Oncogenic Mutations of PIK3CA in Human Cancers

Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 347)

Abstract

The involvement of the PIK3CA gene product p110α, the catalytic subunit of phosphatidylinositol 3-kinase (PI3K), in human cancer has been suggested for over 15 years, and support for this proposal had been provided by both genetic and functional studies, including most recently the discovery of common activating missense mutations of PIK3CA in a wide variety of common human tumor types. This chapter will focus on the discovery of these mutations and describes their relevance to a wide range of common human tumor types.

Of note, the identification and functional analysis of the PIK3CA gene are reviewed in other chapters in this book. However, a brief mention will be made here of its general properties as background to our focus on the discovery of its cancer-specific mutations.

Keywords

Endometrial Cancer Esophageal Squamous Cell Carcinoma Papillary Thyroid Carcinoma PI3K Pathway PIK3CA Mutation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Abubaker J, Bavi PP, Al-Harbi S, Siraj AK, Al-Dayel F, Uddin S, Al-Kuraya K (2007) PIK3CA mutations are mutually exclusive with PTEN loss in diffuse large B-cell lymphoma. Leukemia 21:2368–2370PubMedGoogle Scholar
  2. Abubaker J, Bavi P, Al-Harbi S, Ibrahim M, Siraj AK, Al-Sanea N, Abduljabbar A, Ashari LH, Alhomoud S, Al-Dayel F et al (2008a) Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population. Oncogene 27:3539–3545PubMedGoogle Scholar
  3. Abubaker J, Jehan Z, Bavi P, Sultana M, Al-Harbi S, Ibrahim M, Al-Nuaim A, Ahmed M, Amin T, Al-Fehaily M et al (2008b) Clinicopathological analysis of papillary thyroid cancer with PIK3CA alterations in a Middle Eastern population. J Clin Endocrinol Metab 93:611–618PubMedGoogle Scholar
  4. Actor B, Cobbers JM, Buschges R, Wolter M, Knobbe CB, Lichter P, Reifenberger G, Weber RG (2002) Comprehensive analysis of genomic alterations in gliosarcoma and its two tissue components. Genes Chromosomes Cancer 34:416–427PubMedGoogle Scholar
  5. Akagi I, Miyashita M, Makino H, Nomura T, Hagiwara N, Takahashi K, Cho K, Mishima T, Ishibashi O, Ushijima T et al (2009) Overexpression of PIK3CA is associated with lymph node metastasis in esophageal squamous cell carcinoma. Int J Oncol 34:767–775PubMedGoogle Scholar
  6. Andersson P, Kolaric A, Windahl T, Kirrander P, Soderkvist P, Karlsson MG (2008) PIK3CA, HRAS and KRAS gene mutations in human penile cancer. J Urol 179:2030–2034PubMedGoogle Scholar
  7. Bachman KE, Argani P, Samuels Y, Silliman N, Ptak J, Szabo S, Konishi H, Karakas B, Blair BG, Lin C et al (2004) The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 3:772–775PubMedGoogle Scholar
  8. Bader AG, Kang S, Vogt PK (2006) Cancer-specific mutations in PIK3CA are oncogenic in vivo. Proc Natl Acad Sci USA 103:1475–1479PubMedGoogle Scholar
  9. Barault L, Veyrie N, Jooste V, Lecorre D, Chapusot C, Ferraz JM, Lievre A, Cortet M, Bouvier AM, Rat P et al (2008) 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 Cancer 122:2255–2259PubMedGoogle Scholar
  10. Barbareschi M, Buttitta F, Felicioni L, Cotrupi S, Barassi F, Del Grammastro M, Ferro A, Dalla Palma P, Galligioni E, Marchetti A (2007) Different prognostic roles of mutations in the helical and kinase domains of the PIK3CA gene in breast carcinomas. Clin Cancer Res 13:6064–6069PubMedGoogle Scholar
  11. Bardelli A, Parsons DW, Silliman N, Ptak J, Szabo S, Saha S, Markowitz S, Willson JK, Parmigiani G, Kinzler KW et al (2003) Mutational analysis of the tyrosine kinome in colorectal cancers. Science 300:949PubMedGoogle Scholar
  12. Barr FG, Galili N, Holick J, Biegel JA, Rovera G, Emanuel BS (1993) Rearrangement of the PAX3 paired box gene in the paediatric solid tumour alveolar rhabdomyosarcoma. Nat Genet 3:113–117PubMedGoogle Scholar
  13. Bastian BC, LeBoit PE, Hamm H, Brocker EB, Pinkel D (1998) Chromosomal gains and losses in primary cutaneous melanomas detected by comparative genomic hybridization. Cancer Res 58:2170–2175PubMedGoogle Scholar
  14. Bellacosa A, Testa JR, Staal SP, Tsichlis PN (1991) A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region. Science 254:274–277PubMedGoogle Scholar
  15. Bellacosa A, de Feo D, Godwin AK, Bell DW, Cheng JQ, Altomare DA, Wan M, Dubeau L, Scambia G, Masciullo V et al (1995) Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer 64:280–285PubMedGoogle Scholar
  16. Benvenuti S, Frattini M, Arena S, Zanon C, Cappelletti V, Coradini D, Daidone MG, Pilotti S, Pierotti MA, Bardelli A (2008) PIK3CA cancer mutations display gender and tissue specificity patterns. Hum Mutat 29:284–288PubMedGoogle Scholar
  17. Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M et al (2007) A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12:395–402PubMedGoogle Scholar
  18. Birck A, Ahrenkiel V, Zeuthen J, Hou-Jensen K, Guldberg P (2000) Mutation and allelic loss of the PTEN/MMAC1 gene in primary and metastatic melanoma biopsies. J Invest Dermatol 114:277–280PubMedGoogle Scholar
  19. Bleeker FE, Felicioni L, Buttitta F, Lamba S, Cardone L, Rodolfo M, Scarpa A, Leenstra S, Frattini M, Barbareschi M et al (2008) AKT1(E17K) in human solid tumours. Oncogene 27:5648–5650Google Scholar
  20. Board RE, Thelwell NJ, Ravetto PF, Little S, Ranson M, Dive C, Hughes A, Whitcombe D (2008) Multiplexed assays for detection of mutations in PIK3CA. Clin Chem 54:757–760PubMedGoogle Scholar
  21. Bos JL, Fearon ER, Hamilton SR, Verlaan-de Vries M, van Boom JH, van der Eb AJ, Vogelstein B (1987) Prevalence of ras gene mutations in human colorectal cancers. Nature 327:293–297PubMedGoogle Scholar
  22. 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 64:5048–5050PubMedGoogle Scholar
  23. Buttitta F, Felicioni L, Barassi F, Martella C, Paolizzi D, Fresu G, Salvatore S, Cuccurullo F, Mezzetti A, Campani D, Marchetti A (2006) PIK3CA mutation and histological type in breast carcinoma: high frequency of mutations in lobular carcinoma. J Pathol 208:350–355PubMedGoogle Scholar
  24. 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 associatioin with PIK3CA amplification in gastric carcinoma. Int J Cancer 104:318–327PubMedGoogle Scholar
  25. Campbell IG, Russell SE, Choong DY, Montgomery KG, Ciavarella ML, Hooi CS, Cristiano BE, Pearson RB, Phillips WA (2004) Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res 64:7678–7681PubMedGoogle Scholar
  26. Cancer Genome Atlas Research Network (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068Google Scholar
  27. Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296:1655–1657PubMedGoogle Scholar
  28. Cantley LC, Auger KR, Carpenter C, Duckworth B, Graziani A, Kapeller R, Soltoff S (1991) Oncogenes and signal transduction. Cell 64:281–302PubMedGoogle Scholar
  29. Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM, Hostetter G, Boguslawski S, Moses TY, Savage S et al (2007) A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448:439–444PubMedGoogle Scholar
  30. Catasus L, Gallardo A, Cuatrecasas M, Prat J (2008) PIK3CA mutations in the kinase domain (exon 20) of uterine endometrial adenocarcinomas are associated with adverse prognostic parameters. Mod Pathol 21:131–139PubMedGoogle Scholar
  31. Chang HW, Aoki M, Fruman D, Auger KR, Bellacosa A, Tsichlis PN, Cantley LC, Roberts TM, Vogt PK (1997) Transformation of chicken cells by the gene encoding the catalytic subunit of PI 3-kinase. Science 276:1848–1850PubMedGoogle Scholar
  32. Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, Koutcher JA, Scher HI, Ludwig T, Gerald W et al (2005) Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436:725–730PubMedGoogle Scholar
  33. Cheng JQ, Godwin AK, Bellacosa A, Taguchi T, Franke TF, Hamilton TC, Tsichlis PN, Testa JR (1992) AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas. Proc Natl Acad Sci USA 89:9267–9271PubMedGoogle Scholar
  34. Cheng JQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK, Testa JR (1996) Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci USA 93:3636–3641PubMedGoogle Scholar
  35. Chou CC, Chou MJ, Tzen CY (2008) PIK3CA mutation occurs in nasopharyngeal carcinoma but does not significantly influence the disease-specific survival. Med Oncol 26(3):322–326PubMedGoogle Scholar
  36. Chudnovsky Y, Khavari PA, Adams AE (2005) Melanoma genetics and the development of rational therapeutics. J Clin Invest 115:813–824PubMedGoogle Scholar
  37. Cui B, Zheng B, Zhang X, Stendahl U, Andersson S, Wallin KL (2009) Mutation of PIK3CA: possible risk factor for cervical carcinogenesis in older women. Int J Oncol 34:409–416PubMedGoogle Scholar
  38. Dam V, Morgan BT, Mazanek P, Hogarty MD (2006) Mutations in PIK3CA are infrequent in neuroblastoma. BMC Cancer 6:177PubMedGoogle Scholar
  39. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W et al (2002) Mutations of the BRAF gene in human cancer. Nature 417(6892):949–954PubMedGoogle Scholar
  40. Eichhorn PJ, Gili M, Scaltriti M, Serra V, Guzman M, Nijkamp W, Beijersbergen RL, Valero V, Seoane J, Bernards R, Baselga J (2008) Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 68:9221–9230PubMedGoogle Scholar
  41. Fenic I, Steger K, Gruber C, Arens C, Woenckhaus J (2007) Analysis of PIK3CA and Akt/protein kinase B in head and neck squamous cell carcinoma. Oncol Rep 18:253–259PubMedGoogle Scholar
  42. Gallia GL, Rand V, Siu IM, Eberhart CG, James CD, Marie SK, Oba-Shinjo SM, Carlotti CG, Caballero OL, Simpson AJ et al (2006) PIK3CA gene mutations in pediatric and adult glioblastoma multiforme. Mol Cancer Res 4:709–714PubMedGoogle Scholar
  43. Garcia-Rostan G, Costa AM, Pereira-Castro I, Salvatore G, Hernandez R, Hermsem MJ, Herrero A, Fusco A, Cameselle-Teijeiro J, Santoro M (2005) Mutation of the PIK3CA gene in anaplastic thyroid cancer. Cancer Res 65:10199–10207PubMedGoogle Scholar
  44. Guldberg P, thor Straten P, Birck A, Ahrenkiel V, Kirkin AF, Zeuthen J (1997) Disruption of the MMAC1/PTEN gene by deletion or mutation is a frequent event in malignant melanoma. Cancer Res 57:3660–3663PubMedGoogle Scholar
  45. Hafner C, Lopez-Knowles E, Luis NM, Toll A, Baselga E, Fernandez-Casado A, Hernandez S, Ribe A, Mentzel T, Stoehr R et al (2007) Oncogenic PIK3CA mutations occur in epidermal nevi and seborrheic keratoses with a characteristic mutation pattern. Proc Natl Acad Sci USA 104:13450–13454PubMedGoogle Scholar
  46. Hafner C, Vogt T, Landthaler M, Musebeck J (2008) Somatic FGFR3 and PIK3CA mutations are present in familial seborrhoeic keratoses. Br J Dermatol 159:214–217PubMedGoogle Scholar
  47. Hafner C, Stoehr R, van Oers JM, Zwarthoff EC, Hofstaedter F, Landthaler M, Hartmann A, Vogt T (2009) FGFR3 and PIK3CA mutations are involved in the molecular pathogenesis of solar lentigo. Br J Dermatol 160:546–551PubMedGoogle Scholar
  48. Hartmann C, Bartels G, Gehlhaar C, Holtkamp N, von Deimling A (2005) PIK3CA mutations in glioblastoma multiforme. Acta Neuropathol 109:639–642PubMedGoogle Scholar
  49. Hartmann C, Devermann L, Gehlhaar C, Holtkamp N, von Deimling A (2006) PIK3CA mutations in oligodendroglial tumours. Neuropathol Appl Neurobiol 32:209–212PubMedGoogle Scholar
  50. Hayes MP, Wang H, Espinal-Witter R, Douglas W, Solomon GJ, Baker SJ, Ellenson LH (2006) PIK3CA and PTEN mutations in uterine endometrioid carcinoma and complex atypical hyperplasia. Clin Cancer Res 12:5932–5935PubMedGoogle Scholar
  51. Hayes MP, Douglas W, Ellenson LH (2009) Molecular alterations of EGFR and PIK3CA in uterine serous carcinoma. Gynecol Oncol 113(3):370–373PubMedGoogle Scholar
  52. Hummerdal P, Andersson P, Willander K, Linderholm M, Soderkvist P, Jonsson JI (2006) Absence of hot spot mutations of the PIK3CA gene in acute myeloid leukaemia. Eur J Haematol 77:86–87PubMedGoogle Scholar
  53. Jen J, Powell SM, Papadopoulos N, Smith KJ, Hamilton SR, Vogelstein B, Kinzler KW (1994) Molecular determinants of dysplasia in colorectal lesions. Cancer Res 54:5523–5526PubMedGoogle Scholar
  54. Jhawer M, Goel S, Wilson AJ, Montagna C, Ling YH, Byun DS, Nasser S, Arango D, Shin J, Klampfer L et al (2008) PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res 68:1953–1961PubMedGoogle Scholar
  55. Jones S, Zhang X, Parsons DW, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Kamiyama H, Jimeno A et al (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321:1801–1806PubMedGoogle Scholar
  56. Kang S, Bader AG, Vogt PK (2005) Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci USA 102:802–807PubMedGoogle Scholar
  57. Kang S, Seo SS, Chang HJ, Yoo CW, Park SY, Dong SM (2008) Mutual exclusiveness between PIK3CA and KRAS mutations in endometrial carcinoma. Int J Gynecol Cancer 18:1339–1343PubMedGoogle Scholar
  58. Kato S, Iida S, Higuchi T, Ishikawa T, Takagi Y, Yasuno M, Enomoto M, Uetake H, Sugihara K (2007) PIK3CA mutation is predictive of poor survival in patients with colorectal cancer. Int J Cancer 121:1771–1778PubMedGoogle Scholar
  59. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD (2001) Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol 17:615–675PubMedGoogle Scholar
  60. Kawano O, Sasaki H, Endo K, Suzuki E, Haneda H, Yukiue H, Kobayashi Y, Yano M, Fujii Y (2006) PIK3CA mutation status in Japanese lung cancer patients. Lung Cancer 54:209–215PubMedGoogle Scholar
  61. Kawano O, Sasaki H, Okuda K, Yukiue H, Yokoyama T, Yano M, Fujii Y (2007) PIK3CA gene amplification in Japanese non-small cell lung cancer. Lung Cancer 58:159–160PubMedGoogle Scholar
  62. Kim JS, Lee C, Bonifant CL, Ressom H, Waldman T (2007) Activation of p53-dependent growth suppression in human cells by mutations in PTEN or PIK3CA. Mol Cell Biol 27:662–677PubMedGoogle Scholar
  63. Kita D, Yonekawa Y, Weller M, Ohgaki H (2007) PIK3CA alterations in primary (de novo) and secondary glioblastomas. Acta Neuropathol 113:295–302PubMedGoogle Scholar
  64. 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 13:507–518PubMedGoogle Scholar
  65. 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 31:486–490PubMedGoogle Scholar
  66. Kolasa IK, Rembiszewska A, Felisiak A, Ziolkowska-Seta I, Murawska M, Moes J, Timorek A, Dansonka-Mieszkowska A, Kupryjanczyk J (2009) PIK3CA amplification associates with resistance to chemotherapy in ovarian cancer patients. Cancer Biol Ther 8:21–26PubMedGoogle Scholar
  67. Kozaki K, Imoto I, Pimkhaokham A, Hasegawa S, Tsuda H, Omura K, Inazawa J (2006) PIK3CA mutation is an oncogenic aberration at advanced stages of oral squamous cell carcinoma. Cancer Sci 97:1351–1358PubMedGoogle Scholar
  68. Lai YL, Mau BL, Cheng WH, Chen HM, Chiu HH, Tzen CY (2008) PIK3CA exon 20 mutation is independently associated with a poor prognosis in breast cancer patients. Ann Surg Oncol 15:1064–1069PubMedGoogle Scholar
  69. Lee JW, Soung YH, Kim SY, Lee HW, Park WS, Nam SW, Kim SH, Lee JY, Yoo NJ, Lee SH (2005) PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene 24:1477–1480PubMedGoogle Scholar
  70. Lerma E, Catasus L, Gallardo A, Peiro G, Alonso C, Aranda I, Barnadas A, Prat J (2008) Exon 20 PIK3CA mutations decreases survival in aggressive (HER-2 positive) breast carcinomas. Virchows Arch 453:133–139PubMedGoogle Scholar
  71. Levine DA, Bogomolniy F, Yee CJ, Lash A, Barakat RR, Borgen PI, Boyd J (2005) Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin Cancer Res 11:2875–2878PubMedGoogle Scholar
  72. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R et al (1997) PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943–1947PubMedGoogle Scholar
  73. Li VS, Wong CW, Chan TL, Chan AS, Zhao W, Chu KM, So S, Chen X, Yuen ST, Leung SY (2005) Mutations of PIK3CA in gastric adenocarcinoma. BMC Cancer 5:29PubMedGoogle Scholar
  74. Li SY, Rong M, Grieu F, Iacopetta B (2006) PIK3CA mutations in breast cancer are associated with poor outcome. Breast Cancer Res Treat 96:91–95PubMedGoogle Scholar
  75. Liedtke C, Cardone L, Tordai A, Yan K, Gomez HL, Figureoa LJ, Hubbard RE, Valero V, Souchon EA, Symmans WF et al (2008) PIK3CA-activating mutations and chemotherapy sensitivity in stage II-III breast cancer. Breast Cancer Res 10:R27PubMedGoogle Scholar
  76. Lin Y, Jiang X, Shen Y, Li M, Ma H, Xing M, Lu Y (2009) Frequent mutations and amplifications of the PIK3CA gene in pituitary tumors. Endocr Relat Cancer 16:301–310PubMedGoogle Scholar
  77. Liu P, Li DJ, Qin HD, Zhang RH, Chen LZ, Zeng YX (2007) Screening for mutations in the hotspot mutation regions of PIK3CA gene in nasopharyngeal carcinoma. Ai Zheng 26:15–20PubMedGoogle Scholar
  78. Lopez-Knowles E, Hernandez S, Malats N, Kogevinas M, Lloreta J, Carrato A, Tardon A, Serra C, Real FX (2006) PIK3CA mutations are an early genetic alteration associated with FGFR3 mutations in superficial papillary bladder tumors. Cancer Res 66:7401–7404PubMedGoogle Scholar
  79. 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 19:2739–2744PubMedGoogle Scholar
  80. Maruyama N, Miyoshi Y, Taguchi T, Tamaki Y, Monden M, Noguchi S (2007) Clinicopathologic analysis of breast cancers with PIK3CA mutations in Japanese women. Clin Cancer Res 13:408–414PubMedGoogle Scholar
  81. Massion PP, Taflan PM, Shyr Y, Rahman SM, Yildiz P, Shakthour B, Edgerton ME, Ninan M, Andersen JJ, Gonzalez AL (2004) Early involvement of the phosphatidylinositol 3-kinase/Akt pathway in lung cancer progression. Am J Respir Crit Care Med 170:1088–1094PubMedGoogle Scholar
  82. Mikami M, Nosho K, Yamamoto H, Takahashi T, Maehata T, Taniguchi H, Adachi Y, Imamura A, Fujita M, Hosokawa M et al (2006) Mutational analysis of beta-catenin and the RAS-RAF signalling pathway in early flat-type colorectal tumours. Eur J Cancer 42:3065–3072PubMedGoogle Scholar
  83. Miyake T, Yoshino K, Enomoto T, Takata T, Ugaki H, Kim A, Fujiwara K, Miyatake T, Fujita M, Kimura T (2008) PIK3CA gene mutations and amplifications in uterine cancers, identified by methods that avoid confounding by PIK3CA pseudogene sequences. Cancer Lett 261:120–126PubMedGoogle Scholar
  84. Miyaki M, Iijima T, Yamaguchi T, Takahashi K, Matsumoto H, Yasutome M, Funata N, Mori T (2007) Mutations of the PIK3CA gene in hereditary colorectal cancers. Int J Cancer 121:1627–1630PubMedGoogle Scholar
  85. Mori R, Ishiguro H, Kimura M, Mitsui A, Sasaki H, Tomoda K, Mori Y, Ogawa R, Katada T, Kawano O et al (2008) PIK3CA mutation status in Japanese esophageal squamous cell carcinoma. J Surg Res 145:320–326PubMedGoogle Scholar
  86. Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW (1997) Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 275:1787–1790PubMedGoogle Scholar
  87. 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 109:654–655PubMedGoogle Scholar
  88. Muller CI, Miller CW, Hofmann WK, Gross ME, Walsh CS, Kawamata N, Luong QT, Koeffler HP (2007) Rare mutations of the PIK3CA gene in malignancies of the hematopoietic system as well as endometrium, ovary, prostate and osteosarcomas, and discovery of a PIK3CA pseudogene. Leuk Res 31:27–32PubMedGoogle Scholar
  89. Murugan AK, Hong NT, Fukui Y, Munirajan AK, Tsuchida N (2008) Oncogenic mutations of the PIK3CA gene in head and neck squamous cell carcinomas. Int J Oncol 32:101–111PubMedGoogle Scholar
  90. Nakayama K, Nakayama N, Kurman RJ, Cope L, Pohl G, Samuels Y, Velculescu VE, Wang TL, Shih Ie M (2006) Sequence mutations and amplification of PIK3CA and AKT2 genes in purified ovarian serous neoplasms. Cancer Biol Ther 5:779–785PubMedGoogle Scholar
  91. Oda K, Stokoe D, Taketani Y, McCormick F (2005) High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma. Cancer Res 65:10669–10673PubMedGoogle Scholar
  92. Ogino S, Nosho K, Kirkner GJ, Shima K, Irahara N, Kure S, Chan AT, Engelman JA, Kraft P, Cantley LC et al (2009) PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer. J Clin Oncol 27:1477–1484PubMedGoogle Scholar
  93. Okudela K, Suzuki M, Kageyama S, Bunai T, Nagura K, Igarashi H, Takamochi K, Suzuki K, Yamada T, Niwa H et al (2007) PIK3CA mutation and amplification in human lung cancer. Pathol Int 57:664–671PubMedGoogle Scholar
  94. Ollikainen M, Gylling A, Puputti M, Nupponen NN, Abdel-Rahman WM, Butzow R, Peltomaki P (2007) Patterns of PIK3CA alterations in familial colorectal and endometrial carcinoma. Int J Cancer 121:915–920PubMedGoogle Scholar
  95. Omholt K, Krockel D, Ringborg U, Hansson J (2006) Mutations of PIK3CA are rare in cutaneous melanoma. Melanoma Res 16:197–200PubMedGoogle Scholar
  96. Or YY, Hui AB, To KF, Lam CN, Lo KW (2006) PIK3CA mutations in nasopharyngeal carcinoma. Int J Cancer 118:1065–1067PubMedGoogle Scholar
  97. Page C, Huang M, Jin X, Cho K, Lilja J, Reynolds RK, Lin J (2000) Elevated phosphorylation of AKT and Stat3 in prostate, breast, and cervical cancer cells. Int J Oncol 17:23–28PubMedGoogle Scholar
  98. Pang JC, Chung NY, Chan NH, Poon WS, Thomas T, Ng HK (2006) Rare mutation of PIK3CA in meningiomas. Acta Neuropathol 111:284–285PubMedGoogle Scholar
  99. Parsons DW, Wang TL, Samuels Y, Bardelli A, Cummins JM, DeLong L, Silliman N, Ptak J, Szabo S, Willson JK et al (2005) Colorectal cancer: mutations in a signalling pathway. Nature 436:792PubMedGoogle Scholar
  100. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL et al (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812PubMedGoogle Scholar
  101. Perez-Tenorio G, Alkhori L, Olsson B, Waltersson MA, Nordenskjold B, Rutqvist LE, Skoog L, Stal O (2007) PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer. Clin Cancer Res 13:3577–3584PubMedGoogle Scholar
  102. Phillips WA, Russell SE, Ciavarella ML, Choong DY, Montgomery KG, Smith K, Pearson RB, Thomas RJ, Campbell IG (2006) Mutation analysis of PIK3CA and PIK3CB in esophageal cancer and Barrett’s esophagus. Int J Cancer 118:2644–2646PubMedGoogle Scholar
  103. Philp AJ, Campbell IG, Leet C, Vincan E, Rockman SP, Whitehead RH, Thomas RJ, Phillips WA (2001) The phosphatidylinositol 3′-kinase p85alpha gene is an oncogene in human ovarian and colon tumors. Cancer Res 61:7426–7429PubMedGoogle Scholar
  104. Qiu W, Schonleben F, Li X, Ho DJ, Close LG, Manolidis S, Bennett BP, Su GH (2006) PIK3CA mutations in head and neck squamous cell carcinoma. Clin Cancer Res 12:1441–1446PubMedGoogle Scholar
  105. Qiu W, Tong GX, Manolidis S, Close LG, Assaad AM, Su GH (2008) Novel mutant-enriched sequencing identified high frequency of PIK3CA mutations in pharyngeal cancer. Int J Cancer 122:1189–1194PubMedGoogle Scholar
  106. Rajagopalan H, Bardelli A, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE (2002) Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status. Nature 418:934PubMedGoogle Scholar
  107. Riener MO, Bawohl M, Clavien PA, Jochum W (2008) Rare PIK3CA hotspot mutations in carcinomas of the biliary tract. Genes Chromosomes Cancer 47:363–367PubMedGoogle Scholar
  108. Robertson GP, Furnari FB, Miele ME, Glendening MJ, Welch DR, Fountain JW, Lugo TG, Huang HJ, Cavenee WK (1998) In vitro loss of heterozygosity targets the PTEN/MMAC1 gene in melanoma. Proc Natl Acad Sci USA 95:9418–9423PubMedGoogle Scholar
  109. Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, Yu JS, Malmstrom PO, Mansukhani M, Enoksson J et al (2005) PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res 65:2554–2559PubMedGoogle Scholar
  110. Saal LH, Johansson P, Holm K, Gruvberger-Saal SK, She QB, Maurer M, Koujak S, Ferrando AA, Malmstrom P, Memeo L et al (2007) Poor prognosis in carcinoma is associated with a gene expression signature of aberrant PTEN tumor suppressor pathway activity. Proc Natl Acad Sci USA 104:7564–7569PubMedGoogle Scholar
  111. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ et al (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304:554PubMedGoogle Scholar
  112. Samuels Y, Diaz LA Jr, Schmidt-Kittler O, Cummins JM, Delong L, Cheong I, Rago C, Huso DL, Lengauer C, Kinzler KW et al (2005) Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7:561–573PubMedGoogle Scholar
  113. Santarpia L, El-Naggar AK, Cote GJ, Myers JN, Sherman SI (2008) Phosphatidylinositol 3-kinase/akt and ras/raf-mitogen-activated protein kinase pathway mutations in anaplastic thyroid cancer. J Clin Endocrinol Metab 93:278–284PubMedGoogle Scholar
  114. Sartore-Bianchi A, Martini M, Molinari F, Veronese S, Nichelatti M, Artale S, Di Nicolantonio F, Saletti P, De Dosso S, Mazzucchelli L et al (2009) PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res 69:1851–1857PubMedGoogle Scholar
  115. Schonleben F, Qiu W, Ciau NT, Ho DJ, Li X, Allendorf JD, Remotti HE, Su GH (2006) PIK3CA mutations in intraductal papillary mucinous neoplasm/carcinoma of the pancreas. Clin Cancer Res 12:3851–3855PubMedGoogle Scholar
  116. Sharma SV, Bell DW, Settleman J, Haber DA (2007) Epidermal growth factor receptor mutations in lung cancer. Nat Rev Cancer 7:169–181PubMedGoogle Scholar
  117. 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 21:99–102PubMedGoogle Scholar
  118. Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N et al (2006) The consensus coding sequences of human breast and colorectal cancers. Science 314:268–274PubMedGoogle Scholar
  119. Sparks AB, Morin PJ, Vogelstein B, Kinzler KW (1998) Mutational Analysis of the APC/b-catenin/Tcf Pathway in Colorectal Cancer. Cancer Res 58:1130–1134PubMedGoogle Scholar
  120. Staal SP (1987) Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. Proc Natl Acad Sci USA 84:5034–5037PubMedGoogle Scholar
  121. Stahl JM, Sharma A, Cheung M, Zimmerman M, Cheng JQ, Bosenberg MW, Kester M, Sandirasegarane L, Robertson GP (2004) Deregulated Akt3 activity promotes development of malignant melanoma. Cancer Res 64:7002–7010PubMedGoogle Scholar
  122. Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T et al (1997) Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15:356–362PubMedGoogle Scholar
  123. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, Neve RM, Kuo WL, Davies M, Carey M, Hu Z, Guan Y, Sahin A et al (2008) An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 68:6084–6091PubMedGoogle Scholar
  124. Stephens M, Sloan JS, Robertson PD, Scheet P, Nickerson DA (2006) Automating sequence-based detection and genotyping of SNPs from diploid samples. Nat Genet 38:375–381PubMedGoogle Scholar
  125. Tanaka Y, Kanai F, Tada M, Asaoka Y, Guleng B, Jazag A, Ohta M, Ikenoue T, Tateishi K, Obi S et al (2006) Absence of PIK3CA hotspot mutations in hepatocellular carcinoma in Japanese patients. Oncogene 25:2950–2952PubMedGoogle Scholar
  126. Thompson FH, Emerson J, Olson S, Weinstein R, Leavitt SA, Leong SP, Emerson S, Trent JM, Nelson MA, Salmon SE et al (1995) Cytogenetics of 158 patients with regional or disseminated melanoma. Subset analysis of near-diploid and simple karyotypes. Cancer Genet Cytogenet 83:93–104PubMedGoogle Scholar
  127. Tsao H, Zhang X, Benoit E, Haluska FG (1998) Identification of PTEN/MMAC1 alterations in uncultured melanomas and melanoma cell lines. Oncogene 16:3397–3402PubMedGoogle Scholar
  128. Vanhaesebroeck B, Waterfield MD (1999) Signaling by distinct classes of phosphoinositide 3-kinases. Exp Cell Res 253:239–254PubMedGoogle Scholar
  129. Velasco A, Bussaglia E, Pallares J, Dolcet X, Llobet D, Encinas M, Llecha N, Palacios J, Prat J, Matias-Guiu X (2006) PIK3CA gene mutations in endometrial carcinoma: correlation with PTEN and K-RAS alterations. Hum Pathol 37:1465–1472PubMedGoogle Scholar
  130. Velho S, Oliveira C, Ferreira A, Ferreira AC, Suriano G, Schwartz S Jr, Duval A, Carneiro F, Machado JC, Hamelin R, Seruca R (2005) The prevalence of PIK3CA mutations in gastric and colon cancer. Eur J Cancer 41:1649–1654PubMedGoogle Scholar
  131. Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2:489–501PubMedGoogle Scholar
  132. Wang Y, Helland A, Holm R, Kristensen GB, Borresen-Dale AL (2005) PIK3CA mutations in advanced ovarian carcinomas. Hum Mutat 25:322PubMedGoogle Scholar
  133. Wang Y, Hou P, Yu H, Wang W, Ji M, Zhao S, Yan S, Sun X, Liu D, Shi B et al (2007) High prevalence and mutual exclusivity of genetic alterations in the phosphatidylinositol-3-kinase/akt pathway in thyroid tumors. J Clin Endocrinol Metab 92:2387–2390PubMedGoogle Scholar
  134. Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J et al (2007) The genomic landscapes of human breast and colorectal cancers. Science 318(5853):1108–1113PubMedGoogle Scholar
  135. Wu G, Mambo E, Guo Z, Hu S, Huang X, Gollin SM, Trink B, Ladenson PW, Sidransky D, Xing M (2005a) Uncommon mutation, but common amplifications, of the PIK3CA gene in thyroid tumors. J Clin Endocrinol Metab 90:4688–4693PubMedGoogle Scholar
  136. Wu G, Xing M, Mambo E, Huang X, Liu J, Guo Z, Chatterjee A, Goldenberg D, Gollin SM, Sukumar S et al (2005b) Somatic mutation and gain of copy number of PIK3CA in human breast cancer. Breast Cancer Res 7:R609–R616PubMedGoogle Scholar
  137. Yamamoto H, Shigematsu H, Nomura M, Lockwood WW, Sato M, Okumura N, Soh J, Suzuki M, Wistuba II, Fong KM et al (2008) PIK3CA mutations and copy number gains in human lung cancers. Cancer Res 68:6913–6921PubMedGoogle Scholar
  138. Zhang L, Yang N, Katsaros D, Huang W, Park JW, Fracchioli S, Vezzani C, Rigault de la Longrais IA, Yao W, Rubin SC, Coukos G (2003) The oncogene phosphatidylinositol 3′-kinase catalytic subunit alpha promotes angiogenesis via vascular endothelial growth factor in ovarian carcinoma. Cancer Res 63:4225–4231PubMedGoogle Scholar
  139. Zhao L, Vogt PK (2008) Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc Natl Acad Sci USA 105:2652–2657PubMedGoogle Scholar
  140. Zhou XP, Gimm O, Hampel H, Niemann T, Walker MJ, Eng C (2000) Epigenetic PTEN silencing in malignant melanomas without PTEN mutation. Am J Pathol 157:1123–1128PubMedGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Cancer Genetics Branch, National Human Genome Research InstituteNational Institutes of HealthBethesdaUSA
  2. 2.Department of Oncology, Lombardi Comprehensive Cancer CenterGeorgetown University School of MedicineWashingtonUSA

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