Tiny genetic error responsible for hereditary cancer

When is a genetic predisposition to cancer not a genetic predisposition? When you actually do possess the anti-cancer genes, but it’s been switched off, leaving you susceptible to developing cancer.

Researchers at the University of New South Wales have discovered that some people have key genes disabled by methylation, preventing them from performing their protective charge.

They found that a single error in the DNA sequence at the start of the gene MLH1, a well-known anti-cancer gene, was acting as a biochemical tag, triggering methylation and switching the gene off.

This lent individuals a similar risk of developing specific cancers such as bowel and uterine as individuals who lack the MLH1 gene altogether.

In the study the researchers looked at three generations of a large family, who had cancer at a young age, but in whom no spelling mistakes typical of this hereditary cancer syndrome had been found. Strikingly several members of the family from all generations had methylation tags on their gene.

“When the methylation attaches to the MLH1 gene in these families, it causes it to be completely switched off and as a consequence cancer develops,” said Professor Robyn Ward, a study co-leader and head of the adult cancer program at the Lowy Cancer Research Centre.

“But until now, we did not understand how these methylation tags were being passed from parent to child.

“In this family, biochemical tags attached to the MLH1 gene were present in all three generations. This was intriguing since these markers are usually removed during the production of eggs and sperm," said Dr Megan Hitchins from UNSW's Lowy Cancer Research Centre.

“What we found was that a subtle change near the gene was acting like a magnet to attract methylation. So it was not the methylation itself that was being passed from parent to child, but rather the DNA change, and this acted as a methyl magnet,” she said.

Mysteriously, the error in methylation was not passed through germ cells such as sperm and eggs, but it was recreated in each generation.

The finding raises the option of improved diagnostic tests for cancer susceptibility and new drugs that might be able to reverse the methylation and reactivate the anti-cancer gene.

The study was published in the journal Cancer Cell.