Ogino Shuji, Nosho Katsuhiko, Kirkner Gregory J, Shima Kaori, Irahara Natsumi, Kure Shoko, Chan Andrew T, Engelman Jeffrey A, Kraft Peter, Cantley Lewis C, Giovannucci Edward L, Fuchs Charles S
Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, 44 Binney St, Room JF-215C, Boston, MA 02115 USA.
J Clin Oncol. 2009 Mar 20;27(9):1477-84. doi: 10.1200/JCO.2008.18.6544. Epub 2009 Feb 23.
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.
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.
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).
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.
PIK3CA突变及随后的AKT通路激活在结直肠癌发生过程中起重要作用。然而，关于PIK3CA突变在结肠癌中的预后作用知之甚少。
在两个独立的前瞻性队列中，我们对450例可切除的结肠癌（I至III期）进行研究，通过焦磷酸测序在82例肿瘤（18%）中检测到PIK3CA突变。采用Cox比例风险模型计算结肠癌特异性死亡率和总死亡率的风险比（HR），并根据患者特征和肿瘤分子特征进行调整，包括CpG岛甲基化表型、微卫星不稳定性（MSI）、LINE-1低甲基化以及p53、CIMP、KRAS和BRAF突变。
单因素分析显示，与PIK3CA野生型肿瘤患者相比，PIK3CA突变型肿瘤患者的结肠癌特异性死亡率增加（HR = 1.64；95%CI，0.95至2.86），在调整其他已知或潜在的癌症复发风险因素（包括MSI）后，这一情况仍然存在（多因素HR = 2.23；95%CI，1.21至4.11）。PIK3CA突变对癌症生存的影响似乎因KRAS突变状态而异。在KRAS野生型肿瘤患者中，PIK3CA突变与结肠癌特异性死亡率显著增加相关（HR = 3.80；95%CI，1.56至9.27）。相反，PIK3CA突变对KRAS突变型肿瘤患者的死亡率无显著影响（HR = 1.25；95%CI，0.52至2.96）。
在接受结肠癌根治性切除的患者中，PIK3CA突变与较短的癌症特异性生存期相关。PIK3CA突变的不良影响可能仅限于KRAS野生型肿瘤患者。
