Genetically-defined novel oral squamous cell carcinoma cell lines for the development of molecular therapies
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Muhammad Zaki Hidayatullah Fadlullah1, Ivy Kim-Ni Chiang1,2, Kalen R. Dionne1,2,3, Pei San Yee1, Chai Phei Gan1, Kin Kit Sam1, Kai Hung Tiong1,2, Adrian Kwok Wen Ng1, Daniel Martin4, Kue Peng Lim1, Thomas George Kallarakkal2,5, Wan Mahadzir Wan Mustafa6, Shin Hin Lau7, Mannil Thomas Abraham8, Rosnah Binti Zain2,5, Zainal Ariff Abdul Rahman5, Alfredo Molinolo4, Vyomesh Patel1, J. Silvio Gutkind4, Aik Choon Tan9, Sok Ching Cheong1,5
1Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia
2Oral Cancer Research and Co-ordinating Centre (OCRCC), Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
3Medical Scientist Training Program, University of Colorado Denver, Aurora, CO, USA
4Oral and Pharyngeal Cancer Branch, National Institutes of Health, Bethesda, MD, USA
5Department of Oro-Maxillofacial Surgery and Medical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia
6Department of Oral and Maxillofacial Surgery, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia
7Stomatology Unit, Institute for Medical Research, Kuala Lumpur, Malaysia
8Department of Oral and Maxillofacial Surgery, Tengku Ampuan Rahimah Hospital, Klang, Selangor, Malaysia
9Division of Medical Oncology, School of Medicine, University of Colorado, Aurora, CO, USA
Sok Ching Cheong, email: [email protected]
Keywords: oral squamous cell carcinoma, gene expression, mutation, copy number alteration, cell lines
Received: November 02, 2015 Accepted: March 18, 2016 Published: April 01, 2016
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.
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