Genetic variant rs10251977 (G>A) in EGFR-AS1 modulates the expression of EGFR isoforms A and D

Abstract Tyrosine kinase inhibitor is an effective chemo-therapeutic drug against tumors with deregulated EGFR pathway. Recently, a genetic variant rs10251977 (G>A) in exon 20 of EGFR reported to act as a prognostic marker for HNSCC. Genotyping of this polymorphism in oral cancer patients showed...

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Autores principales:	Shankar Dhamodharan, Mathew Maria Rose, Sundaram Reddy Chakkarappan, Karuppiah Vijayamuthuramalingam Umadharshini, Ramalingam Arulmurugan, Shanmugam Subbiah, Ituro Inoue, Arasambattu Kannan Munirajan
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/faff5b05fc5f4e8b8985d90024ca286f
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spelling	oai:doaj.org-article:faff5b05fc5f4e8b8985d90024ca286f2021-12-02T17:32:59ZGenetic variant rs10251977 (G>A) in EGFR-AS1 modulates the expression of EGFR isoforms A and D10.1038/s41598-021-88161-32045-2322https://doaj.org/article/faff5b05fc5f4e8b8985d90024ca286f2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88161-3https://doaj.org/toc/2045-2322Abstract Tyrosine kinase inhibitor is an effective chemo-therapeutic drug against tumors with deregulated EGFR pathway. Recently, a genetic variant rs10251977 (G>A) in exon 20 of EGFR reported to act as a prognostic marker for HNSCC. Genotyping of this polymorphism in oral cancer patients showed a similar frequency in cases and controls. EGFR-AS1 expressed significantly high level in tumors and EGFR-A isoform expression showed significant positive correlation (r = 0.6464, p < 0.0001) with reference to EGFR-AS1 expression levels, consistent with larger TCGA HNSCC tumor dataset. Our bioinformatic analysis showed enrichment of alternative splicing marks H3K36me3 and presence of intronic polyA sites spanning around exon 15a and 15b of EGFR facilitates skipping of exon 15b, thereby promoting the splicing of EGFR-A isoform. In addition, high level expression of PTBP1 and its binding site in EGFR and EGFR-AS1 enhances the expression of EGFR-A isoform (r = 0.7404, p < 0.0001) suggesting that EGFR-AS1 expression modulates the EGFR-A and D isoforms through alternative splicing. In addition, this polymorphism creates a binding site for miR-891b in EGFR-AS1 and may negatively regulate the EGFR-A. Collectively, our results suggested the presence of genetic variant in EGFR-AS1 modulates the expression of EGFR-D and A isoforms.Shankar DhamodharanMathew Maria RoseSundaram Reddy ChakkarappanKaruppiah Vijayamuthuramalingam UmadharshiniRamalingam ArulmuruganShanmugam SubbiahIturo InoueArasambattu Kannan MunirajanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Shankar Dhamodharan Mathew Maria Rose Sundaram Reddy Chakkarappan Karuppiah Vijayamuthuramalingam Umadharshini Ramalingam Arulmurugan Shanmugam Subbiah Ituro Inoue Arasambattu Kannan Munirajan Genetic variant rs10251977 (G>A) in EGFR-AS1 modulates the expression of EGFR isoforms A and D
description	Abstract Tyrosine kinase inhibitor is an effective chemo-therapeutic drug against tumors with deregulated EGFR pathway. Recently, a genetic variant rs10251977 (G>A) in exon 20 of EGFR reported to act as a prognostic marker for HNSCC. Genotyping of this polymorphism in oral cancer patients showed a similar frequency in cases and controls. EGFR-AS1 expressed significantly high level in tumors and EGFR-A isoform expression showed significant positive correlation (r = 0.6464, p < 0.0001) with reference to EGFR-AS1 expression levels, consistent with larger TCGA HNSCC tumor dataset. Our bioinformatic analysis showed enrichment of alternative splicing marks H3K36me3 and presence of intronic polyA sites spanning around exon 15a and 15b of EGFR facilitates skipping of exon 15b, thereby promoting the splicing of EGFR-A isoform. In addition, high level expression of PTBP1 and its binding site in EGFR and EGFR-AS1 enhances the expression of EGFR-A isoform (r = 0.7404, p < 0.0001) suggesting that EGFR-AS1 expression modulates the EGFR-A and D isoforms through alternative splicing. In addition, this polymorphism creates a binding site for miR-891b in EGFR-AS1 and may negatively regulate the EGFR-A. Collectively, our results suggested the presence of genetic variant in EGFR-AS1 modulates the expression of EGFR-D and A isoforms.
format	article
author	Shankar Dhamodharan Mathew Maria Rose Sundaram Reddy Chakkarappan Karuppiah Vijayamuthuramalingam Umadharshini Ramalingam Arulmurugan Shanmugam Subbiah Ituro Inoue Arasambattu Kannan Munirajan
author_facet	Shankar Dhamodharan Mathew Maria Rose Sundaram Reddy Chakkarappan Karuppiah Vijayamuthuramalingam Umadharshini Ramalingam Arulmurugan Shanmugam Subbiah Ituro Inoue Arasambattu Kannan Munirajan
author_sort	Shankar Dhamodharan
title	Genetic variant rs10251977 (G>A) in EGFR-AS1 modulates the expression of EGFR isoforms A and D
title_short	Genetic variant rs10251977 (G>A) in EGFR-AS1 modulates the expression of EGFR isoforms A and D
title_full	Genetic variant rs10251977 (G>A) in EGFR-AS1 modulates the expression of EGFR isoforms A and D
title_fullStr	Genetic variant rs10251977 (G>A) in EGFR-AS1 modulates the expression of EGFR isoforms A and D
title_full_unstemmed	Genetic variant rs10251977 (G>A) in EGFR-AS1 modulates the expression of EGFR isoforms A and D
title_sort	genetic variant rs10251977 (g>a) in egfr-as1 modulates the expression of egfr isoforms a and d
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/faff5b05fc5f4e8b8985d90024ca286f
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Genetic variant rs10251977 (G>A) in EGFR-AS1 modulates the expression of EGFR isoforms A and D

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