The Molecular Pathogenesis of the Bile Duct

Bile duct cancer (cholangiocarcinoma) is the World’s commonest primary liver cancer, and affects almost 2,000 people per year in the UK. Year on year the incidence of bile duct cancer in the UK is increasing. Unfortunately the outlook for patients with bile duct cancer is poor as it is often diagnosed late. At present surgery represents the only chance of cure, and methods of earlier detection, and novel treatment strategies are urgently required to improve survival.

In our study we are investigating bile duct cancer at a molecular level, looking at cancer-related DNA and microRNA changes. DNA is the hardcopy code in every cell of all of our genetic material which resides on 23 pairs of chromosomes. DNA codes for genes, which are made into proteins by messenger RNA. MicroRNAs are tiny non-coding RNAs (i.e. they do not code for proteins) that can affect the expression of messenger RNA, thus affecting which proteins are made in the body. MicroRNAs have a key role in development, affecting cell growth, cell differentiation (how a cell changes and matures), and organised cell death, and have been shown to play a key role in cancer carrying out these tasks in an unregulated fashion.

Our study involved three phases:

Assessing the role of surgery and medical therapy on the survival of patients with bile duct cancer.

Identifying large DNA changes in the genome of patients with bile duct cancer to identify novel treatment targets.

Identifying microRNA changes in patients with bile duct cancer to identify novel treatment targets and a ‘signature’ that relates to survival.

Findings:

Phase 1: Surgery vs. Medical Therapy

Consistent with other studies worldwide, we found patients had significantly better survival when treated with surgery than with medical therapy (chemotherapy) alone, supporting the role for surgery, and emphasising the need to diagnose bile duct cancer at an earlier stage when it is surgically treatable.

Phase 2: Identifying large DNA changes

We studied cases of bile duct cancer from the UK and from Thailand, where bile duct cancer has the highest incidence in the world. We found very different DNA changes in UK cancers compared to Thai cancers, indicating that more research needs to be performed in the UK to identify genetic changes in bile duct cancer as they appear very different and could therefore respond very differently to novel targeted treatments.

DNA changes were identified in the region that codes for the HER2 gene (well known in breast cancer and treated with Herceptin) in UK bile duct cancers, representing a possible treatment target in bile duct cancer.

Increased amounts of cancer DNA on chromosome 8 was related to worse survival, and will be further investigated as a prognostic marker (to predict better or worse likely survival).

Phase 3: MicroRNA changes

We identified a ‘signature’ of 4 microRNAs that predicted survival. The ‘signature’ more than double predicted survival. More work is required to investigate this signature which was found in cancer tissue, to see if circulating microRNAs in the blood or urine show the same affect and could be used as a simple test to predict survival and better tailor treatment decisions to each individual patient.

We also identified 38 other microRNAs that are expressed differently in bile duct cancer and warrant further investigation, involved in several keep cancer pathways.

This study was funded by LapResearchUK and the Royal College of Surgeons of England, has been presented internationally at several leading scientific conferences, has been published in a leading medical journal, and formed the bases of a PhD thesis from Imperial College London.

Siobhan McKay Specialty Trainee General Surgery, West Midlands

squareglu