Oesophageal squamous cell carcinoma (OSCC) is a significant disease burden with low survival rates of 19%. Patients present and are diagnosed at late stage as early symptoms are non-specific. Screening programmes have been attempted in countries with high incidence of OSCC, however these are not cost-effective and applicable to the global population. There is an unmet need for innovative tools capable of early diagnosis.

Biomarker and bioinformatics analysis led to the hypothesis that branched chain amino acid (BCAA) metabolism and its downstream metabolites were deregulated in OSCC which may provide biomarkers. Pursuing this biology could refine biomarker analysis of OSCC, allow for targeted biomarker analysis and improve accuracy of non-invasive testing methods. This PhD aims to describe OSCC BCAA metabolism, its genetic framework and apply this to a pilot study.

Analysis indicates that OSCC tissues are high expressors of BCAT1 compared to normal squamous mucosa (p = 0.0002), validated at the RNA (n = 52) and protein level (n = 5). Meanwhile, there was a decrease in BCKDH-E1a expression in OSCC tissues compared to normal although these differences were not significant.

A bespoke gas chromatography mass spectrometry (GC-MS) method was developed and validated to quantify three BCAA and three associated branched chain keto acids (BCKA) in liquid samples. Mechanistic in vitro studies indicated BCAA levels influence OSCC proliferation at low levels. Additionally regulation of BCAA metabolism occurs at BCKDH-E1a and its regulatory proteins.

A total of 65 patients (Cancer : control, 45: 20) were recruited for the pilot study. Saliva analysis successfully identified target analytes with a validated method. Meanwhile, VOCs in OSCC breath samples showed links to downstream BCAA metabolic pathway.

These data highlights that preservation of BCAA is an essential part of OSCC metabolism which may contribute to carcinogenesis. Clinical implications and future research directions are discussed.