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 5 299) 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 5 58) and skin (n 5 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.Head and neck squamous cell carcinoma (HNSCC) is diagnosed in over half a million individuals worldwide each year, with an expected global incidence of 750,000 by 2015.1 Survival rates are poor (10-30% at 5 years) among patients presenting with advanced disease.2 Early detection of precancer lesions coupled with early intervention could significantly improve patient outcome, reduce mortality and alleviate healthcare costs.2,3 However, conventional histopathology is currently unable to predict accurately which individual lesions from the oral potentially malignant disorders (OPMD) 4 spectrum will transform to squamous cell carcinoma (SCC). Given similar pathogenesis of other epithelial

Independent evaluation of a FOXM1-based quantitative malignancy diagnostic system (qMIDS) on head and neck squamous cell carcinomas

“…In 2013, we have developed a FOXM1-oncogene associated multi-biomarker ‘quantitative Malignancy Index Diagnostic System’ (qMIDS) [11] for quantifying the aggressiveness of squamous cell carcinoma (SCC). FOXM1 transcription factor has been shown to be amongst the top upregulated oncogenes across 39 cancer types and is a major predictor of poor cancer prognosis [12].…”

“…FOXM1 transcription factor has been shown to be amongst the top upregulated oncogenes across 39 cancer types and is a major predictor of poor cancer prognosis [12]. The qMIDS assay therefore represented the first FOXM1-based cancer diagnostic test which was previously validated on patients living in the UK and Norway [11]. Given that cancer is often heterogeneous, one marker alone would not be reliable or accurate for diagnosis.…”

“…Given that cancer is often heterogeneous, one marker alone would not be reliable or accurate for diagnosis. Hence, qMIDS was demonstrated previously to involve FOXM1 plus 13 FOXM1-associated genes (HOXA7, AURKA, NEK2, CCNB1, CEP55, CENPA, DNMT3B, DNMT1, HELLS, MAPK8, BMI1, ITGB1 and INV) as a panel of 14 biomarkers (and 2 reference genes) for quantitative diagnosis of malignancy [11]. We had previously shown that qMIDS test were able to quantitatively segregate between normal and malignancy whilst unaffected by non-malignant inflammatory condition (lichen planus).…”

The expression and significance of the <i>HOXA7</i> gene in oral squamous cell carcinoma

“…These genes play prominent roles in cell proliferation, differentiation and genome stability (7). HOXA7 is one of these genes, and plays important roles in cell differentiation and cell morphological development.…”

Oral Cancer Biomarkers: Is it a Meaningless Game?

“…20 It is well documented that improved diagnostic and prognostic accuracy to inform the most appropriate intervention could significantly improve patient outcome, reduce mortality and alleviate healthcare costs. 21 Hence, clinicians desperately need a cost-effective, practical, objective method for diagnosing and quantifying patients' risks [22][23][24] for early oral malignancy so that patients could be treated at early stages of the disease when it is most effective. Research strategies and science funding should be focusing on encouraging the translation of the large number of new biomarkers emerged from big data research into cost-effective practical clinical tools to benefit patients.…”