Exome Sequencing Identifies Potentially Druggable Mutations in Nasopharyngeal Carcinoma

In this study, we first performed whole exome sequencing of DNA from 10 untreated and clinically annotated fresh frozen nasopharyngeal carcinoma (NPC) biopsies and matched bloods to identify somatically mutated genes that may be amenable to targeted therapeutic strategies. We identified a total of 3...

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Main Authors: Chow, Y.P., Tan, L.P., Chai, S.J., Abdul Aziz, N., Choo, S.W., Lim, P.V.H., Pathmanathan, R., Mohd Kornain, N.K., Lum, C.L., Pua, K.C., Yap, Y.Y., Tan, T.Y., Teo, S.H., Khoo, A.S.B., Patel, V.
Format: Article
Language:English
Published: Nature Publishing Group 2017
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Online Access:http://eprints.um.edu.my/17153/1/srep42980_%281%29.pdf
http://eprints.um.edu.my/17153/
https://www.nature.com/articles/srep42980
https://doi.org/10.1038/srep42980
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spelling my.um.eprints.171532017-07-04T02:05:42Z http://eprints.um.edu.my/17153/ Exome Sequencing Identifies Potentially Druggable Mutations in Nasopharyngeal Carcinoma Chow, Y.P. Tan, L.P. Chai, S.J. Abdul Aziz, N. Choo, S.W. Lim, P.V.H. Pathmanathan, R. Mohd Kornain, N.K. Lum, C.L. Pua, K.C. Yap, Y.Y. Tan, T.Y. Teo, S.H. Khoo, A.S.B. Patel, V. Practice of dentistry. Dental economics In this study, we first performed whole exome sequencing of DNA from 10 untreated and clinically annotated fresh frozen nasopharyngeal carcinoma (NPC) biopsies and matched bloods to identify somatically mutated genes that may be amenable to targeted therapeutic strategies. We identified a total of 323 mutations which were either non-synonymous (n = 238) or synonymous (n = 85). Furthermore, our analysis revealed genes in key cancer pathways (DNA repair, cell cycle regulation, apoptosis, immune response, lipid signaling) were mutated, of which those in the lipid-signaling pathway were the most enriched. We next extended our analysis on a prioritized sub-set of 37 mutated genes plus top 5 mutated cancer genes listed in COSMIC using a custom designed HaloPlex target enrichment panel with an additional 88 NPC samples. Our analysis identified 160 additional non-synonymous mutations in 37/42 genes in 66/88 samples. Of these, 99/160 mutations within potentially druggable pathways were further selected for validation. Sanger sequencing revealed that 77/99 variants were true positives, giving an accuracy of 78%. Taken together, our study indicated that similar to 72% (n = 71/98) of NPC samples harbored mutations in one of the four cancer pathways (EGFR-PI3KAkt-mTOR, NOTCH, NF-.B, DNA repair) which may be potentially useful as predictive biomarkers of response to matched targeted therapies. Nature Publishing Group 2017 Article PeerReviewed application/pdf en http://eprints.um.edu.my/17153/1/srep42980_%281%29.pdf Chow, Y.P. and Tan, L.P. and Chai, S.J. and Abdul Aziz, N. and Choo, S.W. and Lim, P.V.H. and Pathmanathan, R. and Mohd Kornain, N.K. and Lum, C.L. and Pua, K.C. and Yap, Y.Y. and Tan, T.Y. and Teo, S.H. and Khoo, A.S.B. and Patel, V. (2017) Exome Sequencing Identifies Potentially Druggable Mutations in Nasopharyngeal Carcinoma. Scientific Reports, 7. p. 42980. ISSN 2045-2322 https://www.nature.com/articles/srep42980 https://doi.org/10.1038/srep42980
institution Universiti Malaya
building UM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Malaya
content_source UM Research Repository
url_provider http://eprints.um.edu.my/
language English
topic Practice of dentistry. Dental economics
spellingShingle Practice of dentistry. Dental economics
Chow, Y.P.
Tan, L.P.
Chai, S.J.
Abdul Aziz, N.
Choo, S.W.
Lim, P.V.H.
Pathmanathan, R.
Mohd Kornain, N.K.
Lum, C.L.
Pua, K.C.
Yap, Y.Y.
Tan, T.Y.
Teo, S.H.
Khoo, A.S.B.
Patel, V.
Exome Sequencing Identifies Potentially Druggable Mutations in Nasopharyngeal Carcinoma
description In this study, we first performed whole exome sequencing of DNA from 10 untreated and clinically annotated fresh frozen nasopharyngeal carcinoma (NPC) biopsies and matched bloods to identify somatically mutated genes that may be amenable to targeted therapeutic strategies. We identified a total of 323 mutations which were either non-synonymous (n = 238) or synonymous (n = 85). Furthermore, our analysis revealed genes in key cancer pathways (DNA repair, cell cycle regulation, apoptosis, immune response, lipid signaling) were mutated, of which those in the lipid-signaling pathway were the most enriched. We next extended our analysis on a prioritized sub-set of 37 mutated genes plus top 5 mutated cancer genes listed in COSMIC using a custom designed HaloPlex target enrichment panel with an additional 88 NPC samples. Our analysis identified 160 additional non-synonymous mutations in 37/42 genes in 66/88 samples. Of these, 99/160 mutations within potentially druggable pathways were further selected for validation. Sanger sequencing revealed that 77/99 variants were true positives, giving an accuracy of 78%. Taken together, our study indicated that similar to 72% (n = 71/98) of NPC samples harbored mutations in one of the four cancer pathways (EGFR-PI3KAkt-mTOR, NOTCH, NF-.B, DNA repair) which may be potentially useful as predictive biomarkers of response to matched targeted therapies.
format Article
author Chow, Y.P.
Tan, L.P.
Chai, S.J.
Abdul Aziz, N.
Choo, S.W.
Lim, P.V.H.
Pathmanathan, R.
Mohd Kornain, N.K.
Lum, C.L.
Pua, K.C.
Yap, Y.Y.
Tan, T.Y.
Teo, S.H.
Khoo, A.S.B.
Patel, V.
author_facet Chow, Y.P.
Tan, L.P.
Chai, S.J.
Abdul Aziz, N.
Choo, S.W.
Lim, P.V.H.
Pathmanathan, R.
Mohd Kornain, N.K.
Lum, C.L.
Pua, K.C.
Yap, Y.Y.
Tan, T.Y.
Teo, S.H.
Khoo, A.S.B.
Patel, V.
author_sort Chow, Y.P.
title Exome Sequencing Identifies Potentially Druggable Mutations in Nasopharyngeal Carcinoma
title_short Exome Sequencing Identifies Potentially Druggable Mutations in Nasopharyngeal Carcinoma
title_full Exome Sequencing Identifies Potentially Druggable Mutations in Nasopharyngeal Carcinoma
title_fullStr Exome Sequencing Identifies Potentially Druggable Mutations in Nasopharyngeal Carcinoma
title_full_unstemmed Exome Sequencing Identifies Potentially Druggable Mutations in Nasopharyngeal Carcinoma
title_sort exome sequencing identifies potentially druggable mutations in nasopharyngeal carcinoma
publisher Nature Publishing Group
publishDate 2017
url http://eprints.um.edu.my/17153/1/srep42980_%281%29.pdf
http://eprints.um.edu.my/17153/
https://www.nature.com/articles/srep42980
https://doi.org/10.1038/srep42980
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