Originally published as JCO Early Release 10.1200/JCO.2008.18.6544 on February 23 2009

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ogino, S. Articles by Fuchs, C. S. Search for Related Content PubMed PubMed Citation Articles by Ogino, S. Articles by Fuchs, C. S. Social Bookmarking                            What's this?

PIK3CA Mutation Is Associated With Poor Prognosis Among Patients With Curatively Resected Colon Cancer

From the Department of Medical Oncology, Dana-Farber Cancer Institute; Departments of Pathology and Medicine, Brigham and Women's Hospital and Harvard Medical School; Departments of Epidemiology and Biostatistics, Harvard School of Public Health; Channing Laboratory, Gastrointestinal Unit, Massachusetts General Hospital; Massachusetts General Hospital Cancer Center; and Department of Systems Biology, Beth Israel Deaconess Medical Center, Boston, MA.

Corresponding author: Shuji Ogino, MD, PhD, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, 44 Binney St, Room JF-215C, Boston, MA 02115 USA; e-mail: shuji_ogino{at}dfci.harvard.edu.

Purpose PIK3CA mutation and subsequent activation of the AKT pathway play an important role in colorectal carcinogenesis. However, little is known about the prognostic role of PIK3CA mutation in colon cancer.

Patients and Methods Using 450 resectable colon cancers (stage I to III) in two independent prospective cohorts, we detected PIK3CA mutation in 82 tumors (18%) by pyrosequencing. Cox proportional hazards models were used to calculate hazard ratios (HRs) of colon cancer–specific and overall mortalities, adjusted for patient characteristics and tumoral molecular features, including the CpG island methylation phenotype, microsatellite instability (MSI), LINE-1 hypomethylation, and p53, CIMP, KRAS and BRAF mutation.

Results Compared with patients with PIK3CA wild-type tumors, those with PIK3CA-mutated tumors experienced an increase in colon cancer–specific mortality according to univariate analysis (HR = 1.64; 95% CI, 0.95 to 2.86), which persisted after adjusting for other known or potential risk factors for cancer recurrence (including MSI; multivariate HR = 2.23; 95% CI, 1.21 to 4.11). The effect of PIK3CA mutation on cancer survival seemed to differ according to KRAS mutational status. Among patients with KRAS wild-type tumors, the presence of PIK3CA mutation was associated with a significant increase in colon cancer–specific mortality (HR = 3.80; 95% CI, 1.56 to 9.27). In contrast, PIK3CA mutation conferred no significant effect on mortality among patients with KRAS-mutated tumors (HR = 1.25; 95% CI, 0.52 to 2.96).

Conclusion Among patients who undergo a curative resection of colon cancer, PIK3CA mutation is associated with shorter cancer-specific survival. The adverse effect of PIK3CA mutation may be potentially limited to patients with KRAS wild-type tumors.

Supported by the National Institutes of Health Grants No. P01 CA87969, P01 CA55075, P50 CA127003, and K07 CA122826 (to S.O.); the Bennett Family Fund; and the Entertainment Industry Foundation. K.N. was supported by a fellowship grant from the Japanese Society for Promotion of Science.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health. Funding agencies did not have any role in the design of the study; the collection, analysis, or interpretation of the data; the decision to submit the manuscript for publication; or the writing of the manuscript.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				Y. He, L. J. Van't Veer, I. Mikolajewska-Hanclich, M.-L. F. van Velthuysen, E. C.M. Zeestraten, I. D. Nagtegaal, C. J.H. van de Velde, and C. A.M. Marijnen PIK3CA Mutations Predict Local Recurrences in Rectal Cancer Patients Clin. Cancer Res., November 15, 2009; 15(22): 6956 - 6962. [Abstract] [Full Text] [PDF]

				M. Rahmani, A. Anderson, J. R. Habibi, T. R. Crabtree, M. Mayo, H. Harada, A. Ferreira-Gonzalez, P. Dent, and S. Grant The BH3-only protein Bim plays a critical role in leukemia cell death triggered by concomitant inhibition of the PI3K/Akt and MEK/ERK1/2 pathways Blood, November 12, 2009; 114(20): 4507 - 4516. [Abstract] [Full Text] [PDF]

				S. Kure, K. Nosho, Y. Baba, N. Irahara, K. Shima, K. Ng, J. A. Meyerhardt, E. L. Giovannucci, C. S. Fuchs, and S. Ogino Vitamin D Receptor Expression Is Associated with PIK3CA and KRAS Mutations in Colorectal Cancer Cancer Epidemiol. Biomarkers Prev., October 1, 2009; 18(10): 2765 - 2772. [Abstract] [Full Text] [PDF]

				S. Ogino, K. Nosho, N. Irahara, K. Shima, Y. Baba, G. J. Kirkner, J. A. Meyerhardt, and C. S. Fuchs Prognostic Significance and Molecular Associations of 18q Loss of Heterozygosity: A Cohort Study of Microsatellite Stable Colorectal Cancers J. Clin. Oncol., September 20, 2009; 27(27): 4591 - 4598. [Abstract] [Full Text] [PDF]