PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer.
PIK3CA mutation is associated with poor prognosis among patients with curatively resected colon cancer.
复制标题
DOI：
10.1200/jco.2008.18.6544
复制
发表时间：
2009-03-20
期刊：
影响因子：
--
通讯作者：
Fuchs CS
中科院分区：
文献类型：
--
作者：
Ogino S;Nosho K;Kirkner GJ;Shima K;Irahara N;Kure S;Chan AT;Engelman JA;Kraft P;Cantley LC;Giovannucci EL;Fuchs CS
PIK3CA突变及随后AKT通路的激活在结直肠癌发生中起重要作用。然而，对于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，我们利用450例可切除的结肠癌（I-III期），通过焦磷酸测序在82例（18%）肿瘤中检测到PIK3CA突变。使用Cox比例风险模型计算结肠癌特异性死亡率和总体死亡率的风险比（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（CIMP）、微卫星不稳定性（MSI）以及KRAS和BRAF突变。单变量分析显示，与pik3ca野生型肿瘤患者相比，pik3ca突变肿瘤患者的结肠癌特异性死亡率增加[HR 1.64；95%置信区间（CI）， 0.95-2.86]，在调整了其他已知或潜在的癌症复发危险因素后，这种情况仍然存在（多因素风险比2.23,95% CI, 1.21-4.11）。PIK3CA突变对肿瘤生存的影响似乎因kras突变状态而异。在kras野生型肿瘤患者中，PIK3CA突变的存在与结肠癌特异性死亡率的显著增加相关（HR 3.80, 95% CI, 1.56-9.27）。相比之下，PIK3CA突变对kras突变肿瘤患者的死亡率没有显著影响（HR 1.25; 95% CI, 0.52-2.96），尽管相互作用无统计学意义（p相互作用=0.13）。在接受根治性结肠癌切除术的患者中，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。
PIK3CA mutation and subsequent activation of the AKT pathway play an important role in colorectal carcinogenesis. However, little has been known on the prognostic role of PIK3CA mutation in colon cancer. Utilizing 450 resectable colon cancers (stage I-III) in two independent prospective cohorts, we detected PIK3CA mutation in 82 (18%) tumors by Pyrosequencing. Cox proportional hazard 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 methylator phenotype (CIMP), microsatellite instability (MSI) and KRAS and BRAF mutation. Compared to patients with PIK3CA-wild-type tumors, those with PIK3CA-mutated tumors experienced an increase in colon-cancer specific mortality by the univariate analysis [HR 1.64; 95% confidence interval (CI), 0.95-2.86], which persisted after adjusting for other known or potential risk factors for cancer recurrence (multivariate HR 2.23, 95% CI, 1.21-4.11). The effect of PIK3CA mutation on cancer survival appeared 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, 1.56-9.27). In contrast, PIK3CA mutation conferred no significant effect on mortality among patients with KRAS-mutated tumors (HR 1.25; 95% CI, 0.52-2.96), although the interaction was not statistically significant (Pinteraction=0.13). 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.