Division of Investigative Science, Imperial College London
Doi
Abstract
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