Whole-Exome Sequencing of Nasopharyngeal Carcinoma Families Reveals Novel Variants Potentially Involved in Nasopharyngeal Carcinoma

Abstract Genetic susceptibility is likely involved in nasopharyngeal carcinoma (NPC), a cancer caused by Epstein-Barr virus (EBV) infection. Understanding of genetic factors involved in NPC and how they contribute to EBV-induced carcinogenesis is limited. We conducted whole-exome capture/sequencing...

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Autores principales:	Guoqin Yu, Wan-Lun Hsu, Anna E. Coghill, Kelly J. Yu, Cheng-Ping Wang, Pei-Jen Lou, Zhiwei Liu, Kristie Jones, Aurelie Vogt, Mingyi Wang, Sam M. Mbulaiteye, Hao-Hui Chen, Joseph Boland, Meredith Yeager, Scott R. Diehl, Chien-Jen Chen, Allan Hildesheim, Alisa M. Goldstein
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e5fb76f62f6e481fa602857aaba4b9ad
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spelling	oai:doaj.org-article:e5fb76f62f6e481fa602857aaba4b9ad2021-12-02T15:09:46ZWhole-Exome Sequencing of Nasopharyngeal Carcinoma Families Reveals Novel Variants Potentially Involved in Nasopharyngeal Carcinoma10.1038/s41598-019-46137-42045-2322https://doaj.org/article/e5fb76f62f6e481fa602857aaba4b9ad2019-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-46137-4https://doaj.org/toc/2045-2322Abstract Genetic susceptibility is likely involved in nasopharyngeal carcinoma (NPC), a cancer caused by Epstein-Barr virus (EBV) infection. Understanding of genetic factors involved in NPC and how they contribute to EBV-induced carcinogenesis is limited. We conducted whole-exome capture/sequencing among 251 individuals from 97 multiplex families from Taiwan (205 affected, 21 obligate carriers, and 25 unaffected) using SeqCap EZ Human Exome Library v3.0 and Illumina HiSeq. Aligned sequences were filtered to identify likely-to-be-functional deleterious variants that co-segregated with disease. Ingenuity Pathway analysis was performed. Circulating magnesium levels were measured in 13 individuals in 2 families with NIPAL1 mutations and in 197 sporadic NPC cases and 237 controls. We identified variants in 12 genes likely involved in cancer pathogenesis, viral infection or immune responses to infection. These included genes postulated to be involved in magnesium transport (NIPAL1), EBV cell entry (ITGB6), modulation of EBV infection (BCL2L12, NEDD4L), telomere biology (CLPTM1L, BRD2, HNRNPU), modulation of cAMP signaling (RAPGEF3), DNA repair (PRKDC, MLH1), and Notch signaling (NOTCH1, DLL3). Pathway based analysis demonstrated enrichment for Notch signaling genes (p-value = 0.0006). Evaluation of individuals within NIPAL1 families suggested lower serum magnesium in NPC compared to unaffected members. A significant reduction in serum magnesium levels was observed among sporadic NPC cases compared to controls (7.1% NPC/1.7% controls below normal range; OR = 4.5; 95% CI = 1.4,14) and is consistent with findings demonstrating a role for magnesium channeling in T-cell responses to EBV. We identified novel genes associated with NPC that point to new areas of inquiry to better understand genetic factors that determine the fate of viral infections and/or otherwise predisposes to NPC.Guoqin YuWan-Lun HsuAnna E. CoghillKelly J. YuCheng-Ping WangPei-Jen LouZhiwei LiuKristie JonesAurelie VogtMingyi WangSam M. MbulaiteyeHao-Hui ChenJoseph BolandMeredith YeagerScott R. DiehlChien-Jen ChenAllan HildesheimAlisa M. GoldsteinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-10 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Guoqin Yu Wan-Lun Hsu Anna E. Coghill Kelly J. Yu Cheng-Ping Wang Pei-Jen Lou Zhiwei Liu Kristie Jones Aurelie Vogt Mingyi Wang Sam M. Mbulaiteye Hao-Hui Chen Joseph Boland Meredith Yeager Scott R. Diehl Chien-Jen Chen Allan Hildesheim Alisa M. Goldstein Whole-Exome Sequencing of Nasopharyngeal Carcinoma Families Reveals Novel Variants Potentially Involved in Nasopharyngeal Carcinoma
description	Abstract Genetic susceptibility is likely involved in nasopharyngeal carcinoma (NPC), a cancer caused by Epstein-Barr virus (EBV) infection. Understanding of genetic factors involved in NPC and how they contribute to EBV-induced carcinogenesis is limited. We conducted whole-exome capture/sequencing among 251 individuals from 97 multiplex families from Taiwan (205 affected, 21 obligate carriers, and 25 unaffected) using SeqCap EZ Human Exome Library v3.0 and Illumina HiSeq. Aligned sequences were filtered to identify likely-to-be-functional deleterious variants that co-segregated with disease. Ingenuity Pathway analysis was performed. Circulating magnesium levels were measured in 13 individuals in 2 families with NIPAL1 mutations and in 197 sporadic NPC cases and 237 controls. We identified variants in 12 genes likely involved in cancer pathogenesis, viral infection or immune responses to infection. These included genes postulated to be involved in magnesium transport (NIPAL1), EBV cell entry (ITGB6), modulation of EBV infection (BCL2L12, NEDD4L), telomere biology (CLPTM1L, BRD2, HNRNPU), modulation of cAMP signaling (RAPGEF3), DNA repair (PRKDC, MLH1), and Notch signaling (NOTCH1, DLL3). Pathway based analysis demonstrated enrichment for Notch signaling genes (p-value = 0.0006). Evaluation of individuals within NIPAL1 families suggested lower serum magnesium in NPC compared to unaffected members. A significant reduction in serum magnesium levels was observed among sporadic NPC cases compared to controls (7.1% NPC/1.7% controls below normal range; OR = 4.5; 95% CI = 1.4,14) and is consistent with findings demonstrating a role for magnesium channeling in T-cell responses to EBV. We identified novel genes associated with NPC that point to new areas of inquiry to better understand genetic factors that determine the fate of viral infections and/or otherwise predisposes to NPC.
format	article
author	Guoqin Yu Wan-Lun Hsu Anna E. Coghill Kelly J. Yu Cheng-Ping Wang Pei-Jen Lou Zhiwei Liu Kristie Jones Aurelie Vogt Mingyi Wang Sam M. Mbulaiteye Hao-Hui Chen Joseph Boland Meredith Yeager Scott R. Diehl Chien-Jen Chen Allan Hildesheim Alisa M. Goldstein
author_facet	Guoqin Yu Wan-Lun Hsu Anna E. Coghill Kelly J. Yu Cheng-Ping Wang Pei-Jen Lou Zhiwei Liu Kristie Jones Aurelie Vogt Mingyi Wang Sam M. Mbulaiteye Hao-Hui Chen Joseph Boland Meredith Yeager Scott R. Diehl Chien-Jen Chen Allan Hildesheim Alisa M. Goldstein
author_sort	Guoqin Yu
title	Whole-Exome Sequencing of Nasopharyngeal Carcinoma Families Reveals Novel Variants Potentially Involved in Nasopharyngeal Carcinoma
title_short	Whole-Exome Sequencing of Nasopharyngeal Carcinoma Families Reveals Novel Variants Potentially Involved in Nasopharyngeal Carcinoma
title_full	Whole-Exome Sequencing of Nasopharyngeal Carcinoma Families Reveals Novel Variants Potentially Involved in Nasopharyngeal Carcinoma
title_fullStr	Whole-Exome Sequencing of Nasopharyngeal Carcinoma Families Reveals Novel Variants Potentially Involved in Nasopharyngeal Carcinoma
title_full_unstemmed	Whole-Exome Sequencing of Nasopharyngeal Carcinoma Families Reveals Novel Variants Potentially Involved in Nasopharyngeal Carcinoma
title_sort	whole-exome sequencing of nasopharyngeal carcinoma families reveals novel variants potentially involved in nasopharyngeal carcinoma
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/e5fb76f62f6e481fa602857aaba4b9ad
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Whole-Exome Sequencing of Nasopharyngeal Carcinoma Families Reveals Novel Variants Potentially Involved in Nasopharyngeal Carcinoma

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