Oncotarget

Research Papers:

Genetically-defined novel oral squamous cell carcinoma cell lines for the development of molecular therapies

Muhammad Zaki Hidayatullah Fadlullah, Ivy Kim-Ni Chiang, Kalen R. Dionne, Pei San Yee, Chai Phei Gan, Kin Kit Sam, Kai Hung Tiong, Adrian Kwok Wen Ng, Daniel Martin, Kue Peng Lim, Thomas George Kallarakkal, Wan Mahadzir Wan Mustafa, Shin Hin Lau, Mannil Thomas Abraham, Rosnah Binti Zain, Zainal Ariff Abdul Rahman, Alfredo Molinolo, Vyomesh Patel, J. Silvio Gutkind, Aik Choon Tan, Sok Ching Cheong _

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Oncotarget. 2016; 7:27802-27818. https://doi.org/10.18632/oncotarget.8533

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Abstract

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

Correspondence to:

Sok Ching Cheong, email: sokching.cheong@cancerresearch.my

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

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.

Author Information

Muhammad Zaki Hidayatullah Fadlullah

Ivy Kim-Ni Chiang

Kalen R. Dionne

Pei San Yee

Chai Phei Gan

Kin Kit Sam

Kai Hung Tiong

Adrian Kwok Wen Ng

Daniel Martin

Kue Peng Lim

Thomas George Kallarakkal

Wan Mahadzir Wan Mustafa

Shin Hin Lau

Mannil Thomas Abraham

Rosnah Binti Zain

Zainal Ariff Abdul Rahman

Alfredo Molinolo

Vyomesh Patel

J. Silvio Gutkind

Aik Choon Tan

Sok Ching Cheong
Primary Contact  _


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