title: PIK3CA mutation is predictive of poor survival in patients with colorectal cancer.
abstract: The PI3K-AKT pathway is activated in a variety of human cancers, resulting in disturbance of cell growth, proliferation and survival. Among the factors affecting the pathway, the K-Ras mutation and PIK3CA mutation are the most common oncogenic alterations in colorectal cancer. We hypothesized that these two mutations are important in activation of the PI3K pathway and colorectal carcinogenesis. In this study, we aimed to examine the influence of PIK3CA mutation and K-Ras mutation on AKT activation, and to clarify whether PIK3CA mutation, K-Ras mutation and p-AKT expression may be used as parameters for predicting prognosis in colorectal cancer. Tissue samples from 158 colorectal cancer patients who underwent surgical resection were examined. The sequences of exon 1 of K-Ras and exons 9 and 20 of PIK3CA were determined by direct sequencing using genomic DNA extracted from paraffin-embedded blocks. Activation status of AKT was evaluated by immunohistochemical staining using phospho-specific AKT antibody (Ser473). Correlation between these factors and clinicopathologic findings/patient survival were examined. As a result, PIK3CA mutation was significantly associated with shorter relapse-free survival (RFS) in stage II/III patients (p = 0.0216) and shorter disease-specific survival in all patients (p = 0.0357). In the multivariate analysis, PIK3CA mutation was the only independent and significant prognostic factor for RFS in stage II/III patients (p = 0.0433, HR 2.478). This study revealed the prognostic value of PIK3CA mutation in colorectal cancer patients. Patients with PIK3CA mutation should be followed up carefully. Moreover, our result suggests that inhibition of PIK3CA mutant may be a new molecular target therapy.
authors.affiliation: Department of Surgical Oncology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan. s-katou@daiichi.or.jp
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kato
authors.forename: Satoru
authors.initials: S
authors.lastname: Iida
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Higuchi
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Yoko
authors.initials: Y
authors.lastname: Takagi
authors.forename: Masamichi
authors.initials: M
authors.lastname: Yasuno
authors.forename: Masayuki
authors.initials: M
authors.lastname: Enomoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Uetake
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sugihara
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D014408:Biomarkers, Tumor / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality*; D005260:Female; D011905:Genes, ras; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011237:Predictive Value of Tests; D011379:Prognosis; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human