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Published Online March 11, 2004
Science DOI: 10.1126/science.1096502

Brevia

Submitted on February 6, 2004
Accepted on February 27, 2004

High Frequency of Mutations of the PIK3CA Gene in Human Cancers

Yardena Samuels 1, Zhenghe Wang 1, Alberto Bardelli 1, Natalie Silliman 1, Janine Ptak 1, Steve Szabo 1, Hai Yan 2, Adi Gazdar 3, Steven M. Powell 4, Gregory J. Riggins 1, James K.V. Willson 5, Sanford Markowitz 5, Kenneth W. Kinzler 1, Bert Vogelstein 1, Victor E. Velculescu 1*

1 The Sidney Kimmel Comprehensive Cancer Center and The Howard Hughes Medical Institute, The Johns Hopkins University Medical Institutions, Baltimore, MD 21231, USA.
2 Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
3 Hamon Center for Therapeutic Oncology Research and Dept. of Pathology, UT Southwestern Medical Center, Dallas TX 75390, USA.
4 Division of Gastroenterology/Hepatology, UVA Health System, Charlottesville, VA 22908, USA.
5 Howard Hughes Medical Institute and Ireland Cancer Center, University Hospitals of Cleveland and Case Western University, Cleveland, OH 44106, USA.

* To whom correspondence should be addressed. E-mail: velculescu{at}jhmi.edu.

A gene coding for a well-known lipid kinase is frequently mutated in human tumors, offering a new target for cancer diagnosis and therapy.


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PIK3CA Mutation/PTEN Expression Status Predicts Response of Colon Cancer Cells to the Epidermal Growth Factor Receptor Inhibitor Cetuximab.
M. Jhawer, S. Goel, A. J. Wilson, C. Montagna, Y.-H. Ling, D.-S. Byun, S. Nasser, D. Arango, J. Shin, L. Klampfer, et al. (2008)
Cancer Res. 68, 1953-1961
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Conditional Deletion of Pten Causes Bronchiolar Hyperplasia.
V. Dave, S. E. Wert, T. Tanner, A. R. Thitoff, D. E. Loudy, and J. A. Whitsett (2008)
Am. J. Respir. Cell Mol. Biol. 38, 337-345
   Abstract »    Full Text »    PDF »
Helical domain and kinase domain mutations in p110{alpha} of phosphatidylinositol 3-kinase induce gain of function by different mechanisms.
L. Zhao and P. K. Vogt (2008)
PNAS 105, 2652-2657
   Abstract »    Full Text »    PDF »
Association between Phosphatidylinositol 3-Kinase Regulatory Subunit p85{alpha} Met326Ile Genetic Polymorphism and Colon Cancer Risk.
L. Li, S. J. Plummer, C. L. Thompson, T. C. Tucker, and G. Casey (2008)
Clin. Cancer Res. 14, 633-637
   Abstract »    Full Text »    PDF »
t-Darpp Promotes Cancer Cell Survival by Up-regulation of Bcl2 through Akt-Dependent Mechanism.
A. Belkhiri, A. A. Dar, A. Zaika, M. Kelley, and W. El-Rifai (2008)
Cancer Res. 68, 395-403
   Abstract »    Full Text »    PDF »
Phase I Pharmacokinetic/Pharmacodynamic Study of EKB-569, an Irreversible Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase, in Combination with Irinotecan, 5-Fluorouracil, and Leucovorin (FOLFIRI) in First-Line Treatment of Patients with Metastatic Colorectal Cancer.
G. Folprecht, J. Tabernero, C.-H. Kohne, C. Zacharchuk, L. Paz-Ares, F. Rojo, S. Quinn, E. Casado, R. Salazar, R. Abbas, et al. (2008)
Clin. Cancer Res. 14, 215-223
   Abstract »    Full Text »    PDF »
DNA Damage-Induced Acetylation of Lysine 3016 of ATM Activates ATM Kinase Activity.
Y. Sun, Y. Xu, K. Roy, and B. D. Price (2007)
Mol. Cell. Biol. 27, 8502-8509
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The Structure of a Human p110{alpha}/p85{alpha} Complex Elucidates the Effects of Oncogenic PI3K{alpha} Mutations.
C.-H. Huang, D. Mandelker, O. Schmidt-Kittler, Y. Samuels, V. E. Velculescu, K. W. Kinzler, B. Vogelstein, S. B. Gabelli, and L. M. Amzel (2007)
Science 318, 1744-1748
   Abstract »    Full Text »    PDF »
Targeting Protein Translation in Human Non Small Cell Lung Cancer via Combined MEK and Mammalian Target of Rapamycin Suppression.
M.-E. Legrier, C.-P. H. Yang, H.-G. Yan, L. Lopez-Barcons, S. M. Keller, R. Perez-Soler, S. B. Horwitz, and H. M. McDaid (2007)
Cancer Res. 67, 11300-11308
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Heterozygous disruption of the PTEN promotes intestinal neoplasia in APCmin/+ mouse: roles of osteopontin.
J. Shao, M.K. Washington, R. Saxena, and H. Sheng (2007)
Carcinogenesis 28, 2476-2483
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The Genomic Landscapes of Human Breast and Colorectal Cancers.
L. D. Wood, D. W. Parsons, S. Jones, J. Lin, T. Sjoblom, R. J. Leary, D. Shen, S. M. Boca, T. Barber, J. Ptak, et al. (2007)
Science 318, 1108-1113
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Common and Distinct Genomic Events in Sporadic Colorectal Cancer and Diverse Cancer Types.
E. S. Martin, G. Tonon, R. Sinha, Y. Xiao, B. Feng, A. C. Kimmelman, A. Protopopov, E. Ivanova, C. Brennan, K. Montgomery, et al. (2007)
Cancer Res. 67, 10736-10743
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Malignant astrocytic glioma: genetics, biology, and paths to treatment.
F. B. Furnari, T. Fenton, R. M. Bachoo, A. Mukasa, J. M. Stommel, A. Stegh, W. C. Hahn, K. L. Ligon, D. N. Louis, C. Brennan, et al. (2007)
Genes & Dev. 21, 2683-2710
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Progressive loss of epidermal growth factor receptor in a subpopulation of breast cancers: implications in target-directed therapeutics.
L.-Y. Choong, S. Lim, M. C.-S. Loh, X. Man, Y. Chen, W. Toy, M. Pan, C.-S. Chen, A. Poonepalli, M. P. Hande, et al. (2007)
Mol. Cancer Ther. 6, 2828-2842
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Phase I Study of Everolimus in Pediatric Patients With Refractory Solid Tumors.
M. Fouladi, F. Laningham, J. Wu, M. A. O'Shaughnessy, K. Molina, A. Broniscer, S. L. Spunt, I. Luckett, C. F. Stewart, P. J. Houghton, et al. (2007)
J. Clin. Oncol. 25, 4806-4812
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In vivo Functional Analysis of the Counterbalance of Hyperactive Phosphatidylinositol 3-Kinase p110 Catalytic Oncoproteins by the Tumor Suppressor PTEN.
A. Andres-Pons, I. Rodriguez-Escudero, A. Gil, A. Blanco, A. Vega, M. Molina, R. Pulido, and V. J. Cid (2007)
Cancer Res. 67, 9731-9739
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Different Prognostic Roles of Mutations in the Helical and Kinase Domains of the PIK3CA Gene in Breast Carcinomas.
M. Barbareschi, F. Buttitta, L. Felicioni, S. Cotrupi, F. Barassi, M. Del Grammastro, A. Ferro, P. Dalla Palma, E. Galligioni, and A. Marchetti (2007)
Clin. Cancer Res. 13, 6064-6069
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p66 Shc Tumor Levels Show a Strong Prognostic Correlation with Disease Outcome in Stage IIA Colon Cancer.
S. R. Grossman, S. Lyle, M. B. Resnick, E. Sabo, R. T. Lis, E. Rosinha, Q. Liu, C.-C. Hsieh, G. Bhat, A. R. Frackelton Jr., et al. (2007)
Clin. Cancer Res. 13, 5798-5804
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Suberoylanilide hydroxamic acid (SAHA; vorinostat) suppresses translation of cyclin D1 in mantle cell lymphoma cells.
N. Kawamata, J. Chen, and H. P. Koeffler (2007)
Blood 110, 2667-2673
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Integrative Genomic Analysis of Phosphatidylinositol 3'-Kinase Family Identifies PIK3R3 as a Potential Therapeutic Target in Epithelial Ovarian Cancer.
L. Zhang, J. Huang, N. Yang, J. Greshock, S. Liang, K. Hasegawa, A. Giannakakis, N. Poulos, A. O'Brien-Jenkins, D. Katsaros, et al. (2007)
Clin. Cancer Res. 13, 5314-5321
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The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures.
A. L. Howes, G. G. Chiang, E. S. Lang, C. B. Ho, G. Powis, K. Vuori, and R. T. Abraham (2007)
Mol. Cancer Ther. 6, 2505-2514
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Inhibition of Mammalian Target of Rapamycin Signaling by 2-(Morpholin-1-yl)pyrimido[2,1-{alpha}]isoquinolin-4-one.
L. M. Ballou, E. S. Selinger, J. Y. Choi, D. G. Drueckhammer, and R. Z. Lin (2007)
J. Biol. Chem. 282, 24463-24470
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Oncogenic PIK3CA mutations occur in epidermal nevi and seborrheic keratoses with a characteristic mutation pattern.
C. Hafner, E. Lopez-Knowles, N. M. Luis, A. Toll, E. Baselga, A. Fernandez-Casado, S. Hernandez, A. Ribe, T. Mentzel, R. Stoehr, et al. (2007)
PNAS 104, 13450-13454
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The Role of Phosphoinositide 3-Kinase Pathway Inhibitors in the Treatment of Lung Cancer.
J. A. Engelman (2007)
Clin. Cancer Res. 13, 4637s-4640s
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