TY - JOUR
T1 - Prognostic Role of PIK3CA Mutation in Colorectal Cancer
T2 - Cohort Study and Literature Review
AU - Liao, Xiaoyun
AU - Morikawa, Teppei
AU - Lochhead, Paul
AU - Imamura, Yu
AU - Kuchiba, Aya
AU - Yamauchi, Mai
AU - Nosho, Katsuhiko
AU - Qian, Zhi Rong
AU - Nishihara, Reiko
AU - Meyerhardt, Jeffrey A.
AU - Fuchs, Charles S.
AU - Ogino, Shuji
N1 - PMID: 22357840 [PubMed - indexed for MEDLINE] PMCID: PMC3628835 Free PMC Article
PY - 2012/4/15
Y1 - 2012/4/15
N2 - PURPOSE: Mutations in PIK3CA (the gene encoding the p110alpha; 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSION: Co-existence of PIK3CA (the PI3K p110alpha 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.
AB - PURPOSE: Mutations in PIK3CA (the gene encoding the p110alpha; 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSION: Co-existence of PIK3CA (the PI3K p110alpha 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.
U2 - 10.1158/1078-0432.CCR-11-2410
DO - 10.1158/1078-0432.CCR-11-2410
M3 - Article
C2 - 22357840
SN - 1078-0432
VL - 18
SP - 2257
EP - 2268
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 8
ER -