Exome Sequencing Identifies Potentially Druggable Mutations in Nasopharyngeal Carcinoma

Chow Yock Ping, Lu Ping Tan, San Jiun Chai, Norazlin Abdul Aziz, Siew Woh Choo, Paul Vey Hong Lim, Rajadurai Pathmanathan, Noor Kaslina Mohd Kornain, Chee Lun Lum, Kin Choo Pua, Yoke Yeow Yap, Tee Yong Tan, Soo Hwang Teo, Alan Soo Beng Khoo, Vyomesh Patel

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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 ∼72% (n = 71/98) of NPC samples harbored mutations in one of the four cancer pathways (EGFR-PI3K-Akt-mTOR, NOTCH, NF-ΰ B, DNA repair) which may be potentially useful as predictive biomarkers of response to matched targeted therapies.

Original languageEnglish
Article number42980
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - 3 Mar 2017
Externally publishedYes

Fingerprint

Exome
Mutation
DNA Repair
Genes
Lipids
Neoplasm Genes
Phosphatidylinositol 3-Kinases
DNA Sequence Analysis
Neoplasms
Cell Cycle
Biomarkers
Apoptosis
Biopsy
Nasopharyngeal carcinoma
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Yock Ping, C., Tan, L. P., Chai, S. J., Abdul Aziz, N., Choo, S. W., Lim, P. V. H., ... Patel, V. (2017). Exome Sequencing Identifies Potentially Druggable Mutations in Nasopharyngeal Carcinoma. Scientific Reports, 7, [42980]. https://doi.org/10.1038/srep42980

Exome Sequencing Identifies Potentially Druggable Mutations in Nasopharyngeal Carcinoma. / Yock Ping, Chow; Tan, Lu Ping; Chai, San Jiun; Abdul Aziz, Norazlin; Choo, Siew Woh; Lim, Paul Vey Hong; Pathmanathan, Rajadurai; Kornain, Noor Kaslina Mohd; Lum, Chee Lun; Pua, Kin Choo; Yap, Yoke Yeow; Tan, Tee Yong; Teo, Soo Hwang; Khoo, Alan Soo Beng; Patel, Vyomesh.

In: Scientific Reports, Vol. 7, 42980, 03.03.2017.

Research output: Contribution to journalArticle

Yock Ping, C, Tan, LP, Chai, SJ, Abdul Aziz, N, Choo, SW, Lim, PVH, Pathmanathan, R, Kornain, NKM, Lum, CL, Pua, KC, Yap, YY, Tan, TY, Teo, SH, Khoo, ASB & Patel, V 2017, 'Exome Sequencing Identifies Potentially Druggable Mutations in Nasopharyngeal Carcinoma', Scientific Reports, vol. 7, 42980. https://doi.org/10.1038/srep42980
Yock Ping C, Tan LP, Chai SJ, Abdul Aziz N, Choo SW, Lim PVH et al. Exome Sequencing Identifies Potentially Druggable Mutations in Nasopharyngeal Carcinoma. Scientific Reports. 2017 Mar 3;7. 42980. https://doi.org/10.1038/srep42980
Yock Ping, Chow ; Tan, Lu Ping ; Chai, San Jiun ; Abdul Aziz, Norazlin ; Choo, Siew Woh ; Lim, Paul Vey Hong ; Pathmanathan, Rajadurai ; Kornain, Noor Kaslina Mohd ; Lum, Chee Lun ; Pua, Kin Choo ; Yap, Yoke Yeow ; Tan, Tee Yong ; Teo, Soo Hwang ; Khoo, Alan Soo Beng ; Patel, Vyomesh. / Exome Sequencing Identifies Potentially Druggable Mutations in Nasopharyngeal Carcinoma. In: Scientific Reports. 2017 ; Vol. 7.
@article{4d10daba3d654d4e88bc5bcebc11cdbd,
title = "Exome Sequencing Identifies Potentially Druggable Mutations in Nasopharyngeal Carcinoma",
abstract = "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 ∼72{\%} (n = 71/98) of NPC samples harbored mutations in one of the four cancer pathways (EGFR-PI3K-Akt-mTOR, NOTCH, NF-{\^I}° B, DNA repair) which may be potentially useful as predictive biomarkers of response to matched targeted therapies.",
author = "{Yock Ping}, Chow and Tan, {Lu Ping} and Chai, {San Jiun} and {Abdul Aziz}, Norazlin and Choo, {Siew Woh} and Lim, {Paul Vey Hong} and Rajadurai Pathmanathan and Kornain, {Noor Kaslina Mohd} and Lum, {Chee Lun} and Pua, {Kin Choo} and Yap, {Yoke Yeow} and Tan, {Tee Yong} and Teo, {Soo Hwang} and Khoo, {Alan Soo Beng} and Vyomesh Patel",
year = "2017",
month = "3",
day = "3",
doi = "10.1038/srep42980",
language = "English",
volume = "7",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Exome Sequencing Identifies Potentially Druggable Mutations in Nasopharyngeal Carcinoma

AU - Yock Ping, Chow

AU - Tan, Lu Ping

AU - Chai, San Jiun

AU - Abdul Aziz, Norazlin

AU - Choo, Siew Woh

AU - Lim, Paul Vey Hong

AU - Pathmanathan, Rajadurai

AU - Kornain, Noor Kaslina Mohd

AU - Lum, Chee Lun

AU - Pua, Kin Choo

AU - Yap, Yoke Yeow

AU - Tan, Tee Yong

AU - Teo, Soo Hwang

AU - Khoo, Alan Soo Beng

AU - Patel, Vyomesh

PY - 2017/3/3

Y1 - 2017/3/3

N2 - 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 ∼72% (n = 71/98) of NPC samples harbored mutations in one of the four cancer pathways (EGFR-PI3K-Akt-mTOR, NOTCH, NF-ΰ B, DNA repair) which may be potentially useful as predictive biomarkers of response to matched targeted therapies.

AB - 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 ∼72% (n = 71/98) of NPC samples harbored mutations in one of the four cancer pathways (EGFR-PI3K-Akt-mTOR, NOTCH, NF-ΰ B, DNA repair) which may be potentially useful as predictive biomarkers of response to matched targeted therapies.

UR - http://www.scopus.com/inward/record.url?scp=85014671177&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85014671177&partnerID=8YFLogxK

U2 - 10.1038/srep42980

DO - 10.1038/srep42980

M3 - Article

C2 - 28256603

AN - SCOPUS:85014671177

VL - 7

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

M1 - 42980

ER -