Prognostic Role of PIK3CA Mutation in Colorectal Cancer

Cohort Study and Literature Review

Xiaoyun Liao, Teppei Morikawa, Paul Lochhead, Yu Imamura, Aya Kuchiba, Mai Yamauchi, Katsuhiko Nosho, Zhi Rong Qian, Reiko Nishihara, Jeffrey A. Meyerhardt, Charles S. Fuchs, Shuji Ogino

Research output: Contribution to journalArticle

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Abstract

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.
Original languageEnglish
Pages (from-to)2257-2268
Number of pages12
JournalClinical Cancer Research
Volume18
Issue number8
Early online date22 Feb 2012
DOIs
Publication statusPublished - 15 Apr 2012

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Colorectal Neoplasms
Cohort Studies
Exons
Mutation
Phosphatidylinositol 3-Kinases
Survival
Confidence Intervals
Neoplasms
Microsatellite Instability
CpG Islands
Rectal Neoplasms
Survival Analysis
Proportional Hazards Models
Colonic Neoplasms
Methylation
Catalytic Domain
Carcinogenesis
Phosphotransferases
Prospective Studies
Phenotype

Cite this

Liao, X., Morikawa, T., Lochhead, P., Imamura, Y., Kuchiba, A., Yamauchi, M., ... Ogino, S. (2012). Prognostic Role of PIK3CA Mutation in Colorectal Cancer: Cohort Study and Literature Review. Clinical Cancer Research, 18(8), 2257-2268. https://doi.org/10.1158/1078-0432.CCR-11-2410

Prognostic Role of PIK3CA Mutation in Colorectal Cancer : Cohort Study and Literature Review. / Liao, Xiaoyun; Morikawa, Teppei; Lochhead, Paul; Imamura, Yu; Kuchiba, Aya; Yamauchi, Mai; Nosho, Katsuhiko; Qian, Zhi Rong; Nishihara, Reiko; Meyerhardt, Jeffrey A.; Fuchs, Charles S.; Ogino, Shuji.

In: Clinical Cancer Research, Vol. 18, No. 8, 15.04.2012, p. 2257-2268.

Research output: Contribution to journalArticle

Liao, X, Morikawa, T, Lochhead, P, Imamura, Y, Kuchiba, A, Yamauchi, M, Nosho, K, Qian, ZR, Nishihara, R, Meyerhardt, JA, Fuchs, CS & Ogino, S 2012, 'Prognostic Role of PIK3CA Mutation in Colorectal Cancer: Cohort Study and Literature Review', Clinical Cancer Research, vol. 18, no. 8, pp. 2257-2268. https://doi.org/10.1158/1078-0432.CCR-11-2410
Liao, Xiaoyun ; Morikawa, Teppei ; Lochhead, Paul ; Imamura, Yu ; Kuchiba, Aya ; Yamauchi, Mai ; Nosho, Katsuhiko ; Qian, Zhi Rong ; Nishihara, Reiko ; Meyerhardt, Jeffrey A. ; Fuchs, Charles S. ; Ogino, Shuji. / Prognostic Role of PIK3CA Mutation in Colorectal Cancer : Cohort Study and Literature Review. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 8. pp. 2257-2268.
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abstract = "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.",
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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

VL - 18

SP - 2257

EP - 2268

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 8

ER -