New Lynch syndrome subtype discovered: Implications for cancer treatment, prevention, and family planning

Researchers have identified a new mechanism causing Lynch syndrome, the most common hereditary cancer syndrome predisposing people to cancers of the bowel and endometrium.

This discovery has important implications for identifying people with Lynch syndrome, enabling opportunities for cancer prevention, early detection and personalised treatment.

The study, published in Gastroenterology, and led by researchers Dr Romy Walker and Associate Professor Dan Buchanan from the Colorectal Oncogenomics Group at the Collaborative Centre for Genomic Cancer Medicine—a joint venture of the University of Melbourne and Peter MacCallum Cancer Centre—investigated post-zygotic mosaicism as a cause of Lynch syndrome.

Post-zygotic mosaicism has been identified in many other genetic conditions, but a systematic screen for it has never been undertaken in Lynch syndrome. This study identified the first reported case of post-zygotic mosaicism in Lynch syndrome isolated to a segment of the colon, termed ‘localised mosaicism’.

Dr Walker said that identifying this first reported case of localised MMR gene mosaicism has important clinical implications.

"This discovery provides an opportunity to tailor clinical management differently from the intensive standard of care typically recommended for Lynch syndrome patients. It could inform treatments that may reduce the risk of developing a second primary colorectal cancer," said Dr Walker.

"Understanding localised MMR gene mosaicism is important for the family. Unlike the majority of Lynch syndrome that can be passed onto offspring, this case of localised mosaicism cannot be inherited as the mutation is not present in sperm or egg cell DNA."

This research follows on from Dr Walker's earlier work which identified the first-ever case of soma-wide mosaicism in the MSH6 gene. It significantly furthered the understanding of both localised and soma-wide (affecting the entire body) mosaicism in Lynch syndrome providing guidance on when mosaicism should be investigated in the diagnostic setting.

"Identifying mosaicism is crucial for patients," said Dr. Walker. "However, due to its low prevalence in Lynch syndrome and the multiple tests required that are performed in a step-wise approach, our findings support a targeted approach to mosaicism testing.”

“Rather than testing every patient systematically, we recommend focusing on those with specific clinical features that may indicate mosaicism."