Abstract
<div>Abstract<p><b>Purpose:</b> Mutations in <i>PIK3CA</i> [the gene encoding the p110α catalytic subunit of phosphatidylinositide-3-kinase (PI3K)] play an important role in colorectal carcinogenesis. Experimental evidence suggests that <i>PIK3CA</i> exon 9 and exon 20 mutations trigger different biologic effects, and that concomitant mutations in both exons 9 and 20 synergistically enhance tumorigenic effects. Thus, we hypothesized that <i>PIK3CA</i> exon 9 and exon 20 mutations might have differential effects on clinical outcome in colorectal cancer, and that concomitant <i>PIK3CA</i> exon 9 and 20 mutations might confer aggressive tumor behavior.</p><p><b>Experimental Design:</b> We sequenced <i>PIK3CA</i> by pyrosequencing in 1,170 rectal and colon cancers in two prospective cohort studies, and found 189 (16%) <i>PIK3CA</i> mutated tumors. Mortality HR according to <i>PIK3CA</i> 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 <i>BRAF</i> and <i>KRAS</i> mutations.</p><p><b>Results:</b> Compared with <i>PIK3CA</i> wild-type cases, patients with concomitant <i>PIK3CA</i> mutations in exons 9 and 20 experienced significantly worse cancer-specific survival [log-rank <i>P</i> = 0.031; multivariate HR = 3.51; 95% confidence interval (CI): 1.28–9.62] and overall survival (log-rank <i>P</i> = 0.0008; multivariate HR = 2.68; 95% CI: 1.24–5.77). <i>PIK3CA</i> mutation in either exon 9 or 20 alone was not significantly associated with patient survival. No significant interaction of <i>PIK3CA</i> mutation with <i>BRAF</i> or <i>KRAS</i> mutation was observed in survival analysis.</p><p><b>Conclusion:</b> Coexistence of <i>PIK3CA</i> (the PI3K p110α subunit) exon 9 and 20 mutations, but not <i>PIK3CA</i> mutation in either exon 9 or 20 alone, is associated with poor prognosis of colorectal cancer patients. <i>Clin Cancer Res; 18(8); 2257–68. ©2012 AACR</i>.</p></div>
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