Contents lists available at ScienceDirect Seminars in Cancer Biology journal homepage: www.elsevier.com/locate/semcancer Review Translational genomics and recent advances in oral squamous cell carcinoma Annie Wai Yeeng Chai a , Kue Peng Lim a , Sok Ching Cheong a,b, ⁎ a Head and Neck Cancer Research Team, Cancer Research Malaysia, No. 1, Jalan SS12/1A, Subang Jaya, Selangor, Malaysia b Department of Oral and Maxillofacial Clinical Sciences, Faculty of Dentistry, University of Malaya, Kuala Lumpur, Malaysia ARTICLE INFO Keywords: Translational genomics Oral squamous cell carcinoma Head and neck squamous cell carcinoma Molecular classification Immune subtypes ABSTRACT Oral squamous cell carcinomas (OSCC) are a heterogeneous group of cancers arising from the mucosal lining of the oral cavity. A majority of these cancers are associated with lifestyle risk habits including smoking, excessive alcohol consumption and betel quid chewing. Cetuximab, targeting the epidermal growth factor receptor was approved for the treatment of OSCC in 2006, and remains the only molecular targeted therapy available for OSCC. Here, we reviewed the current findings from genomic analyses of OSCC and discuss how these studies inform on the biological mechanisms underlying OSCC. Exome sequencing revealed that the significantly mu- tated genes are mainly tumour suppressors. Mutations in FAT1, CASP8, CDKN2A, and NOTCH1 are more fre- quently found in OSCC when compared to non-OSCC head and neck cancers and other squamous cell carci- nomas, and HRAS and PIK3CA are the only significantly mutated oncogenes. The distribution of these mutations also differs in populations with distinct risk habits. Gene expression-based molecular classification showed that OSCC can be divided into distinct subtypes and these have a preferential response to different types of therapies, suggesting that these classifications could have clinical implications. More recently, with the approval of checkpoint inhibitors for the treatment of cancers including OSCC, genomics studies also dissected the genetic signatures of the immune compartment to delineate immune-active and -exhausted subtypes that could inform on the immune status of OSCC patients and guide the development of novel therapies to improve response to immunotherapy. Taken together, genomics studies are informing on the biology of both the epithelial and stromal compartments underlying OSCC development, and we discuss the opportunities and challenges in using these to derive clinical benefit for OSCC patients. 1. Introduction Head and neck squamous cell carcinoma (HNSCC) accounted for more than 800 000 new cancers and 450 000 deaths in 2018 [1]. These cancers originate from the mucosa of the upper-aerodigestive track consisting of cancers of the larynx, hypopharynx, tonsil, oropharynx, and oral cavity. Of these, oral squamous cell carcinoma (OSCC) origi- nating from the alveolar ridge, buccal mucosa, floor of the mouth, palate, tongue and other parts within the oral cavity accounted for ∼350 000 new cases and ∼170 000 deaths in 2018. A majority of the global OSCC cases are diagnosed in Asia [1]. Classically, the develop- ment of OSCCs has been linked to lifestyle-related risk factors including smoking and excessive alcohol consumption [2]. In OSCC endemic areas such as south and southeast Asia, betel quid chewing is also commonly associated with the disease where about 50% are linked to this practice [3]. Areca nut, an established carcinogen is the main constituent in the betel quid and in some communities, the quid in- cludes smokeless tobacco. The human papillomavirus (HPV) has also been reported to be an important risk factor in HNSCC [4]. Whilst HPV- infection accounts for ∼60% of oropharyngeal carcinoma, its involve- ment in OSCC is less clear and HPV infections are only found in up to 25% of OSCC [5]. In addition to the diversity in the risk habits asso- ciated with OSCC, the anatomical sites by which cancers arise are also distinct between the different populations. For example, OSCC of the tongue and floor of mouth are more common amongst Caucasian po- pulations whilst those in the tongue and buccal mucosa predominate in Asian communities. These observations could be linked to the diversity in risk habits, where for example, the betel quid is typically chewed and placed in the buccal mucosa for long periods of time exposing this particular site to the carcinogens within the quid [6]. The mainstays of OSCC treatment are surgery, chemotherapy, radiotherapy or a combination of these modalities depending on the https://doi.org/10.1016/j.semcancer.2019.09.011 Received 26 July 2019; Received in revised form 17 September 2019; Accepted 18 September 2019 ⁎ Corresponding author at: Head and Neck Cancer Research Team, Cancer Research Malaysia, No. 1, Jalan SS12/1A, 47500, Subang Jaya, Selangor, Malaysia. E-mail address: sokching.cheong@cancerresearch.my (S.C. Cheong). Seminars in Cancer Biology xxx (xxxx) xxx–xxx 1044-579X/ © 2019 Published by Elsevier Ltd. Please cite this article as: Annie Wai Yeeng Chai, Kue Peng Lim and Sok Ching Cheong, Seminars in Cancer Biology, https://doi.org/10.1016/j.semcancer.2019.09.011