title: Genetically-defined novel oral squamous cell carcinoma cell lines for the development of molecular therapies.
abstract: Emerging biological and translational insights from large sequencing efforts underscore the need for genetically-relevant cell lines to study the relationships between genomic alterations of tumors, and therapeutic dependencies. Here, we report a detailed characterization of a novel panel of clinically annotated oral squamous cell carcinoma (OSCC) cell lines, derived from patients with diverse ethnicity and risk habits. Molecular analysis by RNAseq and copy number alterations (CNA) identified that the cell lines harbour CNA that have been previously reported in OSCC, for example focal amplications in 3q, 7p, 8q, 11q, 20q and deletions in 3p, 5q, 8p, 18q. Similarly, our analysis identified the same cohort of frequently mutated genes previously reported in OSCC including TP53, CDKN2A, EPHA2, FAT1, NOTCH1, CASP8 and PIK3CA. Notably, we identified mutations (MLL4, USP9X, ARID2) in cell lines derived from betel quid users that may be associated with this specific risk factor. Gene expression profiles of the ORL lines also aligned with those reported for OSCC. By focusing on those gene expression signatures that are predictive of chemotherapeutic response, we observed that the ORL lines broadly clustered into three groups (cell cycle, xenobiotic metabolism, others). The ORL lines noted to be enriched in cell cycle genes responded preferentially to the CDK1 inhibitor RO3306, by MTT cell viability assay. Overall, our in-depth characterization of clinically annotated ORL lines provides new insight into the molecular alterations synonymous with OSCC, which can facilitate in the identification of biomarkers that can be used to guide diagnosis, prognosis, and treatment of OSCC.
authors.affiliation: Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
authors.forename: Muhammad Zaki Hidayatullah
authors.initials: MZ
authors.lastname: Fadlullah
authors.affiliation: Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.|Oral Cancer Research and Co-ordinating Centre (OCRCC), Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Ivy Kim-Ni
authors.initials: IK
authors.lastname: Chiang
authors.affiliation: Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.|Oral Cancer Research and Co-ordinating Centre (OCRCC), Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.|Medical Scientist Training Program, University of Colorado Denver - Anschutz Medical Campus, Aurora, CO.
authors.forename: Kalen R
authors.initials: KR
authors.lastname: Dionne
authors.affiliation: Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
authors.forename: Pei San
authors.initials: PS
authors.lastname: Yee
authors.affiliation: Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
authors.forename: Chai Phei
authors.initials: CP
authors.lastname: Gan
authors.affiliation: Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
authors.forename: Kin Kit
authors.initials: KK
authors.lastname: Sam
authors.affiliation: Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.|Oral Cancer Research and Co-ordinating Centre (OCRCC), Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Kai Hung
authors.initials: KH
authors.lastname: Tiong
authors.affiliation: Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
authors.forename: Adrian Kwok Wen
authors.initials: AK
authors.lastname: Ng
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Martin
authors.affiliation: Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
authors.forename: Kue Peng
authors.initials: KP
authors.lastname: Lim
authors.affiliation: Oral Cancer Research and Co-ordinating Centre (OCRCC), Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.|Department of Oro-Maxillofacial Surgery and Medical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Thomas George
authors.initials: TG
authors.lastname: Kallarakkal
authors.affiliation: Department of Oral and Maxillofacial Surgery, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia.
authors.forename: Wan Mahadzir Wan
authors.initials: WM
authors.lastname: Mustafa
authors.affiliation: Stomatology Unit, Institute for Medical Research, Kuala Lumpur, Malaysia.
authors.forename: Shin Hin
authors.initials: SH
authors.lastname: Lau
authors.affiliation: Department of Oral and Maxillofacial Surgery, Tengku Ampuan Rahimah Hospital, Klang, Selangor, Malaysia.
authors.forename: Mannil Thomas
authors.initials: MT
authors.lastname: Abraham
authors.affiliation: Oral Cancer Research and Co-ordinating Centre (OCRCC), Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.|Department of Oro-Maxillofacial Surgery and Medical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Rosnah Binti
authors.initials: RB
authors.lastname: Zain
authors.affiliation: Department of Oro-Maxillofacial Surgery and Medical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Zainal Ariff Abdul
authors.initials: ZA
authors.lastname: Rahman
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Molinolo
authors.affiliation: Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
authors.forename: Vyomesh
authors.initials: V
authors.lastname: Patel
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institutes of Health, Bethesda, MD, USA.
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
authors.affiliation: Division of Medical Oncology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
authors.forename: Aik Choon
authors.initials: AC
authors.lastname: Tan
authors.affiliation: Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.|Department of Oro-Maxillofacial Surgery and Medical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Sok Ching
authors.initials: SC
authors.lastname: Cheong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001114:Areca / Q000009:adverse effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations; D005260:Female; D005784:Gene Amplification; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D017423:Sequence Analysis, RNA; D017384:Sequence Deletion; D059467:Transcriptome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents
keywords: cell lines; copy number alteration; gene expression; mutation; oral squamous cell carcinoma