title: Exploiting FOXM1-orchestrated molecular network for early squamous cell carcinoma diagnosis and prognosis.
abstract: Histopathological discordance with molecular phenotype of many human cancers poses clinically challenging tasks for accurate cancer diagnosis, which impacts on treatment strategy and patient outcome. Hence, an objective, accurate and quantitative method is needed. A quantitative Malignancy Index Diagnostic System (qMIDS) was developed based on 14 FOXM1 (isoform B)-associated genes implicated in the regulation of the cell cycle, differentiation, ageing, genomic stability, epigenetic and stem cell renewal, and two reference genes. Their mRNA expression levels were translated via a prospectively designed algorithm, into a metric scoring system. Subjects from UK and Norway (n = 299) provided 359 head and neck tissue specimens. Diagnostic test performance was assessed using detection rate (DR) and false-positive rate (FPR). The median qMIDS scores were 1.3, 2.9 and 6.7 in healthy tissue, dysplasia and head and neck squamous cell carcinomas (HNSCC), respectively (UK prospective dataset, p<0.001); 1.4, 2.3 and 7.6 in unaffected, oral lichen planus, or HNSCC, respectively (Norwegian retrospective dataset with up to 19 years survival data, p<0.001). At a qMIDS cut-off of 4.0, DR was 94% and FPR was 3.2% (Norwegian dataset); and DR was 91% and FPR was 1.3% (UK dataset). We further demonstrated the transferability of qMIDS for diagnosing premalignant human vulva (n = 58) and skin (n = 21) SCCs, illustrating its potential clinical use for other cancer types. This study provided evidence that qMIDS was able to quantitatively diagnose and objectively stratify cancer aggressiveness. With further validation, qMIDS could enable early HNSCC detection and guide appropriate treatment. Early treatment intervention can lead to long-term reduction in healthcare costs and improve patient outcome.
authors.affiliation: Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, England, United Kingdom. m.t.teh@qmul.ac.uk
authors.forename: Muy-Teck
authors.initials: MT
authors.lastname: Teh
authors.forename: Iain L
authors.initials: IL
authors.lastname: Hutchison
authors.forename: Daniela Elena
authors.initials: DE
authors.lastname: Costea
authors.forename: Evelyn
authors.initials: E
authors.lastname: Neppelberg
authors.forename: Per Gunnar
authors.initials: PG
authors.lastname: Liavaag
authors.forename: Karin
authors.initials: K
authors.lastname: Purdie
authors.forename: Catherine
authors.initials: C
authors.lastname: Harwood
authors.forename: Hong
authors.initials: H
authors.lastname: Wan
authors.forename: Edward W
authors.initials: EW
authors.lastname: Odell
authors.forename: Allan
authors.initials: A
authors.lastname: Hackshaw
authors.forename: Ahmad
authors.initials: A
authors.lastname: Waseem
mesh_terms: D000465:Algorithms; D014408:Biomarkers, Tumor / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis* / Q000235:genetics; D002478:Cells, Cultured; D042241:Early Diagnosis; D005260:Female; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics*; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D006258:Head and Neck Neoplasms / Q000175:diagnosis* / Q000235:genetics; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009664:Norway; D011230:Precancerous Conditions / Q000175:diagnosis* / Q000235:genetics; D011379:Prognosis; D011446:Prospective Studies; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000175:diagnosis* / Q000235:genetics; D014846:Vulvar Neoplasms / Q000175:diagnosis* / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger