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Clinical and Translational Oncology

, Volume 21, Issue 2, pp 145–151 | Cite as

Molecular biomarkers for prognosis of gastrointestinal stromal tumor

  • X. LiuEmail author
  • K.-M. ChuEmail author
Review Article
  • 268 Downloads

Abstract

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. However, the development of molecular markers, especially circulating biomarkers, remains largely undone for the prognosis of GIST. We discussed the clinical-pathological characteristics of GIST and identified potential biomarkers for guidance of therapy and prognosis of GIST. Around 90% of GISTs contain mutations in KIT or PDGFRA and the remaining 10% of GISTs are wild-type. Recent studies have indicated that various DNAs and miRNAs could serve as potential biomarkers for prognosis of GIST, including KIT, PDGFRA, other DNAs (such as BRAF, SDH, SETD2 and ROR2), and microRNAs (miRNAs). The pressing need and challenges in the development of circulating prognostic biomarkers for GIST are also discussed. Although challenges remain, DNAs and miRNAs are promising circulating biomarkers for surveillance and prognosis of GIST. Advances in clarification of aberrant molecular alterations may open new avenues for exploration of reliable and robust biomarkers to improve the management of GIST.

Keywords

GIST Prognosis KIT PDGFRA DNA markers miRNA markers 

Notes

Acknowledgements

The authors would like to thank Ms. Kathy Yu for suggestion and proofreading this review.

Compliance with ethical standards

Conflict of interest

The authors have no conflicts of interest to disclose regarding this manuscript.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed consent

Informed consent is not applicable to this article.

References

  1. 1.
    Joensuu H, Hohenberger P, Corless CL. Gastrointestinal stromal tumour. Lancet. 2013;382(9896):973–83.CrossRefGoogle Scholar
  2. 2.
    Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer. 2011;11(12):865–78.CrossRefGoogle Scholar
  3. 3.
    Gold JS, Gonen M, Gutierrez A, Broto JM, Garcia-del-Muro X, Smyrk TC, et al. Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis. Lancet Oncol. 2009;10(11):1045–52.CrossRefGoogle Scholar
  4. 4.
    Joensuu H, Vehtari A, Riihimaki J, Nishida T, Steigen SE, Brabec P, et al. Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. Lancet Oncol. 2012;13(3):265–74.CrossRefGoogle Scholar
  5. 5.
    Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279(5350):577–80.CrossRefGoogle Scholar
  6. 6.
    Dagher R, Cohen M, Williams G, Rothmann M, Gobburu J, Robbie G, et al. Approval summary: imatinib mesylate in the treatment of metastatic and/or unresectable malignant gastrointestinal stromal tumors. Clin Cancer Res. 2002;8(10):3034–8.Google Scholar
  7. 7.
    Joensuu H, Fletcher C, Dimitrijevic S, Silberman S, Roberts P, Demetri G. Management of malignant gastrointestinal stromal tumours. Lancet Oncol. 2002;3(11):655–64.CrossRefGoogle Scholar
  8. 8.
    Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299(5607):708–10.CrossRefGoogle Scholar
  9. 9.
    Hanks SK, Quinn AM, Hunter T. The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. Science. 1988;241(4861):42–52.CrossRefGoogle Scholar
  10. 10.
    Corless CL, Fletcher JA, Heinrich MC. Biology of gastrointestinal stromal tumors. J Clin Oncol. 2004;22(18):3813–25.CrossRefGoogle Scholar
  11. 11.
    Zhi X, Zhou X, Wang W, Xu Z. Practical role of mutation analysis for imatinib treatment in patients with advanced gastrointestinal stromal tumors: a meta-analysis. PLoS ONE. 2013;8(11):e79275.CrossRefGoogle Scholar
  12. 12.
    Yan L, Zou L, Zhao W, Wang Y, Liu B, Yao H, et al. Clinicopathological significance of c-KIT mutation in gastrointestinal stromal tumors: a systematic review and meta-analysis. Sci Rep. 2015;5:13718.CrossRefGoogle Scholar
  13. 13.
    Wozniak A, Rutkowski P, Schoffski P, Ray-Coquard I, Hostein I, Schildhaus HU, et al. Tumor genotype is an independent prognostic factor in primary gastrointestinal stromal tumors of gastric origin: a European multicenter analysis based on ConticaGIST. Clin Cancer Res. 2014;20(23):6105–16.CrossRefGoogle Scholar
  14. 14.
    Rubio-Casadevall J, Borras JL, Carmona-Garcia MC, Ameijide A, Gonzalez-Vidal A, Ortiz MR, et al. Correlation between mutational status and survival and second cancer risk assessment in patients with gastrointestinal stromal tumors: a population-based study. World J Surg Oncol. 2015;13:47.CrossRefGoogle Scholar
  15. 15.
    Joensuu H, Rutkowski P, Nishida T, Steigen SE, Brabec P, Plank L, et al. KIT and PDGFRA mutations and the risk of GI stromal tumor recurrence. J Clin Oncol. 2015;33(6):634–42.CrossRefGoogle Scholar
  16. 16.
    Agaram NP, Wong GC, Guo T, Maki RG, Singer S, Dematteo RP, et al. Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer. 2008;47(10):853–9.CrossRefGoogle Scholar
  17. 17.
    Agaimy A, Terracciano LM, Dirnhofer S, Tornillo L, Foerster A, Hartmann A, et al. V600E BRAF mutations are alternative early molecular events in a subset of KIT/PDGFRA wild-type gastrointestinal stromal tumours. J Clin Pathol. 2009;62(7):613–6.CrossRefGoogle Scholar
  18. 18.
    Hostein I, Faur N, Primois C, Boury F, Denard J, Emile JF, et al. BRAF mutation status in gastrointestinal stromal tumors. Am J Clin Pathol. 2010;133(1):141–8.CrossRefGoogle Scholar
  19. 19.
    Jasek K, Buzalkova V, Minarik G, Stanclova A, Szepe P, Plank L, et al. Detection of mutations in the BRAF gene in patients with KIT and PDGFRA wild-type gastrointestinal stromal tumors. Virchows Arch. 2017;470(1):29–36.CrossRefGoogle Scholar
  20. 20.
    Janeway KA, Kim SY, Lodish M, Nose V, Rustin P, Gaal J, et al. Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci USA. 2011;108(1):314–8.CrossRefGoogle Scholar
  21. 21.
    Pantaleo MA, Astolfi A, Indio V, Moore R, Thiessen N, Heinrich MC, 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):983–7.CrossRefGoogle Scholar
  22. 22.
    Wagner AJ, Remillard SP, Zhang YX, Doyle LA, George S, Hornick JL. Loss of expression of SDHA predicts SDHA mutations in gastrointestinal stromal tumors. Mod Pathol. 2013;26(2):289–94.CrossRefGoogle Scholar
  23. 23.
    Miettinen M, Killian JK, Wang ZF, Lasota J, Lau C, Jones L, 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):234–40.CrossRefGoogle Scholar
  24. 24.
    Pylkkanen L, Sarlomo-Rikala M, Wessman M, Hamalainen E, Sainio M, Husgafvel-Pursiainen K, et al. Chromosome 22q alterations and expression of the NF2 gene product, merlin, in gastrointestinal stromal tumors. Hum Pathol. 2003;34(9):872–9.CrossRefGoogle Scholar
  25. 25.
    Silva M, Veiga I, Ribeiro FR, Vieira J, Pinto C, Pinheiro M, et al. Chromosome copy number changes carry prognostic information independent of KIT/PDGFRA point mutations in gastrointestinal stromal tumors. BMC Med. 2010;8:26.CrossRefGoogle Scholar
  26. 26.
    Killian JK, Kim SY, Miettinen M, Smith C, Merino M, Tsokos M, et al. Succinate dehydrogenase mutation underlies global epigenomic divergence in gastrointestinal stromal tumor. Cancer Discov. 2013;3(6):648–57.CrossRefGoogle Scholar
  27. 27.
    Boikos SA, Pappo AS, Killian JK, LaQuaglia MP, Weldon CB, George S, 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):922–8.CrossRefGoogle Scholar
  28. 28.
    House MG, Guo M, Efron DT, Lillemoe KD, Cameron JL, Syphard JE, et al. Tumor suppressor gene hypermethylation as a predictor of gastric stromal tumor behavior. J Gastrointest Surg. 2003;7(8):1004–14 (discussion 1014).CrossRefGoogle Scholar
  29. 29.
    Huang KK, McPherson JR, Tay ST, Das K, Tan IB, Ng CC, et al. SETD2 histone modifier loss in aggressive GI stromal tumours. Gut. 2015;65:1960–72.CrossRefGoogle Scholar
  30. 30.
    Schneider-Stock R, Boltze C, Lasota J, Peters B, Corless CL, Ruemmele P, et al. Loss of p16 protein defines high-risk patients with gastrointestinal stromal tumors: a tissue microarray study. Clin Cancer Res. 2005;11(2 Pt 1):638–45.Google Scholar
  31. 31.
    Martinho O, Gouveia A, Silva P, Pimenta A, Reis RM, Lopes JM. Loss of RKIP expression is associated with poor survival in GISTs. Virchows Arch. 2009;455(3):277–84.CrossRefGoogle Scholar
  32. 32.
    Yen CC, Yeh CN, Cheng CT, Jung SM, Huang SC, Chang TW, et al. Integrating bioinformatics and clinicopathological research of gastrointestinal stromal tumors: identification of aurora kinase A as a poor risk marker. Ann Surg Oncol. 2012;19(11):3491–9.CrossRefGoogle Scholar
  33. 33.
    Kubota D, Yoshida A, Tsuda H, Suehara Y, Okubo T, Saito T, et al. Gene expression network analysis of ETV1 reveals KCTD10 as a novel prognostic biomarker in gastrointestinal stromal tumor. PLoS ONE. 2013;8(8):e73896.CrossRefGoogle Scholar
  34. 34.
    Wang CJ, Zhang ZZ, Xu J, Wang M, Zhao WY, Tu L, et al. SLITRK3 expression correlation to gastrointestinal stromal tumor risk rating and prognosis. World J Gastroenterol. 2015;21(27):8398–407.CrossRefGoogle Scholar
  35. 35.
    Edris B, Espinosa I, Muhlenberg T, Mikels A, Lee CH, Steigen SE, et al. ROR2 is a novel prognostic biomarker and a potential therapeutic target in leiomyosarcoma and gastrointestinal stromal tumour. J Pathol. 2012;227(2):223–33.CrossRefGoogle Scholar
  36. 36.
    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.CrossRefGoogle Scholar
  37. 37.
    He L, Hannon GJ. MicroRNAs: small RNAs with a big role in gene regulation. Nat Rev Genet. 2004;5(7):522–31.CrossRefGoogle Scholar
  38. 38.
    Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6(11):857–66.CrossRefGoogle Scholar
  39. 39.
    Koelz M, Lense J, Wrba F, Scheffler M, Dienes HP, Odenthal M. Down-regulation of miR-221 and miR-222 correlates with pronounced kit expression in gastrointestinal stromal tumors. Int J Oncol. 2011;38(2):503–11.CrossRefGoogle Scholar
  40. 40.
    Kim WK, Park M, Kim YK, Tae YK, Yang HK, Lee JM, et al. MicroRNA-494 downregulates KIT and inhibits gastrointestinal stromal tumor cell proliferation. Clin Cancer Res. 2011;17(24):7584–94.CrossRefGoogle Scholar
  41. 41.
    Niinuma T, Suzuki H, Nojima M, Nosho K, Yamamoto H, Takamaru H, et al. Upregulation of miR-196a and HOTAIR drive malignant character in gastrointestinal stromal tumors. Can Res. 2012;72(5):1126–36.CrossRefGoogle Scholar
  42. 42.
    Gao X, Shen K, Wang C, Ling J, Wang H, Fang Y, et al. MiR-320a downregulation is associated with imatinib resistance in gastrointestinal stromal tumors. Acta Biochim Biophys Sin. 2014;46(1):72–5.CrossRefGoogle Scholar
  43. 43.
    Fan R, Zhong J, Zheng S, Wang Z, Xu Y, Li S, et al. microRNA-218 increase the sensitivity of gastrointestinal stromal tumor to imatinib through PI3 K/AKT pathway. Clin Exp Med. 2015;15(2):137–44.CrossRefGoogle Scholar
  44. 44.
    Akcakaya P, Caramuta S, Ahlen J, Ghaderi M, Berglund E, Ostman A, et al. microRNA expression signatures of gastrointestinal stromal tumours: associations with imatinib resistance and patient outcome. Br J Cancer. 2014;111(11):2091–102.CrossRefGoogle Scholar
  45. 45.
    Shi Y, Gao X, Hu Q, Li X, Xu J, Lu S, et al. PIK3C2A is a gene-specific target of microRNA-518a-5p in imatinib mesylate-resistant gastrointestinal stromal tumor. Lab Invest. 2016;96(6):652–60.CrossRefGoogle Scholar
  46. 46.
    Jahr S, Hentze H, Englisch S, Hardt D, Fackelmayer FO, Hesch RD, et al. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res. 2001;61(4):1659–65.Google Scholar
  47. 47.
    Gahan PB, Swaminathan R. Circulating nucleic acids in plasma and serum. Recent developments. Ann N Y Acad Sci. 2008;1137:1–6.CrossRefGoogle Scholar
  48. 48.
    Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci USA. 2008;105(30):10513–8.CrossRefGoogle Scholar
  49. 49.
    Sozzi G, Conte D, Mariani L, Lo Vullo S, Roz L, Lombardo C, et al. Analysis of circulating tumor DNA in plasma at diagnosis and during follow-up of lung cancer patients. Cancer Res. 2001;61(12):4675–8.Google Scholar
  50. 50.
    Shinozaki M, O’Day SJ, Kitago M, Amersi F, Kuo C, Kim J, et al. Utility of circulating B-RAF DNA mutation in serum for monitoring melanoma patients receiving biochemotherapy. Clin Cancer Res. 2007;13(7):2068–74.CrossRefGoogle Scholar
  51. 51.
    Diehl F, Schmidt K, Choti MA, Romans K, Goodman S, Li M, et al. Circulating mutant DNA to assess tumor dynamics. Nat Med. 2008;14(9):985–90.CrossRefGoogle Scholar
  52. 52.
    Bono P, Krause A, von Mehren M, Heinrich MC, Blanke CD, Dimitrijevic S, et al. Serum KIT and KIT ligand levels in patients with gastrointestinal stromal tumors treated with imatinib. Blood. 2004;103(8):2929–35.CrossRefGoogle Scholar
  53. 53.
    Maier J, Lange T, Kerle I, Specht K, Bruegel M, Wickenhauser C, et al. Detection of mutant free circulating tumor DNA in the plasma of patients with gastrointestinal stromal tumor harboring activating mutations of CKIT or PDGFRA. Clin Cancer Res. 2013;19(17):4854–67.CrossRefGoogle Scholar
  54. 54.
    Kang G, Bae BN, Sohn BS, Pyo JS, Kang GH, Kim KM. Detection of KIT and PDGFRA mutations in the plasma of patients with gastrointestinal stromal tumor. Target Oncol. 2015;10(4):597–601.CrossRefGoogle Scholar
  55. 55.
    Schwamb B, Pick R, Fernandez SB, Volp K, Heering J, Dotsch V, et al. FAM96A is a novel pro-apoptotic tumor suppressor in gastrointestinal stromal tumors. Int J Cancer. 2015;137(6):1318–29.CrossRefGoogle Scholar
  56. 56.
    Li CF, Chen LT, Lan J, Chou FF, Lin CY, Chen YY, et al. AMACR amplification and overexpression in primary imatinib-naive gastrointestinal stromal tumors: a driver of cell proliferation indicating adverse prognosis. Oncotarget. 2014;5(22):11588–603.Google Scholar
  57. 57.
    Tarn C, Rink L, Merkel E, Flieder D, Pathak H, Koumbi D, et al. Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors. Proc Natl Acad Sci USA. 2008;105(24):8387–92.CrossRefGoogle Scholar
  58. 58.
    Liu S, Cui J, Liao G, Zhang Y, Ye K, Lu T, et al. MiR-137 regulates epithelial-mesenchymal transition in gastrointestinal stromal tumor. Tumour Biol. 2014;35(9):9131–8.CrossRefGoogle Scholar
  59. 59.
    Fleischhacker M, Schmidt B. Circulating nucleic acids (CNAs) and cancer—a survey. Biochim Biophys Acta. 2007;1775(1):181–232.Google Scholar
  60. 60.
    Hibi K, Goto T, Shirahata A, Saito M, Kigawa G, Nemoto H, et al. Detection of TFPI2 methylation in the serum of gastric cancer patients. Anticancer Res. 2011;31(11):3835–8.Google Scholar
  61. 61.
    Umetani N, Giuliano AE, Hiramatsu SH, Amersi F, Nakagawa T, Martino S, et al. Prediction of breast tumor progression by integrity of free circulating DNA in serum. J Clin Oncol. 2006;24(26):4270–6.CrossRefGoogle Scholar
  62. 62.
    Hayes DN, Kim WY. The next steps in next-gen sequencing of cancer genomes. J Clin Investig. 2015;125(2):462–8.CrossRefGoogle Scholar
  63. 63.
    Ignatiadis M, Dawson SJ. Circulating tumor cells and circulating tumor DNA for precision medicine: dream or reality? Ann Oncol. 2014;25(12):2304–13.CrossRefGoogle Scholar
  64. 64.
    Hechtman JF, Zehir A, Mitchell T, Borsu L, Singer S, Tap W, et al. Novel oncogene and tumor suppressor mutations in KIT and PDGFRA wild type gastrointestinal stromal tumors revealed by next generation sequencing. Genes Chromosomes Cancer. 2015;54(3):177–84.CrossRefGoogle Scholar

Copyright information

© Federación de Sociedades Españolas de Oncología (FESEO) 2018

Authors and Affiliations

  1. 1.Department of SurgeryThe University of Hong KongPokfulamHong Kong
  2. 2.Department of SurgeryQueen Mary HospitalPokfulamHong Kong

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