Skip to main content

Advertisement

SpringerLink
Log in

PIK3CA kinase domain mutation identifies a subgroup of stage III colon cancer patients with poor prognosis

  • Original Paper
  • Published:
Cellular Oncology Aims and scope Submit manuscript

Abstract

Background

PIK3CA mutations in the helical domain (in exon 9) and in the kinase domain (exon 20) cause tumor formation by different means. We aimed to determine the effects of each of these mutations on survival of colon carcinoma patients.

Methods

A large cohort of 685 colon carcinoma patients was tested for PIK3CA mutations in exons 9 and 20 by single nucleotide primer extension (N = 428) or by real time PCR (N = 257).

Results

PIK3CA mutation rate was 13%. 66 of 83 (79.5%) were in exon 9 and 17 of 83 (20.5%) in exon 20. In survival analysis, PIK3CA mutations in exon 9 and 20 had different effects on patient outcome. The PIK3CA exon 20 mutation conferred a poorer disease free survival compared to patients with wild type alleles and exon 9 mutations (Log rank p = 0.04 and p = 0.03 respectively) and cancer specific survival (Log rank p = 0.03 and p = 0.056 respectively) in stage III patients. In stage I and II this negative effect on outcome was not seen.

Conclusions

PIK3CA mutation in exon 20 is a negative prognostic factor in stage III colon cancer patients. Moreover, this negative effect is not present in stage I and II patients.

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

Similar content being viewed by others

References

  1. C.G. Moertel, T.R. Fleming, J.S. Macdonald, D.G. Haller, J.A. Laurie, C.M. Tangen et al., Fluorouracil plus levamisole as effective adjuvant therapy after resection of stage III colon carcinoma: a final report. Ann. Intern. Med. 122(5), 321–326 (1995)

    PubMed  CAS  Google Scholar 

  2. T. Andre, D. Sargent, J. Tabernero, M. O'Connell, M. Buyse, A. Sobrero et al., Current issues in adjuvant treatment of stage II colon cancer. Ann. Surg. Oncol. 13(6), 887–898 (2006)

    Article  PubMed  Google Scholar 

  3. C.B. Diep, L. Thorstensen, G.I. Meling, E. Skovlund, T.O. Rognum, R.A. Lothe, Genetic tumor markers with prognostic impact in Dukes’ stages B and C colorectal cancer patients. J. Clin. Oncol. 21(5), 820–829 (2003)

    Article  PubMed  Google Scholar 

  4. W.S. Jo, J.M. Carethers, Chemotherapeutic implications in microsatellite unstable colorectal cancer. Cancer Biomark. 2(1–2), 51–60 (2006)

    PubMed  CAS  Google Scholar 

  5. D.J. Sargent, S. Marsoni, G. Monges, S.N. Thibodeau, R. Labianca, S.R. Hamilton et al., Defective mismatch repair as a predictive marker for lack of efficacy of fluorouracil-based adjuvant therapy in colon cancer. J. Clin. Oncol. 28(20), 3219–3226 (2010)

    Article  PubMed  CAS  Google Scholar 

  6. F.A. Sinicrope, R.L. Rego, N. Foster, D.J. Sargent, H.E. Windschitl, L.J. Burgart et al., Microsatellite instability accounts for tumor site-related differences in clinicopathologic variables and prognosis in human colon cancers. Am. J. Gastroenterol. 101(12), 2818–2825 (2006)

    Article  PubMed  CAS  Google Scholar 

  7. F.A. Sinicrope, R.L. Rego, K.C. Halling, N. Foster, D.J. Sargent, B. La Plant et al., Prognostic impact of microsatellite instability and DNA ploidy in human colon carcinoma patients. Gastroenterology 131(3), 729–737 (2006)

    Article  PubMed  CAS  Google Scholar 

  8. F.A. Sinicrope, D.J. Sargent, Clinical implications of microsatellite instability in sporadic colon cancers. Curr. Opin. Oncol. 21(4), 369–373 (2009)

    Article  PubMed  CAS  Google Scholar 

  9. A.D. Roth, S. Tejpar, M. Delorenzi, P. Yan, R. Fiocca, D. Klingbiel et al., Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J. Clin. Oncol. 28(3), 466–474 (2010)

    Article  PubMed  CAS  Google Scholar 

  10. A. Farina-Sarasqueta, G. van Lijnschoten, E. Moerland, G.J. Creemers, V.E. Lemmens, H.J. Rutten et al., The BRAF V600E mutation is an independent prognostic factor for survival in stage II and stage III colon cancer patients. Ann. Oncol. 21(12), 2396–2402 (2010)

    Article  PubMed  CAS  Google Scholar 

  11. K. Chen, P. Iribarren, W. Gong, J.M. Wang, The essential role of phosphoinositide 3-kinases (PI3Ks) in regulating pro-inflammatory responses and the progression of cancer. Cell. Mol. Immunol. 2(4), 241–252 (2005)

    PubMed  CAS  Google Scholar 

  12. J.A. Engelman, J. Luo, L.C. Cantley, The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet. 7(8), 606–619 (2006)

    Article  PubMed  CAS  Google Scholar 

  13. L. Zhao, P.K. Vogt, Class I PI3K in oncogenic cellular transformation. Oncogene 27(41), 5486–5496 (2008)

    Article  PubMed  CAS  Google Scholar 

  14. Y. Samuels, Z. Wang, A. Bardelli, N. Silliman, J. Ptak, S. Szabo et al., High frequency of mutations of the PIK3CA gene in human cancers. Science 304(5670), 554 (2004)

    Article  PubMed  CAS  Google Scholar 

  15. A.G. Bader, S. Kang, P.K. Vogt, Cancer-specific mutations in PIK3CA are oncogenic in vivo. Proc. Natl. Acad. Sci. U. S. A. 103(5), 1475–1479 (2006)

    Article  PubMed  CAS  Google Scholar 

  16. X.N. Guo, A. Rajput, R. Rose, J. Hauser, A. Beko, K. Kuropatwinski et al., Mutant PIK3CA-bearing colon cancer cells display increased metastasis in an orthotopic model. Canc. Res. 67(12), 5851–5858 (2007)

    Article  CAS  Google Scholar 

  17. L. Barault, N. Veyrie, V. Jooste, D. Lecorre, C. Chapusot, J.M. Ferraz et al., Mutations in the RAS-MAPK, PI(3)K (phosphatidylinositol-3-OH kinase) signaling network correlate with poor survival in a population-based series of colon cancers. Int. J. Canc. 122(10), 2255–2259 (2008)

    Article  CAS  Google Scholar 

  18. S. Ogino, K. Nosho, G.J. Kirkner, K. Shima, N. Irahara, S. Kure et al., PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer. J. Clin. Oncol. 27(9), 1477–1484 (2009)

    Article  PubMed  CAS  Google Scholar 

  19. S. Velho, C. Moutinho, L. Cirnes, C. Albuquerque, R. Hamelin, F. Schmitt et al., BRAF, KRAS and PIK3CA mutations in colorectal serrated polyps and cancer: primary or secondary genetic events in colorectal carcinogenesis? BMC Canc. 8, 255 (2008)

    Article  Google Scholar 

  20. T. Ikenoue, F. Kanai, Y. Hikiba, T. Obata, Y. Tanaka, J. Imamura et al., Functional analysis of PIK3CA gene mutations in human colorectal cancer. Canc. Res. 65(11), 4562–4567 (2005)

    Article  CAS  Google Scholar 

  21. C.H. Huang, D. Mandelker, O. Schmidt-Kittler, Y. Samuels, V.E. Velculescu, K.W. Kinzler et al., The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science 318(5857), 1744–1748 (2007)

    Article  PubMed  CAS  Google Scholar 

  22. B. Markman, F. Atzori, J. Perez-Garcia, J. Tabernero, J. Baselga, Status of PI3K inhibition and biomarker development in cancer therapeutics. Ann. Oncol. 21(4), 683–691 (2009)

    Article  PubMed  Google Scholar 

  23. M. Barbareschi, F. Buttitta, L. Felicioni, S. Cotrupi, F. Barassi, M. Del Grammastro et al., Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin. Canc. Res. 13(20), 6064–6069 (2007)

    Article  CAS  Google Scholar 

  24. M. Miyaki, T. Iijima, T. Yamaguchi, K. Takahashi, H. Matsumoto, M. Yasutome et al., Mutations of the PIK3CA gene in hereditary colorectal cancers. Int. J. Canc. 121(7), 1627–1630 (2007)

    Article  CAS  Google Scholar 

  25. S. Kato, S. Iida, T. Higuchi, T. Ishikawa, Y. Takagi, M. Yasuno et al., PIK3CA mutation is predictive of poor survival in patients with colorectal cancer. Int. J. Canc. 121(8), 1771–1778 (2007)

    Article  CAS  Google Scholar 

  26. H. Prenen, J. De Schutter, B. Jacobs, W. De Roock, B. Biesmans, B. Claes et al., PIK3CA mutations are not a major determinant of resistance to the epidermal growth factor receptor inhibitor cetuximab in metastatic colorectal cancer. Clin. Canc. Res. 15(9), 3184–3188 (2009)

    Article  CAS  Google Scholar 

  27. C.D. Hurst, T.C. Zuiverloon, C. Hafner, E.C. Zwarthoff, M.A. Knowles, A SNaPshot assay for the rapid and simple detection of four common hotspot codon mutations in the PIK3CA gene. BMC Res. Notes 2, 66 (2009)

    Article  PubMed  Google Scholar 

  28. C. Chaussade, K. Cho, C. Mawson, G.W. Rewcastle, P.R. Shepherd, Functional differences between two classes of oncogenic mutation in the PIK3CA gene. Biochem. Biophys. Res. Commun. 381(4), 577–581 (2009)

    Article  PubMed  CAS  Google Scholar 

  29. Y.L. Lai, B.L. Mau, W.H. Cheng, H.M. Chen, H.H. Chiu, C.Y. Tzen, PIK3CA exon 20 mutation is independently associated with a poor prognosis in breast cancer patients. Ann. Surg. Oncol. 15(4), 1064–1069 (2008)

    Article  PubMed  Google Scholar 

  30. H. Pang, R. Flinn, A. Patsialou, J. Wyckoff, E.T. Roussos, H. Wu et al., Differential enhancement of breast cancer cell motility and metastasis by helical and kinase domain mutations of class IA phosphoinositide 3-kinase. Canc. Res. 69(23), 8868–8876 (2009)

    Article  CAS  Google Scholar 

  31. L. Zhao, P.K. Vogt, Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc. Natl. Acad. Sci. U. S. A. 105(7), 2652–2657 (2008)

    Article  PubMed  CAS  Google Scholar 

  32. N. Miled, Y. Yan, W.C. Hon, O. Perisic, M. Zvelebil, Y. Inbar et al., Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science 317(5835), 239–242 (2007)

    Article  PubMed  CAS  Google Scholar 

  33. V. Lemmens, L. van Steenbergen, M. Janssen-Heijnen, H. Martijn, H. Rutten, J.W. Coebergh, Trends in colorectal cancer in the south of the Netherlands 1975–2007: rectal cancer survival levels with colon cancer survival. Acta Oncol. 49(6), 784–796 (2010)

    Article  PubMed  Google Scholar 

  34. L.N. van Steenbergen, M.A. Elferink, P. Krijnen, V.E. Lemmens, S. Siesling, H.J. Rutten et al., Improved survival of colon cancer due to improved treatment and detection: a nationwide population-based study in The Netherlands 1989–2006. Ann. Oncol. 21(11), 2206–2212 (2010)

    Article  PubMed  Google Scholar 

  35. W. De Roock, B. Claes, D. Bernasconi, J. De Schutter, B. Biesmans, G. Fountzilas et al., Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 11(8), 753–762 (2010)

    Article  PubMed  Google Scholar 

  36. S.M. Johnson, P. Gulhati, B.A. Rampy, Y. Han, P.G. Rychahou, H.Q. Doan et al., Novel expression patterns of PI3K/Akt/mTOR signaling pathway components in colorectal cancer. J. Am. Coll. Surg. 210(5), 776–778 (2010)

    Article  Google Scholar 

  37. H.C. Kwon, S.H. Kim, M.S. Roh, J.S. Kim, H.S. Lee, H.J. Choi et al., Gene expression profiling in lymph node-positive and lymph node-negative colorectal cancer. Dis. Colon. Rectum 47(2), 141–152 (2004)

    Article  PubMed  Google Scholar 

  38. N.T. Ihle, G. Powis, Inhibitors of phosphatidylinositol-3-kinase in cancer therapy. Mol. Aspects Med. 31(2), 135–144 (2010)

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. PAMM Laboratory for Pathology, Eindhoven, the Netherlands

    Arantza Fariña Sarasqueta, Gesina van Lijnschoten & A. J. C. van den Brule

  2. Department of Surgery, Leiden University Medical Centre, Leiden, the Netherlands

    Eliane C. M. Zeestraten, Jan Willem T. Dekker, Peter J. K. Kuppen, Ines J. Goossens-Beumer & Cornelis J. H. van de Velde

  3. Department of Pathology, Leiden University Medical Centre, Leiden, the Netherlands

    Tom van Wezel, Ronald van Eijk & Hans Morreau

  4. Comprehensive Cancer Centre South, Eindhoven, the Netherlands

    Valery E. P. P. Lemmens

  5. Department of Surgery, Catharina Hospital, Eindhoven, the Netherlands

    Harm J. T. Rutten

  6. Fontys University of Applied Sciences, Eindhoven, the Netherlands

    Arantza Fariña Sarasqueta

  7. Department of Molecular Diagnostics, Jeroen Bosch Hospital, P.O. Box 90153, 5200 ME s’, Hertogenbosch, The Netherlands

    A. J. C. van den Brule

Authors
  1. Arantza Fariña Sarasqueta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eliane C. M. Zeestraten
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tom van Wezel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gesina van Lijnschoten
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ronald van Eijk
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jan Willem T. Dekker
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peter J. K. Kuppen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ines J. Goossens-Beumer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Valery E. P. P. Lemmens
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Cornelis J. H. van de Velde
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Harm J. T. Rutten
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hans Morreau
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. A. J. C. van den Brule
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A. J. C. van den Brule.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Figure

(DOC 77 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fariña Sarasqueta, A., Zeestraten, E.C.M., van Wezel, T. et al. PIK3CA kinase domain mutation identifies a subgroup of stage III colon cancer patients with poor prognosis. Cell Oncol. 34, 523–531 (2011). https://doi.org/10.1007/s13402-011-0054-4

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13402-011-0054-4

Keywords

Search

Navigation