Hepatocellular carcinoma (HCC) is the 6th leading cause of cancer-related mortality, with a poor prognosis in patients diagnosed in the later stages. Further understanding of HCC and its genetics may improve our ability to develop new diagnostic, prognostic and treatment strategies.

There is a known association between type 2 diabetes mellitus (T2DM) and several cancers, including HCC. This proof-of-concept study investigates the association between HCC and T2DM in 113 patients with HCC in a UK tertiary centre. The presence of T2DM and alpha-fetoprotein (aFP) positivity were compared with overall survival data but this dataset was not sufficiently powered to reach significance in most areas.

A larger cohort of 1407 patients from Germany was then reviewed, demonstrating that patients with T2DM were less likely to be aFP positive. aFP is a tumour marker with both diagnostic and prognostic implications but is not present in all cases of hepatocellular carcinoma. aFP lost its poor prognostic significance in patients with T2DM when assessing surrogate markers of prognosis, in the absence of survival data. A meta-analysis of the two cohorts showed consistency with these observed associations despite an alternative aFP threshold for positivity. Patients at higher risk of developing HCC presently undergo biannual surveillance ultrasound and aFP assessment to identify these tumours at early stages. This surveillance system may disadvantage patients with T2DM as aFP is less likely to be positive in these cases.

Alongside the clinical assessment of HCC, our understanding of the genetic landscape of HCC and their prognostic implications is evolving, with various novel therapies now available which may ultimately allow precision medicine.

The immune subclass is characterised by more aggressive tumours, and immunofluorescent assessment of 75 tumour samples in this thesis demonstrate an increase of PDL1, PD1 and CD8 in this genetic subclass.

Improving our understanding of the clinical and genetic basis of HCC may aid in our diagnostic capability, prognostication and ultimately treatment strategies.