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-κB, DNA repair) which may be potentially useful as predictive biomarkers of response to matched targeted therapies.
authors.affiliation: Cancer Research Malaysia, 47500 Subang Jaya, Selangor, Malaysia.
authors.forename: Yock Ping
authors.initials: YP
authors.lastname: Chow
authors.affiliation: Molecular Pathology Unit, Cancer Research Centre, Institute for Medical Research, 50588 Kuala Lumpur, Malaysia.
authors.forename: Lu Ping
authors.initials: LP
authors.lastname: Tan
authors.affiliation: Cancer Research Malaysia, 47500 Subang Jaya, Selangor, Malaysia.
authors.forename: San Jiun
authors.initials: SJ
authors.lastname: Chai
authors.affiliation: Molecular Pathology Unit, Cancer Research Centre, Institute for Medical Research, 50588 Kuala Lumpur, Malaysia.
authors.forename: Norazlin
authors.initials: N
authors.lastname: Abdul Aziz
authors.affiliation: Department of Oral and Craniofacial Sciences, Faculty of Dentistry, University of Malaya, 50603 Kuala Lumpur, Malaysia.
authors.forename: Siew Woh
authors.initials: SW
authors.lastname: Choo
authors.affiliation: Tung Shin Hospital, 55100 Kuala Lumpur, Malaysia.
authors.forename: Paul Vey Hong
authors.initials: PV
authors.lastname: Lim
authors.affiliation: Sime Darby Medical Centre, 47500 Selangor, Malaysia.
authors.forename: Rajadurai
authors.initials: R
authors.lastname: Pathmanathan
authors.affiliation: Department of Pathology, Faculty of Medicine, University Teknologi MARA (UiTM), 47000 Sungai Buloh, Selangor, Malaysia.
authors.forename: Noor Kaslina
authors.initials: NK
authors.lastname: Mohd Kornain
authors.affiliation: Department of Otorhinolaryngology, Queen Elizabeth Hospital, 88200 Kota Kinabalu, Sabah, Malaysia.
authors.forename: Chee Lun
authors.initials: CL
authors.lastname: Lum
authors.affiliation: Department of Otorhinolaryngology, Hospital Pulau Pinang, 10990 Penang, Malaysia.
authors.forename: Kin Choo
authors.initials: KC
authors.lastname: Pua
authors.affiliation: Department of Surgery, Clinical Campus Faculty of Medicine and Health Sciences, University Putra Malaysia, Hospital Kuala Lumpur, 50586 Kuala Lumpur, Malaysia.
authors.forename: Yoke Yeow
authors.initials: YY
authors.lastname: Yap
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Sarawak General Hospital, 53586 Kuching, Sarawak, Malaysia.
authors.forename: Tee Yong
authors.initials: TY
authors.lastname: Tan
authors.affiliation: Cancer Research Malaysia, 47500 Subang Jaya, Selangor, Malaysia.
authors.forename: Soo Hwang
authors.initials: SH
authors.lastname: Teo
authors.affiliation: Molecular Pathology Unit, Cancer Research Centre, Institute for Medical Research, 50588 Kuala Lumpur, Malaysia.
authors.forename: Alan Soo-Beng
authors.initials: AS
authors.lastname: Khoo
authors.affiliation: Cancer Research Malaysia, 47500 Subang Jaya, Selangor, Malaysia.
authors.forename: Vyomesh
authors.initials: V
authors.lastname: Patel
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000235:genetics; D002277:Carcinoma / Q000175:diagnosis* / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D059472:Exome / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000175:diagnosis* / Q000235:genetics; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics; D000073359:Exome Sequencing
chemical_list: D014408:Biomarkers, Tumor