cells Review Circulating Non-Coding RNAs in Head and Neck Cancer: Roles in Diagnosis, Prognosis, and Therapy Monitoring Araceli Diez-Fraile 1,†, Joke De Ceulaer 1,†, Charlotte Derpoorter 2,3,4, Christophe Spaas 1, Tom De Backer 1, Philippe Lamoral 1, Johan Abeloos 1,‡ and Tim Lammens 2,3,4,*,‡ 1 Division of Oral and Maxillofacial Surgery, Department of Surgery, AZ Sint-Jan Brugge-Oostende A.V., 8000 Bruges, Belgium; [email protected] (A.D.-F.); [email protected] (J.D.C.); [email protected] (C.S.); [email protected] (T.D.B.); [email protected] (P.L.); [email protected] (J.A.) 2 Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, 9000 Ghent, Belgium; [email protected] 3 Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium 4 Cancer Research Institute Ghent (C.R.I.G.), 9000 Ghent, Belgium * Correspondence: [email protected]; Tel.: +32-9-332-2480 † Shared first authors. ‡ Shared senior authors. Abstract: Head and neck cancer (HNC), the seventh most common form of cancer worldwide, is a group of epithelial malignancies affecting sites in the upper aerodigestive tract. The 5-year overall survival for patients with HNC has stayed around 40–50% for decades, with mortality being attributable mainly to late diagnosis and recurrence. Recently, non-coding RNAs, including tRNA halves, YRNA fragments, microRNAs (miRNAs), and long non-coding RNAs (lncRNAs), have been identified in the blood and saliva of patients diagnosed with HNC. These observations have recently fueled the study of their potential use in early detection, diagnosis, and risk assessment. The present review focuses on recent insights and the potential impact that circulating non-coding Citation: Diez-Fraile, A.; Ceulaer, J.D.; RNA evaluation may have on clinical decision-making in the management of HNC. Derpoorter, C.; Spaas, C.; Backer, T.D.; Lamoral, P.; Abeloos, J.; Lammens, T. Keywords: head and neck cancer; circulating non-coding RNA; liquid biopsy; biomarkers Circulating Non-Coding RNAs in Head and Neck Cancer: Roles in Diagnosis, Prognosis, and Therapy Monitoring. Cells 2021, 10, 48. 1. Introduction https://doi.org/10.3390/cells10010048 Head and neck cancer (HNC) encompasses a wide range of tumors arising from Received: 21 November 2020 numerous anatomic subsites, including the lips, oral cavity, oropharynx, nasopharynx, Accepted: 28 December 2020 hypopharynx, larynx, nasal cavity, paranasal sinuses, and salivary glands (Figure1). Squa- Published: 31 December 2020 mous cell carcinoma (SCC) is the most frequent histological type, accounting for 90% of HNC cases [1]. Globally, HNC the seventh most frequent malignancy, with more than Publisher’s Note: MDPI stays neu- 880,000 new cases reported in 2018, representing 4.9% of the total number of cancer cases [2]. tral with regard to jurisdictional clai- HNC has a high incidence and mortality profile worldwide, with age-standardized inci- ms in published maps and institutio- dence and mortality rates of 10.10 and 5.04 per 100,000, respectively, in 2018 [2]. In western nal affiliations. Europe, Jethwa et al. [3] found that males were affected three times as frequently as females, with the highest rates of HNC occurring in older men, and found that the risk factors for HNC included upper aerodigestive tract mucosa exposure to carcinogens such as tobacco Copyright: © 2020 by the authors. Li- and alcohol [3]. While smoking-related cancers appear to be declining, there have been censee MDPI, Basel, Switzerland. increasing incidences of SCCs of the oropharynx and nasopharynx in young individuals This article is an open access article in recent years; these increases have been linked to infection with human papillomavirus distributed under the terms and con- (HPV) and, less commonly, Epstein–Barr (EBV) virus [1,4]. The observation of substantially ditions of the Creative Commons At- better prognoses for these malignancies among HPV positive patients than for tobacco tribution (CC BY) license (https:// users has suggested that activation of HPV-specific oncogenic signaling pathways may be creativecommons.org/licenses/by/ relevant for HNC prognosis [5–8]. 4.0/). Cells 2021, 10, 48. https://doi.org/10.3390/cells10010048 https://www.mdpi.com/journal/cells CellsCells 20212021, ,1010, ,x 48 22 of of 13 13 FigureFigure 1. 1. HeadHead and and neck neck cancer cancer ( (HNC)HNC) types. types. Regions Regions and frequencies wherewhere headhead andand neckneckcancers can- cersare are diagnosed diagnosed are indicated.are indicated. Typically,Typically, HNCs HNCs present present with with symptoms symptoms from from the the primary primary site, site, such such as as persistent persistent hoarseness,hoarseness, long long-lasting-lasting dysphagia, dysphagia, oral oral mucosa mucosa ulcers, ulcers, epistaxis, epistaxis, or or otalgia. otalgia. Patients Patients in in whomwhom the the primary primary neoplastic neoplastic site site is is the the tongue tongue base, base, upper upper glottis, glottis, or or nasopharynx nasopharynx often often presentpresent with with cervical cervical lymphadenopathy lymphadenopathy as as their their first first presenting presenting sign. sign. Most Most patients patients (60%) (60%) areare diagnosed diagnosed at at an an advanced advanced stage stage of of disease disease (III (III or or IV), IV), at at which which point pointss survival survival rates rates areare reduced reduced relative relative to to those those for for early early stages stages (I (I or or II). II). Distant Distant metastases metastases are are found found in in only only aboutabout 10% 10% of of cases cases at presentation, andand concomitantconcomitant oror delayed delayed second second primary primary tumors tumors of ofthe the upper upper aerodigestive aerodigestive tract tract occur occur in 10–15%in 10–15% of patients.of patient Despites. Despite recent recent advances advances in loco- in locoregional-regional treatment treatment protocols, protocols, including including advanced advanced surgery, surgery, radiotherapy, radiotherapy, chemotherapy, chemother- apy,or combinations or combinations thereof, thereof, 50–60% 50–60% of patients of patients with with locally locally advanced advanced disease disease develop develop loco- locoregional-regional recurrence recurrence and aand further a further 20% progress 20% progress to distant to distant metastasis metastasis [9]. Challenges [9]. Challenges in HNC incare HNC include care rapidinclude detection rapid detection of primary of tumorsprimary during tumors the during earlystages the early of the stages disease, of the the disease,development the development of improved of surveillance improved surveillance methods following methods potentially following curative potentially treatment, cura- tiveunambiguous treatment, distinctionunambiguous of metastasis distinction from of metasta recurrencessis from and recurrences second primary and second tumors, pri- and marythe development tumors, and ofthe therapeutic development options of therapeutic for cases thatoptions are currentlyfor cases consideredthat are currently untreatable. con- sideredIn untreatable. response to these difficulties, new screening modalities have emerged in multiple areasIn ofresponse oncology. to these Key amongdifficulties, these new are screening liquid biopsies, modalities wherein have tumoremerged cells in ormultiple tumor- areasderived of oncology. products Key released amon intog these body are fluid liquid are biopsies, collected wherein and examined tumor withcells or the tumor aim of- deriveddetecting products cancer biomarkersreleased into [10 body]. Multiple fluid are biofluids collected can and be examined used for analysis,with the withaim pe-of detectingripheral bloodcancer beingbiomarkers the most [10] commonly. Multiple biofluids investigated can be specimen. used for Comparedanalysis, with to classicalperiph- excisional biopsies, blood sampling is less invasive and it holds the promise of rapid, safe, eral blood being the most commonly investigated specimen. Compared to classical exci- and highly informative genetic analysis. Hence, blood sampling provides an accessible sional biopsies, blood sampling is less invasive and it holds the promise of rapid, safe, and means of real-time evaluation of the disease and, potentially, the opportunity to identify highly informative genetic analysis. Hence, blood sampling provides an accessible means small tumors not yet visible by medical imaging techniques. It is important to bear in of real-time evaluation of the disease and, potentially, the opportunity to identify small mind that the main costs of a liquid biopsy are the associated laboratory studies and tumors not yet visible by medical imaging techniques. It is important to bear in mind that downstream data analysis. Ideally, liquid biopsies should be inexpensive enough to be the main costs of a liquid biopsy are the associated laboratory studies and downstream analyzed at multiple time points during treatment. Such repeat monitoring can improve data analysis. Ideally, liquid biopsies should be inexpensive enough to be analyzed at HNC outcomes while reducing patient morbidity due to unnecessary treatments, boosting multiple time points during treatment. Such repeat monitoring can improve HNC out- treatment development and optimizing the use of healthcare resources [11]. comes while reducing patient morbidity due to unnecessary treatments,