Skip to main content

Novel Prognostic Biomarker, Pfetin, in Gastrointestinal Stromal Tumors: Proteomics Study

  • Reference work entry
  • First Online:
General Methods in Biomarker Research and their Applications

Abstract

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Recently, a c-kit tyrosine kinase inhibitor, imatinib mesylate, was introduced for the treatment of GIST. Imatinib showed dramatic tumor suppressive effects in metastatic or inoperable cases, and adjuvant treatment with imatinib following surgical resection reduced the risk of recurrence. Although the imatinib treatment is obviously beneficial for GIST patients, GIST spans a wide spectrum from a curable disorder to a highly malignant disease leading to metastasis and death, and risk stratification of GIST patients for imatinib therapy is desirable. To address this issue, we aimed to develop a prognostic biomarker for GIST. We conducted a proteomic study using surgically resected primary tumor tissues from GIST patients who underwent surgery and showed variable prognoses. Quantitative comparison resulted in identification of proteins with differential expression among the GIST patient groups. One of the proteins, pfetin, originally discovered as a gene unique to fetal cochlea, was preferentially expressed in patients with a favorable prognosis. Preferential expression of pfetin in GISTs with a favorable prognosis was confirmed by western blotting and immunohistochemistry. Prognostic utility of pfetin was established by immunohistochemical studies in 486 patients from 6 hospitals. Pfetin expression will be beneficial for selection of GIST patients for adjuvant treatment with imatinib.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 399.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 549.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

2D-DIGE:

Two-Dimensional Difference Gel Electrophoresis

GIST:

Gastrointestinal Stromal Tumor

KCTD:

Potassium Channel Tetramerization Domain

References

  • Altelaar AF, Munoz J, Heck AJ. Next-generation proteomics: towards an integrative view of proteome dynamics. Nat Rev Genet. 2013;14:35–48.

    Article  CAS  PubMed  Google Scholar 

  • Bacci G, Ferrari S, Delepine N, Bertoni F, Picci P, Mercuri M, Bacchini P, Brach del Prever A, Tienghi A, Comandone A, Campanacci M. Predictive factors of histologic response to primary chemotherapy in osteosarcoma of the extremity: study of 272 patients preoperatively treated with high-dose methotrexate, doxorubicin, and cisplatin. J Clin Oncol. 1998;16:658–63.

    CAS  PubMed  Google Scholar 

  • Campostrini N, Areces LB, Rappsilber J, Pietrogrande MC, Dondi F, Pastorino F, Ponzoni M, Righetti PG. Spot overlapping in two-dimensional maps: a serious problem ignored for much too long. Proteomics. 2005;5:2385–95.

    Article  CAS  PubMed  Google Scholar 

  • Chan KH, Chan CW, Chow WH, Kwan WK, Kong CK, Mak KF, Leung MY, Lau LK. Gastrointestinal stromal tumors in a cohort of Chinese patients in Hong Kong. World J Gastroenterol. 2006;12:2223–8.

    Article  PubMed  PubMed Central  Google Scholar 

  • Choi DS, Park JO, Jang SC, Yoon YJ, Jung JW, Choi DY, Kim JW, Kang JS, Park J, Hwang D, et al. Proteomic analysis of microvesicles derived from human colorectal cancer ascites. Proteomics. 2011;11:2745–51.

    Article  CAS  PubMed  Google Scholar 

  • Conti M. Targeting K+ channels for cancer therapy. J Exp Ther Oncol. 2004;4:161–6.

    CAS  PubMed  Google Scholar 

  • de Bono JS, Ashworth A. Translating cancer research into targeted therapeutics. Nature. 2010;467:543–9.

    Article  PubMed  Google Scholar 

  • Dematteo RP, Heinrich MC, El-Rifai WM, Demetri G. Clinical management of gastrointestinal stromal tumors: before and after STI-571. Hum Pathol. 2002;33:466–77.

    Article  CAS  PubMed  Google Scholar 

  • Dematteo RP, Ballman KV, Antonescu CR, Maki RG, Pisters PW, Demetri GD, Blackstein ME, Blanke CD, von Mehren M, Brennan MF, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373:1097–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347:472–80.

    Article  CAS  PubMed  Google Scholar 

  • Di Marcotullio L, Ferretti E, De Smaele E, Argenti B, Mincione C, Zazzeroni F, Gallo R, Masuelli L, Napolitano M, Maroder M, et al. REN(KCTD11) is a suppressor of Hedgehog signaling and is deleted in human medulloblastoma. Proc Natl Acad Sci U S A. 2004;101:10833–8.

    Article  PubMed  PubMed Central  Google Scholar 

  • Duensing A, Medeiros F, McConarty B, Joseph NE, Panigrahy D, Singer S, Fletcher CD, Demetri GD, Fletcher JA. Mechanisms of oncogenic KIT signal transduction in primary gastrointestinal stromal tumors (GISTs). Oncogene. 2004;23:3999–4006.

    Article  CAS  PubMed  Google Scholar 

  • Duncan BK, Miller JH. Mutagenic deamination of cytosine residues in DNA. Nature. 1980;287:560–1.

    Article  CAS  PubMed  Google Scholar 

  • Ebara T, Ohno T, Nakano T. Quantitative medical cost-effectiveness analysis of molecular-targeting cancer drugs in Japan. Daru. 2013;21:40.

    Article  PubMed  PubMed Central  Google Scholar 

  • Felipe A, Vicente R, Villalonga N, Roura-Ferrer M, Martinez-Marmol R, Sole L, Ferreres JC, Condom E. Potassium channels: new targets in cancer therapy. Cancer Detect Prev. 2006;30:375–85.

    Article  CAS  PubMed  Google Scholar 

  • Felipe A, Bielanska J, Comes N, Vallejo A, Roig S, Ramon YCS, Condom E, Hernandez-Losa J, Ferreres JC. Targeting the voltage-dependent K(+) channels Kv1.3 and Kv1.5 as tumor biomarkers for cancer detection and prevention. Curr Med Chem. 2012;19:661–74.

    Article  CAS  PubMed  Google Scholar 

  • Fiske JL, Fomin VP, Brown ML, Duncan RL, Sikes RA. Voltage-sensitive ion channels and cancer. Cancer Metastasis Rev. 2006;25:493–500.

    Article  CAS  PubMed  Google Scholar 

  • Gamse JT, Kuan YS, Macurak M, Brosamle C, Thisse B, Thisse C, Halpern ME. Directional asymmetry of the zebrafish epithalamus guides dorsoventral innervation of the midbrain target. Development. 2005;132:4869–81.

    Article  CAS  PubMed  Google Scholar 

  • Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366:883–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Goettsch WG, Bos SD, Breekveldt-Postma N, Casparie M, Herings RM, Hogendoorn PC. Incidence of gastrointestinal stromal tumours is underestimated: results of a nation-wide study. Eur J Cancer. 2005;41:2868–72.

    Article  PubMed  Google Scholar 

  • Gromova P, Rubin BP, Thys A, Cullus P, Erneux C, Vanderwinden JM. ENDOGLIN/CD105 is expressed in KIT positive cells in the gut and in gastrointestinal stromal tumours. J Cell Mol Med. 2012;16:306–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hasegawa T, Asanuma H, Ogino J, Hirohashi Y, Shinomura Y, Iwaki H, Kikuchi H, Kondo T (2013) Use of potassium channel tetramerization domain-containing 12 as a biomarker for diagnosis and prognosis of gastrointestinal stromal tumor. Hum Pathol. 44(7):1271–1277

    Google Scholar 

  • Hirota S, Isozaki K, Moriyama Y, Hashimoto K, Nishida T, Ishiguro S, Kawano K, Hanada M, Kurata A, Takeda M, et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577–80.

    Article  CAS  PubMed  Google Scholar 

  • Hong BS, Cho JH, Kim H, Choi EJ, Rho S, Kim J, Kim JH, Choi DS, Kim YK, Hwang D, Gho YS. Colorectal cancer cell-derived microvesicles are enriched in cell cycle-related mRNAs that promote proliferation of endothelial cells. BMC Genomics. 2009;10:556.

    Article  PubMed  PubMed Central  Google Scholar 

  • House MG, Guo M, Efron DT, Lillemoe KD, Cameron JL, Syphard JE, Hooker CM, Abraham SC, Montgomery EA, Herman JG, Brock MV. Tumor suppressor gene hypermethylation as a predictor of gastric stromal tumor behavior. J Gastrointest Surg. 2003;7:1004–14; discussion 1014.

    Article  PubMed  Google Scholar 

  • Hu X, Yan F, Wang F, Yang Z, Xiao L, Li L, Xiang S, Zhou J, Ding X, Zhang J. TNFAIP1 interacts with KCTD10 to promote the degradation of KCTD10 proteins and inhibit the transcriptional activities of NF-kappaB and AP-1. Mol Biol Rep. 2012;39:9911–9.

    Article  CAS  PubMed  Google Scholar 

  • Huang MY, Wang HM, Chang HJ, Hsiao CP, Wang JY, Lin SR. Overexpression of S100B, TM4SF4, and OLFM4 genes is correlated with liver metastasis in Taiwanese colorectal cancer patients. DNA Cell Biol. 2012;31:43–9.

    Article  PubMed  PubMed Central  Google Scholar 

  • Igarashi S, Suzuki H, Niinuma T, Shimizu H, Nojima M, Iwaki H, Nobuoka T, Nishida T, Miyazaki Y, Takamaru H, et al. A novel correlation between LINE-1 hypomethylation and the malignancy of gastrointestinal stromal tumors. Clin Cancer Res. 2010;16:5114–23.

    Article  CAS  PubMed  Google Scholar 

  • Joensuu H, Eriksson M, Sundby Hall K, Hartmann JT, Pink D, Schutte J, Ramadori G, Hohenberger P, Duyster J, Al-Batran SE, et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. JAMA. 2012a;307:1265–72.

    Article  CAS  PubMed  Google Scholar 

  • Joensuu H, Vehtari A, Riihimaki J, Nishida T, Steigen SE, Brabec P, Plank L, Nilsson B, Cirilli C, Braconi C, et al. Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. Lancet Oncol. 2012b;13:265–74.

    Article  PubMed  Google Scholar 

  • Judson I. Imatinib in advanced gastrointestinal stromal tumour: when is 800 mg the correct dose? Curr Opin Oncol. 2008;20:433–7.

    Article  CAS  PubMed  Google Scholar 

  • Kelley RK, Venook AP. Nonadherence to imatinib during an economic downturn. N Engl J Med. 2010;363:596–8.

    Article  CAS  PubMed  Google Scholar 

  • Kelloff GJ, Sigman CC. Cancer biomarkers: selecting the right drug for the right patient. Nat Rev Drug Discov. 2012;11:201–14.

    Article  CAS  PubMed  Google Scholar 

  • Kikuta K, Gotoh M, Kanda T, Tochigi N, Shimoda T, Hasegawa T, Katai H, Shimada Y, Suehara Y, Kawai A, et al. Pfetin as a prognostic biomarker in gastrointestinal stromal tumor: novel monoclonal antibody and external validation study in multiple clinical facilities. Jpn J Clin Oncol. 2010;40:60–72.

    Article  PubMed  Google Scholar 

  • Kim HS, Choi DY, Yun SJ, Choi SM, Kang JW, Jung JW, Hwang D, Kim KP, Kim DW. Proteomic analysis of microvesicles derived from human mesenchymal stem cells. J Proteome Res. 2012;11:839–49.

    Article  CAS  PubMed  Google Scholar 

  • Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol. 1998;152:1259–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kondo T, Hirohashi S. Application of highly sensitive fluorescent dyes (CyDye DIGE Fluor saturation dyes) to laser microdissection and two-dimensional difference gel electrophoresis (2D-DIGE) for cancer proteomics. Nat Protoc. 2007;1:2940–56.

    Article  Google Scholar 

  • Kondo T, Suehara Y, Kikuta K, Kubota D, Tajima T, Mukaihara K, Ichikawa H, Kawai A. Proteomic approach toward personalized sarcoma treatment: lessons from prognostic biomarker discovery in gastrointestinal stromal tumor. Proteomics Clin Appl. 2013;7:70–8.

    Article  CAS  PubMed  Google Scholar 

  • Kosaka N, Yoshioka Y, Hagiwara K, Tominaga N, Ochiya T. Functional analysis of exosomal microRNA in cell-cell communication research. Methods Mol Biol. 2013;1024:1–10.

    Article  CAS  PubMed  Google Scholar 

  • Kubota D, Orita H, Yoshida A, Gotoh M, Kanda T, Tsuda H, Hasegawa T, Katai H, Shimada Y, Kaneko K, et al. Pfetin as a prognostic biomarker for gastrointestinal stromal tumor: validation study in multiple clinical facilities. Jpn J Clin Oncol. 2011;41:1194–202.

    Article  PubMed  Google Scholar 

  • Kubota D, Okubo T, Saito T, Suehara Y, Yoshida A, Kikuta K, Tsuda H, Katai H, Shimada Y, Kaneko K, et al. Validation Study on Pfetin and ATP-dependent RNA Helicase DDX39 as Prognostic Biomarkers in Gastrointestinal Stromal Tumour. Jpn J Clin Oncol. 2012;42(8):730–741

    Google Scholar 

  • Kubota D, Mukaihara K, Yoshida A, Suehara Y, Saito T, Okubo T, Gotoh M, Orita H, Tsuda H, Kaneko K, et al. The prognostic value of pfetin: a validation study in gastrointestinal stromal tumors using a commercially available antibody. Jpn J Clin Oncol. 2013;43:669–75.

    Article  PubMed  Google Scholar 

  • Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, Stewart C, Mermel CH, Roberts SA, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499(7457):214-218.

    Google Scholar 

  • Majer IM, Gelderblom H, van den Hout WB, Gray E, Verheggen BG. Cost-effectiveness of 3-Year versus 1-Year Adjuvant Therapy with Imatinib in Patients with High Risk of Gastrointestinal Stromal Tumor Recurrence in the Netherlands; A Modelling Study Alongside the Ssgxviii/Aio Trial. J Med Econ. 2013.

    Google Scholar 

  • Mathivanan S. Vesiclepedia. http://microvesicles.org/

  • Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol. 2006;23:70–83.

    Article  PubMed  Google Scholar 

  • Nakajima K, Tooyama I, Kuriyama K, Kimura H. Immunohistochemical demonstration of GABAB receptors in the rat gastrointestinal tract. Neurochem Res. 1996;21:211–5.

    Article  CAS  PubMed  Google Scholar 

  • Nilsson B, Bumming P, Meis-Kindblom JM, Oden A, Dortok A, Gustavsson B, Sablinska K, Kindblom LG. Gastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era–a population-based study in western Sweden. Cancer. 2005;103:821–9.

    Article  PubMed  Google Scholar 

  • Okamoto Y, Sawaki A, Ito S, Nishida T, Takahashi T, Toyota M, Suzuki H, Shinomura Y, Takeuchi I, Shinjo K, et al. Aberrant DNA methylation associated with aggressiveness of gastrointestinal stromal tumour. Gut. 2012;61:392–401.

    Article  CAS  PubMed  Google Scholar 

  • Pardo LA, Contreras-Jurado C, Zientkowska M, Alves F, Stuhmer W. Role of voltage-gated potassium channels in cancer. J Membr Biol. 2005;205:115–24.

    Article  CAS  PubMed  Google Scholar 

  • Resendes BL, Kuo SF, Robertson NG, Giersch AB, Honrubia D, Ohara O, Adams JC, Morton CC. Isolation from cochlea of a novel human intronless gene with predominant fetal expression. J Assoc Res Otolaryngol. 2004;5:185–202.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ricci R, Arena V, Castri F, Martini M, Maggiano N, Murazio M, Pacelli F, Potenza AE, Vecchio FM, Larocca LM. Role of p16/INK4a in gastrointestinal stromal tumor progression. Am J Clin Pathol. 2004;122:35–43.

    Article  CAS  PubMed  Google Scholar 

  • Rossi F, Ehlers I, Agosti V, Socci ND, Viale A, Sommer G, Yozgat Y, Manova K, Antonescu CR, Besmer P. Oncogenic Kit signaling and therapeutic intervention in a mouse model of gastrointestinal stromal tumor. Proc Natl Acad Sci U S A. 2006;103:12843–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rubin BP, Heinrich MC, Corless CL. Gastrointestinal stromal tumour. Lancet. 2007;369:1731–41.

    Article  CAS  PubMed  Google Scholar 

  • Saito K, Sakurai S, Sano T, Sakamoto K, Asao T, Hosoya Y, Nakajima T, Kuwano H. Aberrant methylation status of known methylation-sensitive CpG islands in gastrointestinal stromal tumors without any correlation to the state of c-kit and PDGFRA gene mutations and their malignancy. Cancer Sci. 2008;99:253–9.

    Article  CAS  PubMed  Google Scholar 

  • Sand PG, Langguth B, Itzhacki J, Bauer A, Geis S, Cardenas-Conejo ZE, Pimentel V, Kleinjung T. Resequencing of the auxiliary GABA(B) receptor subunit gene KCTD12 in chronic tinnitus. Front Syst Neurosci. 2012;6:41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schwanhausser B, Busse D, Li N, Dittmar G, Schuchhardt J, Wolf J, Chen W, Selbach M. Global quantification of mammalian gene expression control. Nature. 2011;473:337–42.

    Article  PubMed  Google Scholar 

  • Schwenk J, Metz M, Zolles G, Turecek R, Fritzius T, Bildl W, Tarusawa E, Kulik A, Unger A, Ivankova K, et al. Native GABA(B) receptors are heteromultimers with a family of auxiliary subunits. Nature. 2010;465:231–5.

    Article  CAS  PubMed  Google Scholar 

  • Suehara Y, Kondo T, Seki K, Shibata T, Fujii K, Gotoh M, Hasegawa T, Shimada Y, Sasako M, Shimoda T, et al. Pfetin as a prognostic biomarker of gastrointestinal stromal tumors revealed by proteomics. Clin Cancer Res. 2008;14:1707–17.

    Article  CAS  PubMed  Google Scholar 

  • Tatsuta M, Iishi H, Baba M, Nakaizumi A, Uehara H, Taniguchi H. Effect of gamma-butyrolactone on baclofen inhibition of gastric carcinogenesis induced by N-methyl-N’-nitro-N-nitrosoguanidine in Wistar rats. Oncology. 1992;49:123–6.

    Article  CAS  PubMed  Google Scholar 

  • Tatsuta M, Iishi H, Baba M, Yano H, Uehara H, Nakaizumi A. Effect of selective and non-selective muscarinic blockade on baclofen inhibition of gastric carcinogenesis induced by N-methyl-N’-nitro-N-nitrosoguanidine in Wistar rats. Carcinogenesis. 1996;17:293–6.

    Article  CAS  PubMed  Google Scholar 

  • The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts. Blood. 2013;121:4439–42.

    Google Scholar 

  • Travis WD, Brambilla E, Riely GJ. New pathologic classification of lung cancer: relevance for clinical practice and clinical trials. J Clin Oncol. 2013;31:992–1001.

    Article  CAS  PubMed  Google Scholar 

  • Trusheim MR, Berndt ER, Douglas FL. Stratified medicine: strategic and economic implications of combining drugs and clinical biomarkers. Nat Rev Drug Discov. 2007;6:287–93.

    Article  CAS  PubMed  Google Scholar 

  • Trusheim MR, Austin MJ, Rausch C, Berndt ER. Uncertain prognosis for high-quality diagnostics: clinical challenges, economic barriers and needed reforms. Pharmacogenomics. 2013;14:325–34.

    Article  CAS  PubMed  Google Scholar 

  • Tryggvason G, Kristmundsson T, Orvar K, Jonasson JG, Magnusson MK, Gislason HG. Clinical study on gastrointestinal stromal tumors (GIST) in Iceland, 1990–2003. Dig Dis Sci. 2007;52:2249–53.

    Article  PubMed  Google Scholar 

  • Unlu M, Morgan ME, Minden JS. Difference gel electrophoresis: a single gel method for detecting changes in protein extracts. Electrophoresis. 1997;18:2071–7.

    Article  CAS  PubMed  Google Scholar 

  • Vera-Badillo FE, Al-Mubarak M, Templeton AJ, Amir E. Benefit and harms of new anti-cancer drugs. Curr Oncol Rep. 2013;15:270–5.

    Article  CAS  PubMed  Google Scholar 

  • Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, Issels R, van Oosterom A, Hogendoorn PC, Van Glabbeke M, et al. Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial. Lancet. 2004;364:1127–34.

    Article  CAS  PubMed  Google Scholar 

  • Zalcberg JR, Verweij J, Casali PG, Le Cesne A, Reichardt P, Blay JY, Schlemmer M, Van Glabbeke M, Brown M, Judson IR. Outcome of patients with advanced gastro-intestinal stromal tumours crossing over to a daily imatinib dose of 800 mg after progression on 400 mg. Eur J Cancer. 2005;41:1751–7.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Tadashi Kondo .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Science+Business Media Dordrecht

About this entry

Cite this entry

Kondo, T. (2015). Novel Prognostic Biomarker, Pfetin, in Gastrointestinal Stromal Tumors: Proteomics Study. In: Preedy, V., Patel, V. (eds) General Methods in Biomarker Research and their Applications. Biomarkers in Disease: Methods, Discoveries and Applications. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-7696-8_26

Download citation

Publish with us

Policies and ethics