High Frequency of Mutations of the
            <i>PIK3CA</i>
            Gene in Human Cancers

Samuels, Yardena; Wang, Zhenghe; Bardelli, Alberto; Silliman, Natalie; Ptak, Janine; Szabo, Steve; Yan, Hai; Gazdar, Adi F.; Powell, Steven M.; Riggins, Gregory J.; Willson, James K.V.; Markowitz, Sanford D.; Kinzler, Kenneth W.; Vogelstein, Bert; Velculescu, Victor E.

doi:10.1126/science.1096502

Cited by 3,181 publications

(2,907 citation statements)

References 4 publications

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“…Though previous studies have investigated the role of PI3K mutation and MSI in CRC, the data are in part conflicting. While Samuels et al (2004) found a significantly higher frequency of PIK3CA mutation in MMR deficient tumors compared to MMR proficient tumors (16/33 vs 58/201, P ¼ 0.014), others failed to highlight this correlation (Velho et al, 2005;Ollikainen et al, 2007). Our study showed significantly higher PIK3CA mutations within the MSI subset of CRC (35.9%).…”

Section: Discussioncontrasting

confidence: 63%

Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population

Abubaker¹,

Bavi²,

Al-harbi³

et al. 2008

Oncogene

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Activation of the phosphatidylinositol 3 0 -kinase (PI3K)/ AKT pathway results in an increase in cell proliferation and survival. Somatic mutations within the PI3K catalytic subunit, PIK3CA are common cause of increasing PI3K activity and are believed to be oncogenic in many cancer types. Few reports addressed the association between PIK3CA mutations and tumor progression specifically in microsatellite instable (MSI) colorectal cancer (CRC). In the present study, we have evaluated PIK3CA mutational status in a series of 410 Middle Eastern CRC and 13 colon cell lines to study the prevalence of PIK3CA mutations in MSI cases, PTEN expression in CRC and possibility of therapeutic targeting of this set of patients. PIK3CA mutations were found in four of the cell lines tested and 51 colorectal carcinomas (12.2%). Three of these four mutated cell lines were MSI. PTEN was inactivated in 66.1% of the CRC. Furthermore, we observed a strong association between PIK3CA mutations and MSI status (P ¼ 0.0046) while PTEN loss was more frequent in microsatellite stable (MSS) CRC (P ¼ 0.043). A high prevalence of genetic alterations in PI3K/AKT pathway in Saudi cohort of CRC, predominance of PIK3CA mutations in the MSI subgroup and their possible involvement in development/progression of this subset of CRC are some of the significant findings of our study.

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Section: Discussioncontrasting

confidence: 63%

Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population

Abubaker¹,

Bavi²,

Al-harbi³

et al. 2008

Oncogene

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“…Amplification of genomic regions and the somatic mutations of PIK3CA genes encoding the PI3K-p110 catalytic subunit have been reported and related to the activation of the PI3K pathway (Samuels et al, 2004). PI3K family members have also been shown to exhibit increased gene copy numbers in ovarian cancer (Zhang et al, 2007), although PI3K-p110 was not systematically analysed in the report.…”

Section: Discussionmentioning

confidence: 99%

E-cadherin directly contributes to PI3K/AKT activation by engaging the PI3K-p85 regulatory subunit to adherens junctions of ovarian carcinoma cells

et al. 2009

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E-cadherin (cadh), a member of a family of integral membrane glycoproteins that represent the major component of adherens junctions (AJs), mediates cell-cell adhesion through the calcium-dependent homophilic interaction of its extracellular domain. Metastatic human carcinomas frequently lose E-cadh expression, whereas epithelial ovarian cancer (EOCs) maintain properties characteristic of Mu¨llerian epithelium during tumor progression, including E-cadh expression. Here, we examined the potential role of cell-cell contacts in EOCs through E-cadh homophilic interactions in PI3K/AKT activation whose altered signaling has been implicated in EOC pathogenesis. We show that E-cadh is predominantly expressed at cell-cell contacts and its functionality is necessary and sufficient for the activation of the PI3K/ AKT pathway. E-cadh knockdown and phosphoinositide-3-kinase (PI3K) inhibition complement each other in impairing cell-cycle progression and proliferation of ovarian carcinoma cells. E-cadh is stably bound to the PI3K complex, and the de novo formation of E-cadh/bcatenin complexes following calcium deprivation and subsequent calcium restoration recruits the PI3K p85 subunit to the site of the cell-cell contacts. The finding that E-cadh-mediated AJ formation contributes to PI3K/AKT activation in EOC cells by a mechanism that appears to be restricted to these cells provides the underpinning for therapeutic strategies that exploit PI3K inhibition to halt EOCs.

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“…49 The reported PIK3CA mutation frequency in sporadic CRC was higher (between 11 and 32%; COSMIC). 30,50 …”

Section: Somatic Mutation Analysismentioning

confidence: 99%

Increased frequency of 20q gain and copy‐neutral loss of heterozygosity in mismatch repair proficient familial colorectal carcinomas

Middeldorp

Eijk

Oosting

et al. 2011

Intl Journal of Cancer

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Many hereditary nonpolyposis colorectal cancers (CRCs) cannot be explained by Lynch syndrome. Other high penetrance genetic risk factors are likely to play a role in these mismatch repair (MMR)-proficient CRC families. Because genomic profiles of CRC tend to vary with CRC susceptibility syndromes, our aim is to analyze the genomic profile of MMR-proficient familial CRC to obtain insight into the biological basis of MMR-proficient familial CRC. We studied 30 MMR-proficient familial colorectal carcinomas, from 15 families, for genomic aberrations, including gains, physical losses, and copy-neutral loss of heterozygosity LOH (cnLOH) using SNP array comparative genomic hybridization. In addition, we performed somatic mutation analysis for KRAS, BRAF, PIK3CA and GNAS. The frequency of 20q gain (77%) is remarkably increased when compared with sporadic CRC, suggesting that 20q gain is involved in tumor progression of familial CRC. There is also a significant increase in the frequency of cnLOH and, as a consequence, a reduced frequency of physical loss compared with sporadic CRC. The most frequent aberrations observed included gains of 7p, 7q, 8q, 13q, 20p and 20q as well as physical losses of 17p, 18p and 18q. Most of these changes are also observed in sporadic CRC. Mutations in KRAS were identified in 37% of the MMRproficient CRCs, and mutations in BRAF were identified in 16%. No mutations were identified in PIK3CA or chromosome 20 candidate gene GNAS. We show that the patterns of chromosomal instability of MMR-proficient familial CRC are clearly distinct from those from sporadic CRC. Both the increased gain on chromosome 20 and the increased levels of cnLOH suggest the presence of yet undiscovered germline defects that can, in part, underlie the cancer risk in these families.

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High Frequency of Mutations of the PIK3CA Gene in Human Cancers

Cited by 3,181 publications

References 4 publications

Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population

Clinicopathological analysis of colorectal cancers with PIK3CA mutations in Middle Eastern population

E-cadherin directly contributes to PI3K/AKT activation by engaging the PI3K-p85 regulatory subunit to adherens junctions of ovarian carcinoma cells

Increased frequency of 20q gain and copy‐neutral loss of heterozygosity in mismatch repair proficient familial colorectal carcinomas

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