Mosaicism mutation identified in Australian cancer patient

World-first case of gene variant identified in Australian cancer patient: Researchers have identified the first ever case of a mutation known as ‘mosaicism’ in one of the genes responsible for fixing errors in our DNA, known as the DNA mismatch repair genes. The discovery could improve the way patients are tested for and diagnosed with Lynch syndrome, which affects approximately 1 in every 280 Australians.

Lynch syndrome is a hereditary condition that increases the risk of many kinds of cancer, including bowel cancer and endometrial cancer, but diagnosing the condition through standard clinical testing is not always effective.

Led by Dr. Romy Walker from the University of Melbourne Centre for Cancer Research, and published in Familial Cancer, the new study used an ultra-sensitive DNA testing methodology called ‘droplet digital polymerase chain reaction’, or ddPCR test, to break down samples into 20,000 tiny droplets and test them individually.

The ddPCR test identified the mosaic mutation and could be used in the future to more effectively diagnose Lynch syndrome.

Dr. Walker said mosaicism in the DNA mismatch repair genes that causes Lynch syndrome is extremely rare, and that in this case standard clinical testing did not identify a pathogenic variant in the patient’s DNA mismatch repair genes.

“There have only been four cases identified worldwide, and this is the first ever recorded case in the MSH6 gene,” Dr. Walker said.

“Mosaicism is a condition where a person has two or more genetically different sets of cells in their body – and when these types of cells outnumber normal cells it can lead to tumour development.

“Somatic or post-zygotic mosaicism is when a person has two or more genetic sets of cells in their body. When cells with multiple genetic sets outnumber normal cells, it can lead to disease development. As a result, tumours are more likely to develop as they multiply throughout the body.

“An NHMRC funded study (the ANGELS study) previously conducted in our lab has shown that more than 85 per cent of suspected Lynch syndrome cases can be diagnosed through genomic sequencing.”

The patient at the centre of the case study, Jenny Keir, had received a diagnosis of ‘suspected Lynch syndrome’ after developing cancer of the uterus and bowel.

She was referred to the ANGELS study, led by Associate Professor Daniel Buchanan’s Colorectal Oncogenomics Group at the University of Melbourne Centre for Cancer Research for extensive genomic tumour testing.

Associate Professor Buchanan said the finding could have broad implications for the testing and diagnosis of Lynch syndrome in the future.

“People who are diagnosed with suspected Lynch syndrome represent a significant proportion of patients who develop cancer of the large bowel or uterus. Mosaicism in the mismatch repair genes isn’t routinely tested for, but we now have the tools to investigate it in a cost-effective way, Associate Professor Buchanan said.

“Although we have found mosaicism in this one patient, it is highly likely there are more cases. We need to let them know, so they can pass the information on to family members and get regular testing to reduce the risk of cancer.”

For the patient at the centre of the study, who is now in recovery, receiving an explanation helped bring a sense of closure.

“It was reassuring to finally have the suspected Lynch syndrome confirmed. The fact that my Lynch Syndrome wasn’t inherited means I no longer need to worry that my sisters, nieces, and nephews might also have it,” Keir said.

“After learning how rare my circumstances are, I like to think I am unique. But the thing is, we don’t actually know how unique I am, because we don’t know how many other people could have the type of variant I have.

“I feel a little bit proud to be able to contribute to an important body of research in some way. My father was a paediatric audiologist at the Royal Children’s Hospital. He developed screening tests in kindergartens to assess auditory processing problems in children. That was his contribution to science. I feel like taking part in this study is my very small contribution to science.”

The next phase of the research involves a systematic review to determine how prevalent mosaicism is in Lynch syndrome.