Oncogenic Mutations of PIK3CA in Human Cancers

Samuels, Yardena; Waldman, Todd

doi:10.1007/82_2010_68

Cited by 254 publications

(270 citation statements)

References 134 publications

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“…Based on in vitro studies, exon 9 and 20 PIK3CA hotspot mutations increase the lipid kinase activity of PIK3CA and activate downstream signaling. In breast epithelial cell culture models, they promote anchorage-independent growth and proliferation, but remain sensitive to pharmacologic inhibition [6,13,[38][39][40][41][42]. Less common mutations such as H1047L and E542G have also been shown to increase PIK3CA signaling activity, but to a lesser degree than E545K and H1047R [43].…”

Section: Discussionmentioning

confidence: 96%

“…PIK3CA mutations most commonly occur in exon 9 (helical domain, E542K, E545K) and exon 20 (kinase domain, H1047R); these two exons account for over 85% of tumor mutations [6,10,13,18,19]. Studies have documented PIK3CA mutations in 8-40% of infiltrating breast carcinomas, [6,7,12,15,16,18,[20][21][22][23][24][25][26][27][28][29][30][31], and this holds across different ethnic groups with varying breast cancer incidence [25,28].…”

Section: Introductionmentioning

confidence: 95%

See 1 more Smart Citation

Phosphatidylinositol-3-kinase and AKT1 mutations occur early in breast carcinoma

Dunlap

Le²,

Shukla³

et al. 2009

Breast Cancer Res Treat

109

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Mutationally activated protein kinases are appealing therapeutic targets in breast carcinoma. Mutations in phosphatidylinositol-3-kinase (PI3KCA) have been described in 8-40% of invasive breast carcinomas, and AKT1 mutations have been characterized in 1-8% of breast carcinomas. However, there is little data on these mutations in breast precursor lesions. To further delineate the molecular evolution of breast tumorigenesis, samples of invasive breast carcinoma with an accompanying in situ component were macro dissected from formalin-fixed paraffin embedded tissue and screened for mutations in PIK3CA exons 7, 9, 20, and AKT1 exon 2. Laser capture micro dissection (LCM) was performed on mutation-positive carcinomas to directly compare the genotypes of separated invasive and in situ tumor cells. Among 81 cases of invasive carcinoma, there were eight mutations in PIK3CA exon 20 (7 H1047R, 1 H1047L) and four mutations in exon 9 (2 E545K, 1 E542K, 1 E545G), totaling 12/81 (14.8%). In 11 cases examined, paired LCM in situ tumor showed the identical PIK3CA mutation in invasive and in situ carcinoma. Likewise, 3 of 78 (3.8%) invasive carcinomas showed an AKT1 E17K mutation, and this mutation was identified in matching in situ carcinoma in both informative cases. Mutational status did not correlate with clinical parameters including hormone receptor status, grade, and lymph node status. The complete concordance of PIK3CA and AKT1 mutations in matched samples of invasive and in situ tumor indicates that these mutations occur early in breast cancer development and has implications with regard to therapeutics targeted to the PI3 kinase pathway.

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Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 95%

Phosphatidylinositol-3-kinase and AKT1 mutations occur early in breast carcinoma

Dunlap

Le²,

Shukla³

et al. 2009

Breast Cancer Res Treat

109

View full text Add to dashboard Cite

show abstract

“…Mutations in PIK3CA are frequent in cancers of various organs, such as colon, breast, endometrium and ovary. These mutations are mostly hot-spot mutations located in exon 9 (E542K and E545K) and exon 20 (H1047R) [94,95]. It is of interest that the mutation sites in PIK3CA are distributed widely in EBVaGC [5] with only 28% of mutations in hot spots.…”

Section: Molecular Abnormalities Demonstrated By ‘Omics' Studiesmentioning

confidence: 99%

Epstein-Barr Virus-Associated Gastric Carcinoma: Use of Host Cell Machineries and Somatic Gene Mutations

2015

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Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a distinct subtype of gastric carcinoma, consisting of clonal growth of EBV-infected epithelial cells. Its unique characteristics have been demonstrated by epidemiological, clinical and pathological studies using in situ hybridization for EBV-encoded small RNAs. An oncogenic process for EBVaGC has also been revealed. EBV uses various host-cell machineries, including cell division machinery to propagate clonal virus genomes, DNA-methylation machinery to epigenetically control infected cells, and microRNA and exosome machineries to modify the behavior and microenvironment of infected cells. Recent comprehensive molecular analyses from The Cancer Genome Atlas project demonstrate that EBVaGC is a representative molecular subtype that is distinct from microsatellite unstable, genomically stable and chromosome unstable subtypes. In addition to having the highest level of DNA methylation in CpG islands of promoter regions, EBVaGC harbors particular gene alterations, including a high frequency of mutations in PIK3CA and ARID1A, mutation in BCOR, and amplification of PD-L1 and PD-L2. Although currently undetermined, the virus might use the altered cellular functions that are induced by these somatic mutations. Further investigation of virus-driven oncogenesis will enable hitherto unknown functions of stomach epithelial cell machineries to be elucidated, which may reveal potential therapeutic targets for EBVaGC.

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“…PTEN, a tumor suppressor, antagonizes PI3K [119]. It has been shown, that PI3KCA is mutated in over 25% of diVerent human cancers, including gastrointestinal, breast, diVerent brain and head and neck cancer [100]. Studies regarding the correlation of PI3K mutations and clinicopathological data in OSCC are still required.…”

Section: Pi3k/nf-kbmentioning

confidence: 99%

Update of prognostic and predictive biomarkers in oropharyngeal squamous cell carcinoma: a review

Grimminger

Danenberg

2010

Eur Arch Otorhinolaryngol

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Oropharyngeal squamous cell carcinomas (OSCC) constitute about 5% of all cancers in the western world and the incidence and mortality rates of this tumor have shown little improvement over the last 30 years. Molecular targeted therapy, a promising strategy for the treatment of OSCC and other cancers, requires the understanding of specific molecular events of carcinogenesis and the different pathological, partly interrelated pathways. Extended knowledge of the prognostic or predictive value of molecular biomarkers in oropharyngeal cancer is necessary to allow a better characterization and classification of the tumor, improve the appraisal of clinical outcome and help to specify individual multimodal therapy with increased efficiency. This work affords an updated summary regarding recent data about tissue biomarkers in patients with OSCC, based on the six essential hallmarks of cancer described by Hanahan and Weinberg (Cell 100(1):57-70, 2000) providing the characterization of a malignant cell.

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Oncogenic Mutations of PIK3CA in Human Cancers

Cited by 254 publications

References 134 publications

Phosphatidylinositol-3-kinase and AKT1 mutations occur early in breast carcinoma

Phosphatidylinositol-3-kinase and AKT1 mutations occur early in breast carcinoma

Epstein-Barr Virus-Associated Gastric Carcinoma: Use of Host Cell Machineries and Somatic Gene Mutations

Update of prognostic and predictive biomarkers in oropharyngeal squamous cell carcinoma: a review

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