Prognostic role of PIK3CA mutation in colorectal cancer: cohort study and literature review.
Prognostic role of PIK3CA mutation in colorectal cancer: cohort study and literature review.
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DOI：
10.1158/1078-0432.ccr-11-2410
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发表时间：
2012-04-15
期刊：
影响因子：
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通讯作者：
Ogino S
中科院分区：
文献类型：
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作者：
Liao X;Morikawa T;Lochhead P;Imamura Y;Kuchiba A;Yamauchi M;Nosho K;Qian ZR;Nishihara R;Meyerhardt JA;Fuchs CS;Ogino S
PIK 3CA（编码磷脂酰肌醇-3-激酶（PI 3 K）的p110α催化亚基的基因）突变在结直肠癌发生中起重要作用。实验证据表明，PIK 3CA外显子9和外显子20突变触发不同的生物学效应，并且外显子9和20中的伴随突变协同增强致瘤效应。因此，我们假设PIK 3CA外显子9和外显子20突变可能对结直肠癌的临床结果具有不同的影响，并且伴随的PIK 3CA外显子9和20突变可能赋予侵袭性肿瘤行为。我们在两项前瞻性队列研究中通过焦磷酸测序对1170例直肠癌和结肠癌进行了PIK 3CA测序，发现了189例（16%）PIK 3CA突变肿瘤。使用考克斯比例风险模型计算根据PIK 3CA状态的死亡率风险比（HR），调整临床和分子特征，包括微卫星不稳定性、CpG岛甲基化表型、LINE-1甲基化以及BRAF和KRAS突变。与PIK 3CA野生型病例相比，在外显子9和20中伴随PIK 3CA突变的患者经历了显著更差的癌症特异性生存期[对数秩P=0.031;多变量HR=3.51; 95%置信区间（CI），1.28-9.62]和总生存期（对数秩P=0.0008 ;多变量HR=2.68; 95% CI，1.24-5.77）。PIK 3CA突变在外显子9或20单独与患者生存率没有显着相关。在生存分析中未观察到PIK 3CA突变与BRAF或KRAS突变的显著相互作用。PIK 3CA（PI 3 K p110α亚基）外显子9和20突变的共存，而不是PIK 3CA外显子9或20单独突变，与结直肠癌患者的不良预后相关。
Mutations in PIK3CA (the gene encoding the p110α catalytic subunit of phosphatidylinositide-3-kinase, PI3K) play an important role in colorectal carcinogenesis. Experimental evidence suggests that PIK3CA exon 9 and exon 20 mutations trigger different biological effects, and that concomitant mutations in both exons 9 and 20 synergistically enhance tumorigenic effects. Thus, we hypothesized that PIK3CA exon 9 and exon 20 mutations might have differential effects on clinical outcome in colorectal cancer, and that concomitant PIK3CA exon 9 and 20 mutations might confer aggressive tumor behavior. We sequenced PIK3CA by pyrosequencing in 1170 rectal and colon cancers in two prospective cohort studies, and found 189 (16%) PIK3CA-mutated tumors. Mortality hazard ratio (HR) according to PIK3CA status was computed using Cox proportional hazards model, adjusting for clinical and molecular features including microsatellite instability, CpG island methylator phenotype, LINE-1 methylation, and BRAF and KRAS mutations. Compared to PIK3CA wild-type cases, patients with concomitant PIK3CA mutations in exons 9 and 20 experienced significantly worse cancer-specific survival [log-rank P=0.031; multivariate HR=3.51; 95% confidence interval (CI), 1.28–9.62] and overall survival (log-rank P=0.0008 ; multivariate HR=2.68; 95% CI, 1.24–5.77). PIK3CA mutation in either exon 9 or 20 alone was not significantly associated with patient survival. No significant interaction of PIK3CA mutation with BRAF or KRAS mutation was observed in survival analysis. Co-existence of PIK3CA (the PI3K p110α subunit) exon 9 and 20 mutations, but not PIK3CA mutation in either exon 9 or 20 alone, is associated with poor prognosis of colorectal cancer patients.