New genetic clues to origins of oesophageal cancer

In collaboration with the Press Association

Using new genetic sequencing techniques, US scientists have revealed some of the key underlying gene faults underpinning the most common type of oesophageal cancer, known as adenocarcinoma.

The researchers found that cancer cells featured a pattern of rare genetic differences that could potentially be targeted by new therapies, according to a study published in Nature Genetics.

Oesophageal adenocarcinoma now accounts for just over half of all oesophageal cancers, yet there are relatively few new treatment approaches. It usually starts from faulty cells at the base of the oesophagus that have become damaged by exposure to acid that has come up from the stomach.

There is no conclusive explanation as to why rates of oesophageal adenocarcinoma are increasing, but researchers have speculated that it may be due to a rise in obesity, since excess weight in the abdomen puts increased pressure on the stomach, causing acid to come up into the oesophagus.

"Adenocarcinomas of the oesophagus, particularly those that arise at the gastroesophageal junction, were extremely uncommon 40 years ago and now account for approximately 15,000 new cases in the United States each year," according to Dr Adam Bass, of the Dana-Farber Cancer Institute.

"Unfortunately, it's also a disease with a generally poor prognosis: five years after diagnosis, only about 15 per cent of patients are still alive."

Bass and his team set out to identify genetic abnormalities within oesophageal adenocarcinoma cells to help better understand these tumours, diagnose them earlier, and develop more effective treatments.

Researchers sequenced specific portions of DNA in cells from 149 tumour tissue samples, reading all the individual letters of the genetic code within those sections.

"We discovered a pattern of DNA changes that had not been seen before in any other cancer type," said co-author Dr Gad Getz, of the Broad Institute and Massachusetts General Hospital.

The DNA double helix contains four rungs - known as nucleotides - that are often referred to by the letters C, T, G, and A.

The research team discovered that in many places where an A was followed by another A, the second one was replaced by a C - a process known as transversion.

This type of transversion was seen in around a third of all gene faults in the cancers, accounting for almost half of the altered genes in some tumour samples.

A to C changes are rarely seen in other types of cancer, but there is some evidence that such changes can be caused by so-called 'oxidative damage' - when cells cannot neutralise the potentially harmful products of oxygen's reactions with other molecules.

Stomach acid is capable of producing this type of damage, suggesting that reflux may indeed be behind this pattern of genetic mutations.

The team also found evidence of faults in genes involved in cell movement, suggesting a possible explanation for why oesophageal cancers can spread so aggressively through the body, although this needs to be explored in more detail.

Professor Rebecca Fitzgerald, oesophageal cancer lead for the International Cancer Genome Consortium, said the research was a useful addition to our growing genetic understanding of oesophageal cancer. 

"The findings suggest that the particular pattern of genetic damage found in oesophageal cancer may be caused by gastric reflux, although more work will be needed to confirm this, and to unpick the role it plays in the disease's development. Thanks to studies like these, including our own, the next few years are set to transform our understanding of oesophageal cancer. This progress will be vital - the disease can be difficult to treat successfully, and rates have been climbing in recent years," she said.

Dr Bass added: "It also presents us with a slate of known genetic abnormalities that can someday be used to diagnose the disease at an early stage, classify tumours by the particular mutations within oesophageal adenocarcinoma, and ultimately develop treatment geared to precisely those mutations."

Copyright Press Association 2013

References

  • Dulak A.M. et al. (2013). Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity, Nature Genetics, DOI: