title: A novel genomic signature reclassifies an oral cancer subtype.
abstract: Verrucous carcinoma of the oral cavity (OVC) is considered a subtype of classical oral squamous cell carcinoma (OSCC). Diagnosis is problematic, and additional biomarkers are needed to better stratify patients. To investigate their molecular signature, we performed low-coverage copy number (CN) sequencing on 57 OVC and exome and RNA sequencing on a subset of these and compared the data to the same OSCC parameters. CN results showed that OVC lacked any of the classical OSCC patterns such as gain of 3q and loss of 3p and demonstrated considerably fewer genomic rearrangements compared to the OSCC cohort. OVC and OSCC samples could be clearly differentiated. Exome sequencing showed that OVC samples lacked mutations in genes commonly associated with OSCC (TP53, NOTCH1, NOTCH2, CDKN2A and FAT1). RNA sequencing identified genes that were differentially expressed between the groups. In silico functional analysis showed that the mutated and differentially expressed genes in OVC samples were involved in cell adhesion and keratinocyte proliferation, while those in the OSCC cohort were enriched for cell death and apoptosis pathways. This is the largest and most detailed genomic and transcriptomic analysis yet performed on this tumour type, which, as an example of non-metastatic cancer, may shed light on the nature of metastases. These three independent investigations consistently show substantial differences between the cohorts. Taken together, they lead to the conclusion that OVC is not a subtype of OSCC, but should be classified as a distinct entity.
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.|Pathology and Clinical Laboratory Department, King Fahad Medical City, Riyadh, Saudi Arabia.
authors.forename: Manar
authors.initials: M
authors.lastname: Samman
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
authors.forename: Henry M
authors.initials: HM
authors.lastname: Wood
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
authors.forename: Caroline
authors.initials: C
authors.lastname: Conway
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
authors.forename: Lucy
authors.initials: L
authors.lastname: Stead
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
authors.forename: Catherine
authors.initials: C
authors.lastname: Daly
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Chalkley
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
authors.forename: Stefano
authors.initials: S
authors.lastname: Berri
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
authors.forename: Burcu
authors.initials: B
authors.lastname: Senguven
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
authors.forename: Lisa
authors.initials: L
authors.lastname: Ross
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Egan
authors.affiliation: St James's Institute of Oncology, St James's University Hospital, Leeds, United Kingdom.
authors.forename: Preetha
authors.initials: P
authors.lastname: Chengot
authors.affiliation: Leeds Dental Institute, Leeds General Infirmary, Leeds, United Kingdom.
authors.forename: Thian K
authors.initials: TK
authors.lastname: Ong
authors.affiliation: Oral Medicine and Oral Oncology Unit, Department of Oncology, University of Torino, Turin, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Pentenero
authors.affiliation: Oral Medicine and Oral Oncology Unit, Department of Oncology, University of Torino, Turin, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Gandolfo
authors.affiliation: Pathology Unit, Department of Medical Sciences, University of Torino, Turin, Italy.
authors.forename: Adele
authors.initials: A
authors.lastname: Cassenti
authors.affiliation: Pathology Unit, Department of Medical Sciences, University of Torino, Turin, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Cassoni
authors.affiliation: National Guard Health Affairs, Riyadh, Saudi Arabia.
authors.forename: Abdulaziz
authors.initials: A
authors.lastname: Al Ajlan
authors.affiliation: National Guard Health Affairs, Riyadh, Saudi Arabia.
authors.forename: Alaa
authors.initials: A
authors.lastname: Samkari
authors.affiliation: Department of Histopathology, Queen Victoria Hospital.
authors.forename: William
authors.initials: W
authors.lastname: Barrett
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.|St James's Institute of Oncology, St James's University Hospital, Leeds, United Kingdom.
authors.forename: Kenneth
authors.initials: K
authors.lastname: MacLennan
authors.affiliation: St James's Institute of Oncology, St James's University Hospital, Leeds, United Kingdom.|Leeds Dental Institute, Leeds General Infirmary, Leeds, United Kingdom.
authors.forename: Alec
authors.initials: A
authors.lastname: High
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
authors.forename: Pamela
authors.initials: P
authors.lastname: Rabbitts
mesh_terms: D018289:Carcinoma, Verrucous / Q000235:genetics* / Q000473:pathology*; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D003198:Computer Simulation; D059472:Exome; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D006801:Humans; D009062:Mouth Neoplasms / Q000235:genetics* / Q000473:pathology*; D017422:Sequence Analysis, DNA / Q000379:methods; D017423:Sequence Analysis, RNA / Q000379:methods
keywords: genomics; molecular signature; oral verrucous carcinoma