Background: Cholangiocarcinoma (CC) is a malignancy of the bile ducts and mortality is high as
patients present too late for curative surgery. In most cases of CC the aetiology is
unknown, whilst diagnosis and staging are challenging. The hepatobiliary system
excretes carcinogenic toxins and genetic mutations in biliary transporters lead to
dysfunction and cholestasis, potentially contributing to cholangiocarcinogenesis.
Polymorphisms in the NKG2D receptor have previously been associated with CC in
primary sclerosing cholangitis (PSC). Such a role has not been investigated in sporadic
CC. CC is difficult to diagnose, particularly in those with PSC. The transition from
benign to malignant biliary disease is likely to be reflected in changes to the plasma
proteome. However, current plasma biomarkers do not reliably distinguish benign from
malignant biliary strictures. Elevation of neutrophil gelatinase-associated lipocalin
(NGAL) has been demonstrated in the bile of patients with CC but has not been
investigated as a plasma protein biomarker. Staging of CC is inaccurate, with only a
minority of operated patients cured. Higher resolution MRI would improve diagnosis
and staging. The work presented in this thesis represents a multimodality approach to
enhance the diagnosis of CC:
Genetic studies: Genetic variation in major biliary transporter proteins, and the NKG2D receptor, were
investigated. Single nucleotide polymorphisms (SNPs) in candidate genes were
selected using HapMap. DNA from 173 CC patients and 265 healthy controls was
genotyped. SNPs in ABCB11, MDR3 and ATP8B1 were nominally associated with
altered susceptibility to CC, suggesting a potential role in cholangiocarcinogenesis.
The previous association of NKG2D variation with CC in PSC was not replicated in
sporadic CC, suggesting a possible difference in pathogenesis.
Protein studies: Plasma from subjects with CC, benign disease, and from healthy controls was studied.
Two proteomic techniques, liquid chromatography-tandem mass spectrometry (LCMS/
MS) and surfaced enhanced laser desorption ionization time-of-flight MS (SELDITOF
MS), were utilised. Differentially expressed proteins were identified where
possible. LC-MS/MS fully identified six proteins that were differentially expressed in CC
compared to gall stone disease patients. SELDI-TOF MS identified seven m/z peaks
that showed significant utility in discriminating CC from PSC controls. An ELISA
approach was used to study plasma NGAL levels in CC. Although differentially
expressed between CC and healthy control groups, the utility of NGAL in discriminating
CC from PSC was limited.
Imaging studies: An endoscope-mounted MR coil and intraductal MR detector coil were developed.
Quantitative resolution and signal-to-noise-ratio (SNR) testing, and qualitative tissue
discrimination appraisal, were undertaken. Sub-0.7mm resolution and excellent SNRs
have been demonstrated. High-resolution has been demonstrated in imaged tissue.
Imaging with the new devices compares favourably with endoscopic ultrasound
imaging