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Title: The molecular pathogenesis of cholangiocarcinoma
Author: McKay, Siobhan
ISNI:       0000 0004 2737 0001
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Introduction: Cholangiocarcinoma (CC) is a malignancy of the biliary tract. It has a dismal prognosis and complete surgical resection offers the only chance of cure. The aim of this study was to identify prognostic DNA/microRNA signatures, and to identify key targets and pathways in CC to improve treatment. Methods: We performed a retrospective study to assess the role of surgery and adjuvant therapy on the survival outcomes of patients with CC based on the experience of two institutions. We investigated the molecular pathogenesis of CC assessing DNA copy number alterations and differential miRNA expression. We used array comparative genomic hybridization (CGH) (1Mb BAC array-CGH, and 180K Oligonucleotide array-CGH) on 71 UK and 24 Thai cases CC. We performed microRNA-arrays (Agilent Human miRNA slides V3) on 34 CC and 10 normal cholangiocyte samples. Results: Survival analysis showed a statistically significant difference in survival between those resected and those receiving medical management only. Thai CC cases exhibited a lower proportion of CNA compared to UK cases. A common UK alteration was seen at 17q12, the region encoding ErbB-2. The copy number gain at 17q12 was validated using CISH and IHC for ErbB-2 expression, revealing heterogeneous expression. Copy number gain of chromosome 8q24.21-24.3 was significantly related to survival. Median survival was 14.4 months vs 28.3 months with and without the gain (p = 0.016). Thirty-eight miRNAs showed significantly different expression, including several microRNAs implicated in other malignancies, with predicted gene targets including the p53 signaling pathway and the TGF-beta signaling pathway. We identified a 4-microRNA signature that correlated with overall survival. With a median survival of 15.7 months vs 35.6 months: p = 0.00016. Conclusion: This study illustrates the genetic variability of CC, highlights several potential therapeutic targets, and identified a DNA and miRNA signature that correlated with prognosis.
Supervisor: Stamp, Gordon ; Spalding, Duncan ; Hutchins, Robert Sponsor: Royal College of Surgeons of England
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral