PIK3CA mutation and methylation influences the outcome of colorectal cancer

Iida, Satoru; Kato, Shunsuke; Ishiguro, Megumi; Matsuyama, Takatoshi; Ishikawa, Toshiaki; Kobayashi, Hirotoshi; Higuchi, Tetsuro; Uetake, Hiroyuki; Enomoto, Masayuki; Sugihara, Kenichi

doi:10.3892/ol.2011.544

Cited by 27 publications

(28 citation statements)

References 34 publications

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“…Full texts and data integrity were then reviewed and another 249 articles were excluded. Finally, 27 clinical cohort studies were included in this meta-analysis (Liang et al, 1999;Wiencke et al, 1999;Wang et al, 2001;Yi et al, 2001;Hibi et al, 2002;Nakayama et al, 2002;van Rijnsoever et al, 2002;Zou et al, 2002;Cheng et al, 2003;Norrie et al, 2003;Yang et al, 2003;Sanz-Casla et al, 2005;Iacopetta et al, 2006;Ishiguro et al, 2006;Li et al, 2006;Miranda et al, 2006;Krtolica et al, 2007;Mas et al, 2007;Nakayama et al, 2007;Kazama et al, 2008;Wettergren et al, 2008;Goto et al, 2009;Aoyagi et al, 2011;Miladi-Abdennadher et al, 2011;Iida et al, 2012;Sameer et al, 2012;Veganzones-de-Castro et al, 2012). The publication years of the eligible studies ranged from 1999 to 2012.…”

Section: Characteristics Of Included Studiesmentioning

confidence: 99%

“…Therefore, it is biologically plausible that genetic mutations of the p16 gene may modulate the development and progression of CRC (Lopes et al, 2008). However, some other studies demonstrated that the relationship between p16 and the development and progression of CRC remains controversial Iida et al, 2012). Therefore, we performed a meta-analysis of all available data to evaluate the relationships between p16 gene promoter methylation and the clinicopathologic features of CRC.…”

Section: Introductionmentioning

confidence: 99%

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Relationships Betweenp16Gene Promoter Methylation and Clinicopathologic Features of Colorectal Cancer: A Meta-Analysis of 27 Cohort Studies

Chen

Liú²,

Zhao³

et al. 2014

DNA and Cell Biology

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Many existing studies have demonstrated that p16 promoter methylation might be correlated with the clinicopathologic features of colorectal cancer (CRC), but individually published results are inconclusive. This meta-analysis aimed to derive a more precise estimation of the relationships between p16 promoter methylation and the clinicopathologic features of CRC. We searched the CISCOM, CINAHL, Web of Science, PubMed, Google Scholar, EBSCO, Cochrane Library, and CBM databases from inception through August 1, 2013. Meta-analysis was performed using the STATA 12.0 software. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated under fixed- or random-effects models. Twenty-seven clinical cohort studies were included with a total of 3311 CRC patients. Our meta-analysis results revealed that p16 promoter methylation was associated with pathological characteristics of CRC (tumor, nodes, metastasis stage: OR=1.55, 95% CI: 1.14-2.13, p=0.006; lymph node metastasis: OR=2.40, 95% CI: 1.37-4.19, p=0.002; histologic grade: OR=2.72, 95% CI: 1.63-4.54, p<0.001; Dukes stage: OR=2.06, 95% CI: 1.57-2.71, p=0.002; tumor size: OR=1.99, 95% CI: 1.03-3.85, p=0.041; location: OR=2.49, 95% CI: 1.95-3.18, p<0.001, respectively). Subgroup analysis by ethnicity suggested that there were also significant correlations between p16 gene promoter methylation and pathological characteristics of CRC among both Caucasian and Asian populations (all p<0.05). Our meta-analysis suggests that promoter methylation of the p16 gene may be strongly correlated with the clinicopathologic features of CRC. Thus, p16 gene promoter methylation may be a potential biomarker for CRC.

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Section: Characteristics Of Included Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Relationships Betweenp16Gene Promoter Methylation and Clinicopathologic Features of Colorectal Cancer: A Meta-Analysis of 27 Cohort Studies

Chen

Liú²,

Zhao³

et al. 2014

DNA and Cell Biology

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“…A gain of transformative enzymatic function in both cell lines and orthotopic models results from mutation within both regions [6], [7]. For colorectal carcinoma, the prevalence of PIK3CA mutation was reported to be between 7% and 32%, with G>A transversions in exon 9 being the most commonly observed configuration [4], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21].…”

Section: Introductionmentioning

confidence: 99%

PIK3CA Activating Mutation in Colorectal Carcinoma: Associations with Molecular Features and Survival

et al. 2013

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Mutations in PIK3CA are present in 10 to 15% of colorectal carcinomas. We aimed to examine how PIK3CA mutations relate to other molecular alterations in colorectal carcinoma, to pathologic phenotype and survival. PIK3CA mutation testing was carried out using direct sequencing on 757 incident tumors from the Melbourne Collaborative Cohort Study. The status of O-6-methylguanine-DNA methyltransferase (MGMT) was assessed using both immunohistochemistry and methyLight techniques. Microsatellite instability, CpG island phenotype (CIMP), KRAS and BRAF V600E mutation status, and pathology review features were derived from previous reports. PIK3CA mutation was observed in 105 of 757 (14%) of carcinomas, characterized by location in the proximal colon (54% vs. 34%; P<0.001) and an increased frequency of KRAS mutation (48% vs. 25%; P<0.001). High-levels of CIMP were more frequently found in PIK3CA-mutated tumors compared with PIK3CA wild-type tumors (22% vs. 11%; P = 0.004). There was no difference in the prevalence of BRAF V600E mutation between these two tumor groups. PIK3CA-mutated tumors were associated with loss of MGMT expression (35% vs. 20%; P = 0.001) and the presence of tumor mucinous differentiation (54% vs. 32%; P<0.001). In patients with wild-type BRAF tumors, PIK3CA mutation was associated with poor survival (HR 1.51 95% CI 1.04–2.19, P = 0.03). In summary, PIK3CA-mutated colorectal carcinomas are more likely to develop in the proximal colon, to demonstrate high levels of CIMP, KRAS mutation and loss of MGMT expression. PIK3CA mutation also contributes to significantly decreased survival for patients with wild-type BRAF tumors.

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“…68-82 Studies which used Pyrosequencing assay 60,83,84 (which is more sensitive than Sanger sequencing 85 ) generally show higher frequencies of PIK3CA mutations than Sanger sequencing studies. 61,62,69,80,86 Considering mutations in other less-commonly mutated exons as well as false negativity in molecular assays (particularly, Sanger sequencing), it is estimated that approximately 20% of colorectal cancers in the general population harbor PIK3CA mutations. Interestingly, the prevalence of PIK3CA mutations in colorectal cancer increases continuously from rectum (approximately 10%) to cecum (approximately 25%), 62,87 supporting the “colorectal continuum” paradigm, 88 and an important interplay of gut microbiota and host response.…”

Section: Introduction: Aspirin As Anti-cancer Drugmentioning

confidence: 99%

Discovery of colorectal cancer PIK3CA mutation as potential predictive biomarker: power and promise of molecular pathological epidemiology

et al. 2013

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Regular use of aspirin reduces incidence and mortality of various cancers, including colorectal cancer. Anti-cancer effect of aspirin represents one of the “Provocative Questions” in cancer research. Experimental and clinical studies support a carcinogenic role for PTGS2 (cyclooxygenase-2), which is an important enzymatic mediator of inflammation, and a target of aspirin. Recent “Molecular Pathological Epidemiology” (MPE) research has shown that aspirin use is associated with better prognosis and clinical outcome in PIK3CA-mutated colorectal carcinoma, suggesting somatic PIK3CA mutation as a molecular biomarker that predicts response to aspirin therapy. The PI3K enzyme plays a pivotal role in the PI3K-AKT signaling pathway. Activating PIK3CA oncogene mutations are observed in various malignancies including breast cancer, ovarian cancer, brain tumor, hepatocellular carcinoma, lung cancer and colon cancer. The prevalence of PIK3CA mutations increases continuously from rectal to cecal cancers, supporting the “colorectal continuum” paradigm, and an important interplay of gut microbiota and host immune/inflammatory reaction. MPE represents an interdisciplinary integrative science, conceptually defined as “epidemiology of molecular heterogeneity of disease”. Because exposome and interactome vary from person to person and influence disease process, each disease process is unique (the unique disease principle). Hence, MPE concept and paradigm can extend to non-neoplastic diseases including diabetes mellitus, cardiovascular diseases, metabolic diseases, etc. MPE research opportunities are currently limited by paucity of tumor molecular data in existing large-scale population-based studies. However, genomic, epigenomic, and molecular pathology testing (e.g., analyses for microsatellite instability, MLH1 promoter CpG island methylation, and KRAS and BRAF mutations in colorectal tumors) is becoming routine clinical practice. In order for integrative molecular and population science to be routine practice, we must first reform education curricula by integrating both population and molecular biologic sciences. As consequences, next-generation hybrid molecular biological and population scientists can advance science, moving closer to personalized precision medicine and health care.

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PIK3CA mutation and methylation influences the outcome of colorectal cancer

Cited by 27 publications

References 34 publications

Relationships Betweenp16Gene Promoter Methylation and Clinicopathologic Features of Colorectal Cancer: A Meta-Analysis of 27 Cohort Studies

Relationships Betweenp16Gene Promoter Methylation and Clinicopathologic Features of Colorectal Cancer: A Meta-Analysis of 27 Cohort Studies

PIK3CA Activating Mutation in Colorectal Carcinoma: Associations with Molecular Features and Survival

Discovery of colorectal cancer PIK3CA mutation as potential predictive biomarker: power and promise of molecular pathological epidemiology

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