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Barrett’s Genetics and Oesophageal Cancer Risk

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Barrett’s Genetics and Oesophageal Cancer Risk

Tumour Suppressor Genes in Barrett’s Oesophagus

When biopsy samples are taken during surveillance endoscopy, the doctor is looking for genetic biomarkers that predict the risk that cancer will develop. The biopsies will often be sent for immunohistochemistry tests. This rather long word means that the samples are stained with special dyes, which pick up important features in the cells. These special dyes pick up more than the standard dyes which are used routinely for all samples.

Barrett’s Genetics and Oesophageal Cancer Risk

LEGEND: Standard staining of a biopsy sample using haematoxylin and eosin (H&E) from a patient with Barrett’s oesophagus

 
Barrett’s Genetics and Oesophageal Cancer Risk

LEGEND: Immunohistochemistryfor P53, showing increased expression of this biomarker in a patient. This waspublished by one of our research collaborators Murray L et al. Gut 2006 55(10): 1390–1397

 

LEGEND: Analysis of the cell nuclei from individual cells detects changes in the number of chromosomes. Normal cells are diploid and abnormal cells are aneuploid.

Diploid Aneuploidy
Barrett’s Genetics and Oesophageal Cancer Risk Barrett’s Genetics and Oesophageal Cancer Risk

In Barrett’s oesophagus, there is a series of immunohistochemical stains for genetic changes in cells which may be helpful in determining future cancer risk. These include

Tumour suppressor genes such as

  • p53
  • p16

Cell cycle regulation markers such as

  • Cyclin A
  • Ki67
  • Geminin
  • PLK1

Other biomarkers of risk

  • Cox 2
  • DNA ploidy

There are many other immunohistochemical stains which may be useful in other diseases but are not useful in Barrett’s oesophagus.

What is the value of immunohistochemistry?

The special dyes and imaging techniques allow the pathologist to be more confident as to whether this patient is at high or low risk of progressing to cancer.

p53 expression

Patients with a high expression of p53 in the biopsy samples, have a likelihood of developing oesophageal cancer in the next five years, that is thought to be significantly higher than in people who do not have this high expression.

Cyclin A expression

We and colleagues in Cambridge showed that finding this particular biomarker in biopsy samples is also a sign that the patient is at higher risk of developing cancer in the next 5 years.

DNA content (aneuploidy) is an important risk factor for cancer

In a landmark series of studies, the Hutchinson Research Labs in Seattle, USA, led by Professor Peter Reid, showed that changes in the amount of DNA in cells, called aneuploidy, was an independent risk factor for developing oesophageal adenocarcinoma (cancer).

Professor Reid followed up almost 250 people with Barrett’s oesophagus who did not have high-grade dysplasia for many years. He used a highly specialised test called flow cytometry. He demonstrated that people who had aneuploidy – altered DNA content – in biopsy samples, had a 28% chance of developing cancer within 5 years. If they did not have this change, their risk was almost zero.

The problem with Professor Reid’s work was that it is not possible for a routine laboratory to do the special ‘flow cytometry’ tests needed to detect the DNA abnormalities.

In our laboratory at UCL, we developed a different way of assessing this DNA content. It is called image cytometry. This technique allows us to assess DNA content more easily from Barrett’s oesophagus biopsy samples. We have shown that our approach works as well as Professor Reid’s.

We believe that we can much more reliably determine if patients are at high or low risk of developing cancer by combining standard analysis of biopsies with DNA content analysis and assessment of other biomarkers.

Combining Biomarkers to Assess Risk

We worked together with colleagues in Cambridge and Belfast to assess almost 500 patients with Barrett’s oesophagus for biomarkers of cancer risk.

Some of these patients developed cancer. Most did not. We worked out which biomarkers could be used together as a panel to determine that risk.

We published some of this work in the prestigious Gastroenterology journal – the top journal in the world in this area in 2013.

Genetics and Familial Risk

It is known that some families are more at risk of developing oesophageal cancer on the background of Barrett’s oesophagus. Currently, very little is known about what predisposes some people to higher risks than others. A big study has shown that there is a gene which is more common in these people. It is not common enough, however, to explain the problem. This is an area which may develop over the next few years.

Conclusion

Immunohistochemistry and other techniques can be used to detect tumour suppressor genes and other biomarkers, which predict the risk that Barrett’s Oesophagus will turn cancerous. For most people, this will never happen. But for the few in whom it will, early detection will allow them to receive curative treatment. We do not yet know enough about familial risk to be able to predict which family members should undergo specialist treatment.

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If you would like immunohistochemical assessment of your tumour suppressor genes and other biomarkers of risk, make an appointment with one of our specialists. Please tell our office staff that you want to see an expert in Barrett’s oesophagus.