Oncogenic <i>PIK3CA</i> mutations in colorectal cancers and polyps

Whitehall, Vicki; Rickman, Celestine; Bond, Catherine; Ramsnes, Ingunn; Greco, Sonia; Umapathy, Aarti; McKeone, Diane; Faleiro, Rebecca J.; Buttenshaw, Ron; Worthley, Daniel L.; Nayler, Samuel; Zhao, Zhen; Montgomery, Grant W.; Mallitt, Kylie‐Ann; Jass, Jeremy R.; Matsubara, Nagahide; Notohara, Kenji; Ishii, Tatsuhiro; Leggett, Barbara A.

doi:10.1002/ijc.26440

Cited by 77 publications

(84 citation statements)

References 33 publications

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“…Although previous studies have investigated the role of the PIK3CA mutation and gene methylation in CRC, the data are inconclusive. Certain studies reported a significantly higher frequency of the PIK3CA mutation in the CpG island methylator phenotype (CIMP)-high tumor compared with CIMP-negative tumors and a significant correlation between the PIK3CA mutation and RASSF2 gene methylation (29,32,33), whereas other studies failed to observe this correlation (11,34). In the present study, although CIMP status was not examined, the PIK3CA mutation did not exhibit an association with the methylation status of the genes examined.…”

Section: Discussioncontrasting

confidence: 74%

PIK3CA mutation and methylation influences the outcome of colorectal cancer

et al. 2011

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Abstract. Colorectal cancer (CRC) occurs through the accumulation of genetic and epigenetic alterations. The epigenetic abnormalities, in cooperation with genetic alterations, are capable of causing aberrant gene function that results in cancer. In the present study, we examined mutations and methylation status in 164 CRCs to determine whether the combination of genetic and epigenetic alterations may be used to classify CRC patients in relation to their clinicopathological characteristics and outcomes. Mutation analyses for the KRAS and PIK3CA genes were performed using direct sequencing, and the MethyLight method was used to determine the methylation status of BNIP3, p16 and hMLH1. The combination of the KRAS mutation with methylation status did not have any association with clinicopathological characteristics and outcomes. However, patients with the PIK3CA mutation and/ or high methylation (2 or 3 methylated genes) had significantly poorer outcomes in disease-specific survival (DSS) compared with those with wild-type PIK3CA and 0 or 1 methylated genes (P=0.0059). Additionally, multivariate analysis revealed that the PIK3CA mutation and/or a high level of methylation predicts a poor DSS independently of clinicopathological characteristics. Our results suggest that a combination of genetic and epigenetic alterations is a potent biomarker for predicting the prognosis of CRC.

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Section: Discussioncontrasting

confidence: 74%

PIK3CA mutation and methylation influences the outcome of colorectal cancer

et al. 2011

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“…Two recent studies on stage I-IV colorectal cancers have suggested that exon 20 mutations correlate more strongly with BRAF mutation, CIMP-high/-low (CIMP-H/-L) and MSI-H status (31,32), and one reported that exon 9 mutations may more closely associate with KRAS mutation (31,32). The latter has further been observed in a study on metastatic colorectal cancer (30).…”

Section: Introductionmentioning

confidence: 84%

“…39) and Whitehall and colleagues (31)]. The 8 most numerous states plus an omnibus state consisting of the remaining genotypes were modeled using mixed effects logistic regression or, alternatively, a 3-stage hierarchical multinomial-Dirichlet model.…”

Section: Integrated Analysis Of Pik3ca Exon 9 and 20 Mutations For CLmentioning

confidence: 99%

“…Some studies have reported significant cooccurrence of PIK3CA and KRAS mutations (5,26,(28)(29)(30)(31)(32), whereas others have failed to show this (8,25). Other, inconsistent data have been reported for PIK3CA mutation and MSI or CpG island methylator phenotype (CIMP) status (4,8,26,28,31,32). Poorer outcomes have been suggested for PIK3CA-mutated tumors for patients with early-stage resectable disease (27,28), but this was not replicated in a recent large series (32).…”

Section: Introductionmentioning

confidence: 98%

“…PIK3CA mutations have been reported to be more frequent in women (8,25,26), proximal (26), welldifferentiated (5), and mucinous tumors (5), but these findings have not been consistent (4,8,27,28). Some studies have reported significant cooccurrence of PIK3CA and KRAS mutations (5,26,(28)(29)(30)(31)(32), whereas others have failed to show this (8,25). Other, inconsistent data have been reported for PIK3CA mutation and MSI or CpG island methylator phenotype (CIMP) status (4,8,26,28,31,32).…”

Section: Introductionmentioning

confidence: 98%

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PIK3CA and PTEN Gene and Exon Mutation-Specific Clinicopathologic and Molecular Associations in Colorectal Cancer

Day

Jorissen

Lipton

et al. 2013

Clinical Cancer Research

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112

115

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Purpose: PIK3CA and PTEN mutations are prevalent in colorectal cancer and potential markers of response to mitogen-activated protein/extracellular signal-regulated kinase inhibitors and anti-EGF receptor antibody therapy. Relationships between phosphoinositide 3-kinase (PI3K) pathway mutation, clinicopathologic characteristics, molecular features, and prognosis remain controversial.Experimental Design: A total of 1,093 stage I-IV colorectal cancers were screened for PIK3CA (exons 9 and 20), KRAS (codons 12-13), BRAF (codon 600) mutations, and microsatellite instability (MSI). PTEN (exons 3-8) and CpG island methylator phenotype (CIMP) status were determined in 744 and 489 cases. PIK3CA data were integrated with 17 previous reports (n ¼ 5,594).Results: PIK3CA and PTEN mutations were identified in 11.9% and 5.8% of colorectal cancers. PTEN mutation was associated with proximal tumors, mucinous histology, MSI-high (MSI-H), CIMP-high (CIMP-H), and BRAF mutation (P < 0.02). PIK3CA mutation was related to older age, proximal tumors, mucinous histology, and KRAS mutation (P < 0.04). In integrated cohort analysis, PIK3CA exon 9 and 20 mutations were overrepresented in proximal, CIMP-low (CIMP-L), and KRAS-mutated cancers (P 0.011). Comparing PIK3CA exonic mutants, exon 20 mutation was associated with MSI-H, CIMP-H, and BRAF mutation, and exon 9 mutation was associated with KRAS mutation (P 0.027). Disease-free survival for stage II/III colorectal cancers did not differ by PI3K pathway status.Conclusion: PI3K pathway mutation is prominent in proximal colon cancers, with PIK3CA exon 20 and PTEN mutations associated with features of the sessile-serrated pathway (MSI-H/CIMP-H/BRAF mut ), and PIK3CA exon 9 (and to a lesser extent exon 20) mutation associated with features of the traditional serrated pathway (CIMP-L/KRAS mut ) of tumorigenesis. Our data highlight the PI3K pathway as a therapeutic target in distinct colorectal cancer subtypes.

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PTEN expression is consistent in colorectal cancer primaries and metastases and associates with patient survival

Atreya

Sangale

et al. 2013

Cancer Medicine

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Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) negatively regulates the phosphoinositide-3-kinase (PI3K) signaling pathway. In colorectal cancer (CRC), observed frequencies of loss of PTEN expression, concordant expression in primary tumors and metastases, and the association of PTEN status with outcome vary markedly by detection method. We determined the degree to which PTEN expression is consistent in 70 matched human CRC primaries and liver metastases using a validated immunohistochemistry assay. We found loss of PTEN expression in 12.3% of assessable CRC primaries and 10.3% of assessable liver metastases. PTEN expression (positive or negative) was concordant in 98% of matched colorectal primaries and liver metastases. Next we related PTEN status to mutations in RAS and PI3K pathway genes (KRAS, NRAS, BRAF, and PIK3CA) and to overall survival (OS). PTEN expression was not significantly associated with the presence or absence of mutations in RAS or PI3K pathway genes. The median OS of patients whose tumors did not express PTEN was 9 months, compared to 49 months for patients whose tumors did express PTEN (HR = 6.25, 95% confidence intervals (CI) (1.98, 15.42), P = 0.0017). The association of absent PTEN expression with increased risk of death remained significant in multivariate analysis (HR = 6.31, 95% CI (2.03, 17.93), P = 0.0023). In summary, PTEN expression was consistent in matched CRC primaries and in liver metastases. Therefore, future investigations of PTEN in metastatic CRC can use primary tumor tissue. In patients with liver-only metastases, loss of PTEN expression predicted poor OS.We observed concordant PTEN expression in 98% of colorectal cancer (CRC) primary and liver metastasis pairs using a validated immunohistochemistry assay. Consistent PTEN expression at both disease sites is significant because tumor tissue is usually available from CRC primaries but not metastases. Loss of PTEN expression associated with poor survival of CRC patients with liver-only metastases.

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Oncogenic PIK3CA mutations in colorectal cancers and polyps

Cited by 77 publications

References 33 publications

PIK3CA mutation and methylation influences the outcome of colorectal cancer

PIK3CA mutation and methylation influences the outcome of colorectal cancer

PIK3CA and PTEN Gene and Exon Mutation-Specific Clinicopathologic and Molecular Associations in Colorectal Cancer

PTEN expression is consistent in colorectal cancer primaries and metastases and associates with patient survival

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