Identifying Novel Biomarkers Ready for Evaluation in Low-Prevalence Populations for the Early Detection of Upper Gastrointestinal Cancers : A Systematic Review

Funding This study and the journal’s rapid service fee were supported by the CanTest Collaborative (funded by Cancer Research UK C8640/A23385) of which Fiona M. Walter is Director, Jon Emery is an Associate Director, Mike Messenger is co-investigator, and Natalia Calanzani and Garth Funston are researchers. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Paige Druce, Kristi Milley and Jon Emery are supported by the Cancer Australia Primary Care Collaborative Cancer Clinical Trials Group (PC4). Mike Messenger is funded by the NIHR Leeds In Vitro Diagnostic Co-operative (UK). No Open Access Fee was received by the journal for the publication of this article.Peer reviewedPublisher PD

Identifying Novel Biomarkers Ready for Evaluation in Low-Prevalence Populations for the Early Detection of Lower Gastrointestinal Cancers: A Systematic Review and Meta-Analysis

Abstract: Introduction: Lower gastrointestinal (GI) cancers are a major cause of cancer deaths worldwide. Prognosis improves with earlier diagnosis, and non-invasive biomarkers have the potential to aid with early detection. Substantial investment has been made into the development of biomarkers; however, studies are often carried out in specialist settings and few have been evaluated for low-prevalence populations. Methods: We aimed to identify novel biomarkers for the detection of lower GI cancers that have the potential to be evaluated for use in primary care. MEDLINE, Embase, Emcare and Web of Science were systematically searched for studies published in English from January 2000 to October 2019. Reference lists of included studies were also assessed. Studies had to report on measures of diagnostic performance for biomarkers (single or in panels) used to detect colorectal or anal cancers. We included all designs and excluded studies with fewer than 50 cases/controls. Data were extracted from published studies on types of biomarkers, populations and outcomes. Narrative synthesis was used, and measures of specificity and sensitivity were meta-analysed where possible. Results: We identified 142 studies reporting on biomarkers for lower GI cancers, for 24,844 cases and 45,374 controls. A total of 378 unique biomarkers were identified. Heterogeneity of study design, population type and sample source precluded meta-analysis for all markers except methylated septin 9 (mSEPT9) and pyruvate kinase type tumour M2 (TuM2-PK). The estimated sensitivity and specificity of mSEPT9 was 80.6% (95% CI 76.6–84.0%) and 88.0% (95% CI 79.1–93.4%) respectively; TuM2-PK had an estimated sensitivity of 81.6% (95% CI 75.2–86.6%) and specificity of 80.1% (95% CI 76.7–83.0%). Conclusion: Two novel biomarkers (mSEPT9 and TuM2-PK) were identified from the literature with potential for use in lower-prevalence populations. Further research is needed to validate these biomarkers in primary care for screening and assessment of symptomatic patients

Allelic polymorphism in the T cell receptor and its impact on immune responses

In comparison to human leukocyte antigen (HLA) polymorphism, the impact of allelic sequence variation within T cell receptor (TCR) loci is much less understood. Particular TCR loci have been associated with autoimmunity, but the molecular basis for this phenomenon is undefined. We examined the T cell response to an HLA-B*3501-restricted epitope (HPVGEADYFEY) from Epstein-Barr virus (EBV), which is frequently dominated by a TRBV9*01 public TCR (TK3). However, the common allelic variant TRBV9*02, which differs by a single amino acid near the CDR2β loop (Gln55→His55), was never used in this response. The structure of the TK3 TCR, its allelic variant, and a nonnaturally occurring mutant (Gln55→Ala55) in complex with HLA-B*3501 revealed that the Gln55→His55 polymorphism affected the charge complementarity at the TCR-peptide-MHC interface, resulting in reduced functional recognition of the cognate and naturally occurring variants of this EBV peptide. Thus, polymorphism in the TCR loci may contribute toward variability in immune responses and the outcome of infection