A novel carcinogenic PI3Kα mutation suggesting the role of helical domain in transmitting nSH2 regulatory signals to kinase domain

Ghalamkari, Safoura; Alavi, Shahryar; Mianesaz, Hamidreza; Khosravian, Farinaz; Bahreini, Amir; Salehi, Mansoor

doi:10.1016/j.lfs.2020.118759

Cited by 4 publications

(3 citation statements)

References 37 publications

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“…A similar pattern of mutations in 13 patients by sex in a hospital-based series of glioma patients can be seen in the dataset of Tanaka et al 26 Helical and kinase domain mutations trigger gain of function through different mechanisms: the effects of helical domain mutations have been argued to be independent of binding of p85 but require RAS-GTP, whereas the effects of the kinase domain mutations have been argued to be active without RAS-GTP binding and to be highly dependent on the interaction with p85. 28 , 29 Helical domain mutations appear to affect enzymatic function via altering transmission of signal to the kinase domain, 30 whereas kinase domain mutations appear to be activating due to a perturbation of the PIK3CA interaction with the cell membrane. 31 , 32 These differential functions can impact clinical outcomes: in breast cancer, helical domain mutations are associated with early recurrence and death, compared to optimal prognosis for kinase domain mutations.…”

Section: Discussionmentioning

confidence: 99%

Environmental and sex-specific molecular signatures of glioma causation

et al. 2021

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Background The relative importance of genetic and environmental risk factors in gliomagenesis remains uncertain. Methods Using whole-exome sequencing data from 1105 adult gliomas, we evaluate the relative contribution to cancer cell lineage proliferation and survival of single-nucleotide mutations in tumors by IDH mutation subtype and sex. We also quantify the contributions of COSMIC cancer mutational signatures to these tumors, identifying possible risk exposures. Results IDH-mutant tumors exhibited few unique recurrent substitutions—all in coding regions, while IDH-wildtype tumors exhibited many substitutions in non-coding regions. The importance of previously reported mutations in IDH1/2, TP53, EGFR, PTEN, PIK3CA and PIK3R1 was confirmed; however, the largest cancer effect in IDH wildtype tumors was associated with mutations in the low-prevalence BRAF V600E. Males and females exhibited mutations in a similar set of significantly overburdened genes, with some differences in variant sites—notably in the phosphoinositide 3-kinase (PI3K) pathway. In IDH-mutant tumors, PIK3CA mutations were located in the helical domain for females and the kinase domain for males; variants of import also differed by sex for PIK3R1. Endogenous age-related mutagenesis was the primary molecular signature identified; a signature associated with exogenous exposure to haloalkanes was identified and noted more frequently in males. Conclusions Cancer-causing mutations in glioma primarily originated as a consequence of endogenous rather than exogenous factors. Mutations in helical versus kinase domains of genes in the phosphoinositide 3-kinase (PI3K) pathway are differentially selected in males and females. Additionally, a rare environmental risk factor is suggested for some cases of glioma— particularly in males.

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Section: Discussionmentioning

confidence: 99%

Environmental and sex-specific molecular signatures of glioma causation

et al. 2021

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“…Mapping of the noncanonical PIK3CA mutations onto inactive apo, lipid-bound, and inhibitor-bound structures of the PI3Kα heterodimer outlined potential mechanisms behind their activating effects. A breadth of biochemical and biophysical studies on canonical mutations as well as a number of noncanonical mutations, including in vitro lipid binding and kinase assays (29,30), hydrogen-deuterium exchange mass spectrometry (30), and molecular dynamics simulations (32,(60)(61)(62), have demonstrated several mechanisms by which PI3Kα autoinhibition is subverted in cancer. These include (a) disruption of critical interdomain inhibitory contacts, (b) conformational rearrangement of the regulatory arch and subsequent reorientation of the activation loop for catalysis, and (c) enhanced affinity of the enzyme for anionic membrane lipids due to an increase in positive charge at the membrane-binding interface.…”

Section: Methodsmentioning

confidence: 99%

Therapeutic implications of activating noncanonical PIK3CA mutations in head and neck squamous cell carcinoma

Jin

Keam

Cho

et al. 2021

Journal of Clinical Investigation

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“…This kinase activity activates downstream signaling in response to growth factors leading to cell growth. Therefore, mutations that affect the activity of this domain result in uncontrolled growth and cancer [116]. In HPV-tumors, the mutations are not localized to any single region and occur throughout the gene [109].…”

Section: Mutation In Pik3camentioning

confidence: 99%

Genetic Drivers of Head and Neck Squamous Cell Carcinoma: Aberrant Splicing Events, Mutational Burden, HPV Infection and Future Targets

Dlamini

Alaouna

Mbatha

et al. 2021

Genes

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Head and neck cancers include cancers that originate from a variety of locations. These include the mouth, nasal cavity, throat, sinuses, and salivary glands. These cancers are the sixth most diagnosed cancers worldwide. Due to the tissues they arise from, they are collectively named head and neck squamous cell carcinomas (HNSCC). The most important risk factors for head and neck cancers are infection with human papillomavirus (HPV), tobacco use and alcohol consumption. The genetic basis behind the development and progression of HNSCC includes aberrant non-coding RNA levels. However, one of the most important differences between healthy tissue and HNSCC tissue is changes in the alternative splicing of genes that play a vital role in processes that can be described as the hallmarks of cancer. These changes in the expression profile of alternately spliced mRNA give rise to various protein isoforms. These protein isoforms, alternate methylation of proteins, and changes in the transcription of non-coding RNAs (ncRNA) can be used as diagnostic or prognostic markers and as targets for the development of new therapeutic agents. This review aims to describe changes in alternative splicing and ncRNA patterns that contribute to the development and progression of HNSCC. It will also review the use of the changes in gene expression as biomarkers or as the basis for the development of new therapies.

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A novel carcinogenic PI3Kα mutation suggesting the role of helical domain in transmitting nSH2 regulatory signals to kinase domain

Cited by 4 publications

References 37 publications

Environmental and sex-specific molecular signatures of glioma causation

Environmental and sex-specific molecular signatures of glioma causation

Therapeutic implications of activating noncanonical PIK3CA mutations in head and neck squamous cell carcinoma

Genetic Drivers of Head and Neck Squamous Cell Carcinoma: Aberrant Splicing Events, Mutational Burden, HPV Infection and Future Targets

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