrath, D. (2014). Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer. Molecular Systems Biology, 10(5), 728.  https://doi.org/10.1002/msb.20134892.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Loriot, C., Domingues, M., Berger, A., Menara, M., Ruel, M., Morin, A., et al. (2015). Deciphering the molecular basis of invasiveness in Sdhb-deficient cells. Oncotarget, 6(32), 32955–32965.  https://doi.org/10.18632/oncotarget.5106.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Røsland, G. V., Dyrstad, S. E., Tusubira, D., Helwa, R., Tan, T. Z., Lotsberg, M. L., Pettersen, I. K. N., Berg, A., Kindt, C., Hoel, F., Jacobsen, K., Arason, A. J., Engelsen, A. S. T., Ditzel, H. J., Lønning, P. E., Krakstad, C., Thiery, J. P., Lorens, J. B., Knappskog, S., & Tronstad, K. J. (2019). Epithelial to mesenchymal transition (EMT) is associated with attenuation of succinate dehydrogenase (SDH) in breast cancer through reduced expression of SDHC. Cancer & Metabolism, 7, 6–6.  https://doi.org/10.1186/s40170-019-0197-8.CrossRefGoogle Scholar
  46. 46.
    Miettinen, M., Killian, J. K., Wang, Z. F., Lasota, J., Lau, C., Jones, L., Walker, R., Pineda, M., Zhu, Y. J., Kim, S. Y., Helman, L., & Meltzer, P. (2013). Immunohistochemical loss of succinate dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA germline mutation. The American Journal of Surgical Pathology, 37(2), 234–240.  https://doi.org/10.1097/PAS.0b013e3182671178.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Burnichon, N., Briere, J. J., Libe, R., Vescovo, L., Riviere, J., Tissier, F., et al. (2010). SDHA is a tumor suppressor gene causing paraganglioma. Human Molecular Genetics, 19(15), 3011–3020.  https://doi.org/10.1093/hmg/ddq206.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Pantaleo, M. A., Astolfi, A., Indio, V., Moore, R., Thiessen, N., Heinrich, M. C., Gnocchi, C., Santini, D., Catena, F., Formica, S., Martelli, P. L., Casadio, R., Pession, A., & Biasco, G. (2011). SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing. Journal of the National Cancer Institute, 103(12), 983–987.  https://doi.org/10.1093/jnci/djr130.CrossRefPubMedGoogle Scholar
  49. 49.
    Bannon, A. E., Kent, J. D., Forquer, I., Town, A., Klug, L. R., McCann, K. E., et al. (2017). Biochemical, molecular, and clinical characterization of succinate dehydrogenase subunit a variants of unknown significance. Clinical Cancer Research.  https://doi.org/10.1158/1078-0432.ccr-17-1397.CrossRefGoogle Scholar
  50. 50.
    Killian, J. K., Miettinen, M., Walker, R. L., Wang, Y., Zhu, Y. J., Waterfall, J. J., et al. (2014). Recurrent epimutation of SDHC in gastrointestinal stromal tumors. Science Translational Medicine, 6(268), 1–9.  https://doi.org/10.1126/scitranslmed.3009961.CrossRefGoogle Scholar
  51. 51.
    Carney, J. A., Sheps, S. G., Go, V. L. W., & Gordon, H. (1977). The triad of gastric leiomyosarcoma, functioning extra-adrenal paraganglioma and pulmonary chondroma. New England Journal of Medicine, 296(26), 1517–1518.  https://doi.org/10.1056/nejm197706302962609.CrossRefPubMedGoogle Scholar
  52. 52.
    Matyakhina, L., Bei, T. A., McWhinney, S. R., Pasini, B., Cameron, S., Gunawan, B., et al. (2007). Genetics of carney triad: recurrent losses at chromosome 1 but lack of germline mutations in genes associated with paragangliomas and gastrointestinal stromal tumors. The Journal of Clinical Endocrinology & Metabolism, 92(8), 2938–2943.  https://doi.org/10.1210/jc.2007-0797.CrossRefGoogle Scholar
  53. 53.
    Stratakis, C. A., & Carney, J. A. (2009). The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications. Journal of Internal Medicine, 266(1), 43–52.  https://doi.org/10.1111/j.1365-2796.2009.02110.x.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Sicklick, J. K., & Lopez, N. E. (2013). Optimizing surgical and imatinib therapy for the treatment of gastrointestinal stromal tumors. Journal of Gastrointestinal Surgery, 17(11), 1997–2006.  https://doi.org/10.1007/s11605-013-2243-0.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Mei, L., Du, W., Idowu, M., von Mehren, M., & Boikos, S. A. (2018). Advances and challenges on management of gastrointestinal stromal tumors. Frontiers in Oncology, 8, 135.  https://doi.org/10.3389/fonc.2018.00135.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    DeMatteo, R. P., Lewis, J. J., Leung, D., Mudan, S. S., Woodruff, J. M., & Brennan, M. F. (2000). Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Annals of Surgery, 231(1), 51–58.CrossRefGoogle Scholar
  57. 57.
    Janeway, K. A., Liegl, B., Harlow, A., Le, C., Perez-Atayde, A., Kozakewich, H., et al. (2007). Pediatric KIT wild-type and platelet-derived growth factor receptor alpha-wild-type gastrointestinal stromal tumors share KIT activation but not mechanisms of genetic progression with adult gastrointestinal stromal tumors. Cancer Research, 67(19), 9084–9088.  https://doi.org/10.1158/0008-5472.CAN-07-1938.CrossRefPubMedGoogle Scholar
  58. 58.
    Willobee, B. A., Quiroz, H. J., Sussman, M. S., Thorson, C. M., Sola, J. E., & Perez, E. A. (2018). Current treatment strategies in pediatric gastrointestinal stromal cell tumor. Translational Gastroenterology and Hepatology, 3, 53–53.  https://doi.org/10.21037/tgh.2018.07.09.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Fero, K. E., Coe, T. M., Fanta, P. T., Tang, C. M., Murphy, J. D., & Sicklick, J. K. (2017). Surgical management of adolescents and young adults with gastrointestinal stromal tumors: a US population-based analysis. JAMA Surgery, 152(5), 443–451.  https://doi.org/10.1001/jamasurg.2016.5047.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Weldon, C. B., Madenci, A. L., Boikos, S. A., Janeway, K. A., George, S., von Mehren, M., Pappo, A. S., Schiffman, J. D., Wright, J., Trent, J. C., Pacak, K., Stratakis, C. A., Helman, L. J., & la Quaglia, M. P. (2017). Surgical management of wild-type gastrointestinal stromal tumors: a report from the National Institutes of Health Pediatric and Wildtype GIST Clinic. Journal of Clinical Oncology, 35(5), 523–528.  https://doi.org/10.1200/jco.2016.68.6733.CrossRefPubMedGoogle Scholar
  61. 61.
    Norton, J. A., Kim, T., Kim, J., McCarter, M. D., Kelly, K. J., Wong, J., et al. (2018). SSAT state-of-the-art conference: current surgical management of gastric tumors. Journal of Gastrointestinal Surgery, 22(1), 32–42.  https://doi.org/10.1007/s11605-017-3533-8.CrossRefPubMedGoogle Scholar
  62. 62.
    Heinrich, M. C., Rankin, C., Blanke, C. D., Demetri, G. D., Borden, E. C., Ryan, C. W., von Mehren, M., Blackstein, M. E., Priebat, D. A., Tap, W. D., Maki, R. G., Corless, C. L., Fletcher, J. A., Owzar, K., Crowley, J. J., Benjamin, R. S., & Baker, L. H. (2017). Correlation of long-term results of imatinib in advanced gastrointestinal stromal tumors with next-generation sequencing results: analysis of Phase 3 SWOG Intergroup Trial S0033. JAMA Oncology, 3(7), 944–952.  https://doi.org/10.1001/jamaoncol.2016.6728.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Demetri, G. D., van Oosterom, A. T., Garrett, C. R., Blackstein, M. E., Shah, M. H., Verweij, J., et al. (2006). Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. The Lancet, 368(9544), 1329–1338.  https://doi.org/10.1016/S0140-6736(06)69446-4.CrossRefGoogle Scholar
  64. 64.
    Heinrich, M. C., Maki, R. G., Corless, C. L., Antonescu, C. R., Harlow, A., Griffith, D., Town, A., McKinley, A., Ou, W. B., Fletcher, J. A., Fletcher, C. D., Huang, X., Cohen, D. P., Baum, C. M., & Demetri, G. D. (2008). Primary and secondary kinase genotypes correlate with the biological and clinical activity of sunitinib in imatinib-resistant gastrointestinal stromal tumor. Journal of Clinical Oncology, 26(33), 5352–5359.  https://doi.org/10.1200/JCO.2007.15.7461.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Ben-Ami, E., Barysauskas, C. M., Von Mehren, M., Heinrich, M. C., Corless, C. L., Butrynski, J. E., et al. (2016). 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. Annals of Oncology, 27(9), 1794–1799.  https://doi.org/10.1093/annonc/mdw228.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Ganjoo, K. N., Villalobos, V. M., Kamaya, A., Fisher, G. A., Butrynski, J. E., Morgan, J. A., Wagner, A. J., D'Adamo, D., McMillan, A., Demetri, G. D., & George, S. (2014). A multicenter phase II study of pazopanib in patients with advanced gastrointestinal stromal tumors (GIST) following failure of at least imatinib and sunitinib. Annals of Oncology, 25(1), 236–240.  https://doi.org/10.1093/annonc/mdt484.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Tsang, L. L. H., Quarterman, C. P., Gescher, A., & Slack, J. A. (1991). Comparison of the cytotoxicity in vitro of temozolomide and dacarbazine, prodrugs of 3-methyl-(triazen-1-yl)imidazole-4-carboxamide. [journal article]. Cancer Chemotherapy and Pharmacology, 27(5), 342–346.  https://doi.org/10.1007/bf00688855.CrossRefPubMedGoogle Scholar
  68. 68.
    Trent, J. C., Beach, J., Burgess, M. A., Papadopolous, N., Chen, L. L., Benjamin, R. S., & Patel, S. R. (2003). A two-arm phase II study of temozolomide in patients with advanced gastrointestinal stromal tumors and other soft tissue sarcomas. Cancer, 98(12), 2693–2699.  https://doi.org/10.1002/cncr.11875.CrossRefPubMedGoogle Scholar
  69. 69.
    Garcia Del Muro, X., Lopez-Pousa, A., Martin, J., Buesa, J. M., Martinez-Trufero, J., Casado, A., et al. (2005). A phase II trial of temozolomide as a 6-week, continuous, oral schedule in patients with advanced soft tissue sarcoma. Cancer, 104(8), 1706–1712.  https://doi.org/10.1002/cncr.21384.CrossRefPubMedGoogle Scholar
  70. 70.
    Hadoux, J., Favier, J., Scoazec, J. Y., Leboulleux, S., Al Ghuzlan, A., Caramella, C., et al. (2014). SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma. International Journal of Cancer, 135(11), 2711–2720.  https://doi.org/10.1002/ijc.28913.CrossRefPubMedGoogle Scholar
  71. 71.
    Eisenhauer, E. A., Therasse, P., Bogaerts, J., Schwartz, L. H., Sargent, D., Ford, R., Dancey, J., Arbuck, S., Gwyther, S., Mooney, M., Rubinstein, L., Shankar, L., Dodd, L., Kaplan, R., Lacombe, D., & Verweij, J. (2009). New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1). European Journal of Cancer, 45(2), 228–247.  https://doi.org/10.1016/j.ejca.2008.10.026.CrossRefPubMedGoogle Scholar
  72. 72.
    Letouze, E., Martinelli, C., Loriot, C., Burnichon, N., Abermil, N., Ottolenghi, C., et al. (2013). SDH mutations establish a hypermethylator phenotype in paraganglioma. Cancer Cell, 23.  https://doi.org/10.1016/j.ccr.2013.04.018.CrossRefGoogle Scholar
  73. 73.
    Wallace, E. M., Rizzi, J. P., Han, G., Wehn, P. M., Cao, Z., Du, X., et al. (2016). A small-molecule antagonist of HIF2alpha is efficacious in preclinical models of renal cell carcinoma. Cancer Research, 76(18), 5491–5500.  https://doi.org/10.1158/0008-5472.CAN-16-0473.CrossRefPubMedGoogle Scholar
  74. 74.
    Courtney, K. D., Infante, J. R., Lam, E. T., Figlin, R. A., Rini, B. I., Brugarolas, J., Zojwalla, N. J., Lowe, A. M., Wang, K., Wallace, E. M., Josey, J. A., & Choueiri, T. K. (2017). Phase I dose-escalation trial of PT2385, a first-in-class hypoxia-inducible factor-2α antagonist in patients with previously treated advanced clear cell renal cell carcinoma. Journal of Clinical Oncology, 36(9), 867–874.  https://doi.org/10.1200/JCO.2017.74.2627.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Tufton, N., Shapiro, L., Srirangalingam, U., Richards, P., Sahdev, A., Kumar, A. V., McAndrew, L., Martin, L., Berney, D., Monson, J., Chew, S. L., Waterhouse, M., Druce, M., Korbonits, M., Metcalfe, K., Drake, W. M., Storr, H. L., & Akker, S. A. (2017). Outcomes of annual surveillance imaging in an adult and paediatric cohort of succinate dehydrogenase B mutation carriers. Clin Endocrinol (Oxf), 86(2), 286–296.  https://doi.org/10.1111/cen.13246.CrossRefGoogle Scholar
  76. 76.
    Gimenez-Roqueplo, A.-P., Favier, J., Rustin, P., Rieubland, C., Crespin, M., Nau, V., Khau van Kien, P., Corvol, P., Plouin, P. F., Jeunemaitre, X., & COMETE Network. (2003). Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Research, 63(17), 5615–5621.PubMedGoogle Scholar
  77. 77.
    Amar, L., Baudin, E., Burnichon, N., Peyrard, S., Silvera, S., Bertherat, J., et al. (2007). Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. Journal of Clinical Endocrinology and Metabolism, 92(10), 3822–3828.  https://doi.org/10.1210/jc.2007-0709.CrossRefPubMedGoogle Scholar
  78. 78.
    Neumann, H. H., Pawlu, C., Pęczkowska, M., et al. (2004). Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations. Journal of the American Medical Association, 292(8), 943–951.  https://doi.org/10.1001/jama.292.8.943.CrossRefPubMedGoogle Scholar
  79. 79.
    Benn, D. E., Gimenez-Roqueplo, A. P., Reilly, J. R., Bertherat, J., Burgess, J., Byth, K., Croxson, M., Dahia, P. L., Elston, M., Gimm, O., Henley, D., Herman, P., Murday, V., Niccoli-Sire, P., Pasieka, J. L., Rohmer, V., Tucker, K., Jeunemaitre, X., Marsh, D. J., Plouin, P. F., & Robinson, B. G. (2006). Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. Journal of Clinical Endocrinology and Metabolism, 91(3), 827–836.  https://doi.org/10.1210/jc.2005-1862.CrossRefPubMedGoogle Scholar
  80. 80.
    Timmers, H. J. L. M., Kozupa, A., Eisenhofer, G., Raygada, M., Adams, K. T., Solis, D., et al. (2007). Clinical presentations, biochemical phenotypes, and genotype-phenotype correlations in patients with succinate dehydrogenase subunit B-associated pheochromocytomas and paragangliomas. The Journal of Clinical Endocrinology & Metabolism, 92(3), 779–786.  https://doi.org/10.1210/jc.2006-2315.CrossRefGoogle Scholar
  81. 81.
    Eisenhofer, G., Pacak, K., Huynh, T.-T., Qin, N., Bratslavsky, G., Linehan, W. M., Mannelli, M., Friberg, P., Grebe, S. K., Timmers, H. J., Bornstein, S. R., & Lenders, J. W. (2010). Catecholamine metabolomic and secretory phenotypes in phaeochromocytoma. Endocrine-Related Cancer, 18(1), 97–111.  https://doi.org/10.1677/ERC-10-0211.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Eisenhofer, G., Goldstein, D. S., Sullivan, P., Csako, G., Brouwers, F. M., Lai, E. W., Adams, K. T., & Pacak, K. (2005). Biochemical and clinical manifestations of dopamine-producing paragangliomas: utility of plasma methoxytyramine. The Journal of Clinical Endocrinology & Metabolism, 90(4), 2068–2075.  https://doi.org/10.1210/jc.2004-2025.CrossRefGoogle Scholar
  83. 83.
    Eisenhofer, G., Lenders, J. W. M., Timmers, H., Mannelli, M., Grebe, S. K., Hofbauer, L. C., et al. (2011). Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma. Clinical Chemistry, 57(3), 411–420.  https://doi.org/10.1373/clinchem.2010.153320.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Tufton, N., Sahdev, A., & Akker, S. A. (2017). Radiological surveillance screening in asymptomatic succinate dehydrogenase mutation carriers. Journal of the Endocrine Society, 1(7), 897–907.  https://doi.org/10.1210/js.2017-00230.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Pushpa Neppala
    • 1
  • Sudeep Banerjee
    • 2
    • 3
  • Paul T. Fanta
    • 4
    • 5
  • Mayra Yerba
    • 2
  • Kevin A. Porras
    • 1
  • Adam M. Burgoyne
    • 5
    Email author
  • Jason K. Sicklick
    • 2
    • 4
    Email author
  1. 1.UC San Diego School of MedicineUniversity of California, San DiegoLa JollaUSA
  2. 2.Division of Surgical Oncology, Department of Surgery, UC San Diego Moores Cancer CenterUniversity of California, San DiegoLa JollaUSA
  3. 3.Department of SurgeryDavid Geffen School of Medicine at UCLALos AngelesUSA
  4. 4.Center for Personalized Cancer Therapy, UC San Diego Moores Cancer CenterUniversity of California, San DiegoLa JollaUSA
  5. 5.Division of Hematology-Oncology, Department of Medicine, UC San Diego Moores Cancer CenterUniversity of California, San DiegoLa JollaUSA

Personalised recommendations