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Prognostic role of PIK3CA mutation in colorectal cancer: cohort study and literature review.

ABSTRACT: Mutations in PIK3CA [the gene encoding the p110? 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 biologic 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 1,170 rectal and colon cancers in two prospective cohort studies, and found 189 (16%) PIK3CA mutated tumors. Mortality 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 with 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.Coexistence of PIK3CA (the PI3K p110? 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.

SUBMITTER: Liao X

PROVIDER: S-EPMC3628835 | biostudies-literature | 2012 Apr

REPOSITORIES: biostudies-literature

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Prognostic role of PIK3CA mutation in colorectal cancer: cohort study and literature review.

Liao Xiaoyun X Morikawa Teppei T Lochhead Paul P Imamura Yu Y Kuchiba Aya A Yamauchi Mai M Nosho Katsuhiko K Qian Zhi Rong ZR Nishihara Reiko R Meyerhardt Jeffrey A JA Fuchs Charles S CS Ogino Shuji S

Clinical cancer research : an official journal of the American Association for Cancer Research 20120222 8

<h4>Purpose</h4>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 biologic 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 ...[more]

PMID: 22357840

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Project description:BACKGROUND:Regular use of aspirin after a diagnosis of colon cancer has been associated with a superior clinical outcome. Experimental evidence suggests that inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2) (also known as cyclooxygenase-2) by aspirin down-regulates phosphatidylinositol 3-kinase (PI3K) signaling activity. We hypothesized that the effect of aspirin on survival and prognosis in patients with cancers characterized by mutated PIK3CA (the phosphatidylinositol-4,5-bisphosphonate 3-kinase, catalytic subunit alpha polypeptide gene) might differ from the effect among those with wild-type PIK3CA cancers. METHODS:We obtained data on 964 patients with rectal or colon cancer from the Nurses' Health Study and the Health Professionals Follow-up Study, including data on aspirin use after diagnosis and the presence or absence of PIK3CA mutation. We used a Cox proportional-hazards model to compute the multivariate hazard ratio for death. We examined tumor markers, including PTGS2, phosphorylated AKT, KRAS, BRAF, microsatellite instability, CpG island methylator phenotype, and methylation of long interspersed nucleotide element 1. RESULTS:Among patients with mutated-PIK3CA colorectal cancers, regular use of aspirin after diagnosis was associated with superior colorectal cancer-specific survival (multivariate hazard ratio for cancer-related death, 0.18; 95% confidence interval [CI], 0.06 to 0.61; P<0.001 by the log-rank test) and overall survival (multivariate hazard ratio for death from any cause, 0.54; 95% CI, 0.31 to 0.94; P=0.01 by the log-rank test). In contrast, among patients with wild-type PIK3CA, regular use of aspirin after diagnosis was not associated with colorectal cancer-specific survival (multivariate hazard ratio, 0.96; 95% CI, 0.69 to 1.32; P=0.76 by the log-rank test; P=0.009 for interaction between aspirin and PIK3CA variables) or overall survival (multivariate hazard ratio, 0.94; 95% CI, 0.75 to 1.17; P=0.96 by the log-rank test; P=0.07 for interaction). CONCLUSIONS:Regular use of aspirin after diagnosis was associated with longer survival among patients with mutated-PIK3CA colorectal cancer, but not among patients with wild-type PIK3CA cancer. The findings from this molecular pathological epidemiology study suggest that the PIK3CA mutation in colorectal cancer may serve as a predictive molecular biomarker for adjuvant aspirin therapy. (Funded by The National Institutes of Health and others.).

Project description:BackgroundKRAS mutations in codons 12 and 13 are established predictive biomarkers for anti-EGFR therapy in colorectal cancer. Previous studies suggest that KRAS codon 61 and 146 mutations may also predict resistance to anti-EGFR therapy in colorectal cancer. However, clinicopathological, molecular, and prognostic features of colorectal carcinoma with KRAS codon 61 or 146 mutation remain unclear.MethodsWe utilized a molecular pathological epidemiology database of 1267 colon and rectal cancers in the Nurse's Health Study and the Health Professionals Follow-up Study. We examined KRAS mutations in codons 12, 13, 61 and 146 (assessed by pyrosequencing), in relation to clinicopathological features, and tumor molecular markers, including BRAF and PIK3CA mutations, CpG island methylator phenotype (CIMP), LINE-1 methylation, and microsatellite instability (MSI). Survival analyses were performed in 1067 BRAF-wild-type cancers to avoid confounding by BRAF mutation. Cox proportional hazards models were used to compute mortality hazard ratio, adjusting for potential confounders, including disease stage, PIK3CA mutation, CIMP, LINE-1 hypomethylation, and MSI.ResultsKRAS codon 61 mutations were detected in 19 cases (1.5%), and codon 146 mutations in 40 cases (3.2%). Overall KRAS mutation prevalence in colorectal cancers was 40% (=505/1267). Of interest, compared to KRAS-wild-type, overall, KRAS-mutated cancers more frequently exhibited cecal location (24% vs. 12% in KRAS-wild-type; P?<?0.0001), CIMP-low (49% vs. 32% in KRAS-wild-type; P?<?0.0001), and PIK3CA mutations (24% vs. 11% in KRAS-wild-type; P?<?0.0001). These trends were evident irrespective of mutated codon, though statistical power was limited for codon 61 mutants. Neither KRAS codon 61 nor codon 146 mutation was significantly associated with clinical outcome or prognosis in univariate or multivariate analysis [colorectal cancer-specific mortality hazard ratio (HR)?=?0.81, 95% confidence interval (CI)?=?0.29-2.26 for codon 61 mutation; colorectal cancer-specific mortality HR?=?0.86, 95% CI?=?0.42-1.78 for codon 146 mutation].ConclusionsTumors with KRAS mutations in codons 61 and 146 account for an appreciable proportion (approximately 5%) of colorectal cancers, and their clinicopathological and molecular features appear generally similar to KRAS codon 12 or 13 mutated cancers. To further assess clinical utility of KRAS codon 61 and 146 testing, large-scale trials are warranted.

Project description:The abundance of tumour-infiltrating T-cells has been associated with microsatellite instability (MSI) and a favourable prognosis in colorectal cancer. However, numerous molecular alterations have been associated with clinical outcome, and potentially confounding the biological and prognostic significance of tumour-infiltrating T-cells. We utilized a database of clinically and molecularly-annotated colon and rectal carcinoma cases (N = 768; stage I-IV) in two prospective cohort studies (the Nurses' Health Study and the Health Professionals Follow-up Study) and quantified the densities of CD3(+), CD8(+), CD45RO(+) (PTPRC), and FOXP3(+) cells within neoplastic epithelial areas using an Ariol image analysis system and tissue microarray. We used Cox proportional hazard models to compute the mortality hazard ratio, adjusting for clinical and molecular features including KRAS, BRAF, and PIK3CA mutations, MSI, CIMP, and LINE-1 hypomethylation. The densities of CD8(+), CD45RO(+), and FOXP3(+) cells were significantly associated with patient survival in univariate analyses (P(trend) < 0.007). In the multivariate model, tumour-infiltrating CD45RO(+)-cell density, but not CD3(+), CD8(+) or FOXP3(+)-cell density, was significantly associated with survival (p = 0.0032). In multivariate linear regression analysis, MSI-high (p < 0.0001) and high-level tumour LINE-1 methylation (p = 0.0013) were independently associated with higher CD45RO(+)-cell density. The survival benefit associated with CD45RO(+) cells was independent of MSI and LINE-1 status. In conclusion, tumour-infiltrating CD45RO(+)-cell density is a prognostic biomarker associated with longer survival of colorectal cancer patients, independent of clinical, pathological, and molecular features. In addition, MSI-high and tumour LINE-1 methylation level are independent predictors of CD45RO(+)-cell density. Our data offer a possible mechanism by which MSI confers an improved clinical outcome and support efforts to augment the host immune response in the tumour microenvironment as a strategy of targeted immunotherapy.

Dataset Information

Prognostic role of PIK3CA mutation in colorectal cancer: cohort study and literature review.

Publications

Prognostic role of PIK3CA mutation in colorectal cancer: cohort study and literature review.

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