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PIK3CA alterations in primary (de novo) and secondary glioblastomas

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Abstract

We assessed alterations in the EGFR/PTEN/PI3K pathway in 107 primary (de novo) glioblastomas and 32 secondary glioblastomas that progressed from low-grade or anaplastic astrocytomas. SSCP followed by DNA sequencing in exons 9 and 20 of the PIK3CA gene revealed missense mutations in 5/107 (5%) primary and 1/32 (3%) secondary glioblastomas. Quantitative real-time PCR showed PIK3CA amplification (>3 copy numbers) in 14/107 (13%) primary and 3/32 (9%) secondary glioblastomas. Only one glioblastoma showed both PIK3CA mutation and amplification. Taken together with previously published data on EGFR amplification and PTEN mutations, at least one alteration in the EGFR, PTEN, or PIK3CA genes was detected in 63% of primary glioblastomas, which was significantly more frequent than in secondary glioblastomas (31%; P < 0.001). Furthermore, this signaling pathway was altered by either PTEN mutations or PIK3CA amplification in 10 of 12 (83%) malignant glioma cell lines analyzed. These results suggest that the EGFR/PTEN/PI3K pathway is frequently altered in glioblastomas and is a promising target for therapy, in particular for primary glioblastomas.

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References

  1. Bader AG, Kang S, Zhao L, Vogt PK (2005) Oncogenic PI3K deregulates transcription and translation. Nat Rev Cancer 5:921–929

    Article  PubMed  CAS  Google Scholar 

  2. Batchelor TT, Betensky RA, Esposito JM, Pham LD, Dorfman MV, Piscatelli N, Jhung S, Rhee D, Louis DN (2004) Age-dependent prognostic effects of genetic alterations in glioblastoma. Clin Cancer Res 10:228–233

    Article  PubMed  CAS  Google Scholar 

  3. Berggren P, Kumar R, Sakano S, Hemminki L, Wada T, Steineck G, Adolfsson J, Larsson P, Norming U, Wijkstrom H, Hemminki K (2003) Detecting homozygous deletions in the CDKN2A(p16(INK4a))/ARF(p14(ARF)) gene in urinary bladder cancer using real-time quantitative PCR. Clin Cancer Res 9:235–242

    PubMed  CAS  Google Scholar 

  4. Bertelsen BI, Steine SJ, Sandvei R, Molven A, Laerum OD (2006) Molecular analysis of the PI3K-AKT pathway in uterine cervical neoplasia: frequent PIK3CA amplification and AKT phosphorylation. Int J Cancer 118:1877–1883

    Article  PubMed  CAS  Google Scholar 

  5. Biernat W, Huang H, Yokoo H, Kleihues P, Ohgaki H (2004) Predominant expression of mutant EGFR (EGFRvIII) is rare in primary glioblastomas. Brain Pathol 14:131–136

    Article  PubMed  CAS  Google Scholar 

  6. Broderick DK, Di C, Parrett TJ, Samuels YR, Cummins JM, McLendon RE, Fults DW, Velculescu VE, Bigner DD, Yan H (2004) Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas. Cancer Res 64:5048–5050

    Article  PubMed  CAS  Google Scholar 

  7. Byun DS, Cho K, Ryu BK, Lee MG, Park JI, Chae KS, Kim HJ, Chi SG (2003) Frequent monoallelic deletion of PTEN and its reciprocal association with PIK3CA amplification in gastric carcinoma. Int J Cancer 104:318–327

    Article  PubMed  CAS  Google Scholar 

  8. Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296:1655–1657

    Article  PubMed  CAS  Google Scholar 

  9. Collins VP (2004) Brain tumours: classification and genes. J Neurol Neurosurg Psychiatry 75(Suppl 2):ii2–11

    Google Scholar 

  10. Dresemann G (2005) Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: a patient series. Ann Oncol 16:1702–1708

    Article  PubMed  CAS  Google Scholar 

  11. Haas-Kogan DA, Prados MD, Tihan T, Eberhard DA, Jelluma N, Arvold ND, Baumber R, Lamborn KR, Kapadia A, Malec M, Berger MS, Stokoe D (2005) Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. J Natl Cancer Inst 97:880–887

    Article  PubMed  CAS  Google Scholar 

  12. Hartmann C, Bartels G, Gehlhaar C, Holtkamp N, von Deimling A (2005) PIK3CA mutations in glioblastoma multiforme. Acta Neuropathol (Berl) 109:639–642

    Article  CAS  Google Scholar 

  13. Hill C, Hunter SB, Brat DJ (2003) Genetic markers in glioblastoma: prognostic significance and future therapeutic implications. Adv Anat Pathol 10:212–217

    Article  PubMed  CAS  Google Scholar 

  14. Hui AB, Lo KW, Yin XL, Poon WS, Ng HK (2001) Detection of multiple gene amplifications in glioblastoma multiforme using array-based comparative genomic hybridization. Lab Invest 81:717–723

    PubMed  CAS  Google Scholar 

  15. Ichimura K, Ohgaki H, Kleihues P, Collins VP (2004) Molecular pathogenesis of astrocytic tumours. J Neurooncol 70:137–160

    Article  PubMed  Google Scholar 

  16. Ishii N, Maier D, Merlo A, Tada M, Sawamura Y, Diserens AC, Van Meir EG (1999) Frequent co-alterations of TP53, p16/CDKN2A, p14ARF, PTEN tumor suppressor genes in human glioma cell lines. Brain Pathol 9:469–479

    Article  PubMed  CAS  Google Scholar 

  17. Karakas B, Bachman KE, Park BH (2006) Mutation of the PIK3CA oncogene in human cancers. Br J Cancer 94:455–459

    Article  PubMed  CAS  Google Scholar 

  18. Knobbe CB, Reifenberger G (2003) Genetic alterations and aberrant expression of genes related to the phosphatidyl-inositol-3′-kinase/protein kinase B (Akt) signal transduction pathway in glioblastomas. Brain Pathol 13:507–518

    Article  PubMed  CAS  Google Scholar 

  19. Knobbe CB, Trampe-Kieslich A, Reifenberger G (2005) Genetic alteration and expression of the phosphoinositol-3-kinase/Akt pathway genes PIK3CA and PIKE in human glioblastomas. Neuropathol Appl Neurobiol 31:486–490

    Article  PubMed  CAS  Google Scholar 

  20. Ma YY, Wei SJ, Lin YC, Lung JC, Chang TC, Whang-Peng J, Liu JM, Yang DM, Yang WK, Shen CY (2000) PIK3CA as an oncogene in cervical cancer. Oncogene 19:2739–2744

    Article  PubMed  CAS  Google Scholar 

  21. Maehama T, Dixon JE (1998) The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273:13375–13378

    Article  PubMed  CAS  Google Scholar 

  22. Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ, Lu KV, Yoshimoto K, Huang JH, Chute DJ, Riggs BL, Horvath S, Liau LM, Cavenee WK, Rao PN, Beroukhim R, Peck TC, Lee JC, Sellers WR, Stokoe D, Prados M, Cloughesy TF, Sawyers CL, Mischel PS (2005) Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353:2012–2024

    Article  PubMed  CAS  Google Scholar 

  23. Mizoguchi M, Nutt CL, Mohapatra G, Louis DN (2004) Genetic alterations of phosphoinositide 3-kinase subunit genes in human glioblastomas. Brain Pathol 14:372–377

    Article  PubMed  CAS  Google Scholar 

  24. Mohapatra G, Bollen AW, Kim DH, Lamborn K, Moore DH, Prados MD, Feuerstein BG (1998) Genetic analysis of glioblastoma multiforme provides evidence for subgroups within the grade. Genes Chromosomes Cancer 21:195–206

    Article  PubMed  CAS  Google Scholar 

  25. Mueller W, Mizoguchi M, Silen E, D’Amore K, Nutt CL, Louis DN (2005) Mutations of the PIK3CA gene are rare in human glioblastoma. Acta Neuropathol (Berl) 109:654–655

    Article  Google Scholar 

  26. Myers MP, Stolarov JP, Eng C, Li J, Wang SI, Wigler MH, Parsons R, Tonks NK (1997) P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci USA 94:9052–9057

    Article  PubMed  CAS  Google Scholar 

  27. Nigro JM, Takahashi MA, Ginzinger DG, Law M, Passe S, Jenkins RB, Aldape K (2001) Detection of 1p and 19q loss in oligodendroglioma by quantitative microsatellite analysis, a real-time quantitative polymerase chain reaction assay. Am J Pathol 158:1253–1262

    PubMed  CAS  Google Scholar 

  28. Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, Burkhard C, Schuler D, Probst-Hensch NM, Maiorka PC, Baeza N, Pisani P, Yonekawa Y, Yasargil MG, Lutolf UM, Kleihues P (2004) Genetic pathways to glioblastoma: a population-based study. Cancer Res 64:6892–6899

    Article  PubMed  CAS  Google Scholar 

  29. Ohgaki H, Kleihues P (2005) Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 64:479–489

    PubMed  CAS  Google Scholar 

  30. Pedrero JM, Carracedo DG, Pinto CM, Zapatero AH, Rodrigo JP, Nieto CS, Gonzalez MV (2005) Frequent genetic and biochemical alterations of the PI 3-K/AKT/PTEN pathway in head and neck squamous cell carcinoma. Int J Cancer 114:242–248

    Article  PubMed  CAS  Google Scholar 

  31. Reardon DA, Egorin MJ, Quinn JA, Rich JN, Gururangan S, Vredenburgh JJ, Desjardins A, Sathornsumetee S, Provenzale JM, Herndon JE, Dowell JM, Badruddoja MA, McLendon RE, Lagattuta TF, Kicielinski KP, Dresemann G, Sampson JH, Friedman AH, Salvado AJ, Friedman HS (2005) Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme. J Clin Oncol 23:9359–9368

    Article  PubMed  CAS  Google Scholar 

  32. Rich JN, Reardon DA, Peery T, Dowell JM, Quinn JA, Penne KL, Wikstrand CJ, Van Duyn LB, Dancey JE, McLendon RE, Kao JC, Stenzel TT, Ahmed Rasheed BK, Tourt-Uhlig SE, Herndon JE, Vredenburgh JJ, Sampson JH, Friedman AH, Bigner DD, Friedman HS (2004) Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 22:133–142

    Article  PubMed  CAS  Google Scholar 

  33. Roth W, Fontana A, Trepel M, Reed JC, Dichgans J, Weller M (1997) Immunochemotherapy of malignant glioma: synergistic activity of CD95 ligand and chemotherapeutics. Cancer Immunol Immunother 44:55–63

    Article  PubMed  CAS  Google Scholar 

  34. Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, Yu JS, Malmstrom PO, Mansukhani M, Enoksson J, Hibshoosh H, Borg A, Parsons R (2005) PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res 65:2554–2559

    Article  PubMed  CAS  Google Scholar 

  35. Sambrook J et al. (eds) (1989) Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory Press, New York

  36. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304:554

    Article  PubMed  CAS  Google Scholar 

  37. Shayesteh L, Lu Y, Kuo WL, Baldocchi R, Godfrey T, Collins C, Pinkel D, Powell B, Mills GB, Gray JW (1999) PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet 21:99–102

    Article  PubMed  CAS  Google Scholar 

  38. Singh B, Reddy PG, Goberdhan A, Walsh C, Dao S, Ngai I, Chou TC, Charoenrat P, Levine AJ, Rao PH, Stoffel A (2002) p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomas. Genes Dev 16:984–993

    Article  PubMed  CAS  Google Scholar 

  39. Stewart LA (2002) Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 359:1011–1018

    Article  PubMed  CAS  Google Scholar 

  40. Tamura M, Gu J, Matsumoto K, Aota S, Parsons R, Yamada KM (1998) Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science 280:1614–1617

    Article  PubMed  CAS  Google Scholar 

  41. Tohma Y, Gratas C, Biernat W, Peraud A, Fukuda M, Yonekawa Y, Kleihues P, Ohgaki H (1998) PTEN (MMAC1) mutations are frequent in primary glioblastomas (de novo) but not in secondary glioblastomas. J Neuropathol Exp Neurol 57:684–689

    PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Dr. Ole Laerum for kindly providing the DNA sample of OVCAR-3 cells with PIK3CA amplification. We thank Mrs Anne-Marie Camus for technical assistance. This work was supported by grants from the Foundation of Promotion of Cancer Research, Sumitomo Life Social Welfare Services Foundation, The Cell Science Research Foundation, and Hokkoku Cancer Foundation, Japan.

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Authors and Affiliations

  1. International Agency for Research on Cancer, 150 cours Albert Thomas, 69372, Lyon Cedex 08, France

    Daisuke Kita & Hiroko Ohgaki

  2. Department of Neurosurgery, University Hospital Zurich, 8091, Zurich, Switzerland

    Yasuhiro Yonekawa

  3. Department of Neurology, University of Tubingen Medical School, Tübingen, Germany

    Michael Weller

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  1. Daisuke Kita
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  2. Yasuhiro Yonekawa
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  4. Hiroko Ohgaki
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Correspondence to Hiroko Ohgaki.

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Kita, D., Yonekawa, Y., Weller, M. et al. PIK3CA alterations in primary (de novo) and secondary glioblastomas. Acta Neuropathol 113, 295–302 (2007). https://doi.org/10.1007/s00401-006-0186-1

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  • DOI: https://doi.org/10.1007/s00401-006-0186-1

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