New research has found that inherited mutations in the MUTYH gene, which repairs oxidative DNA damage, are linked to an increased mutation rate in healthy tissues and a higher risk of developing bowel cancer.
The study from the Wellcome Sanger Institute, Cardiff University, and collaborators found that individuals with two mutated copies of the gene, one from each parent, had increased mutation rates in healthy intestine cells, causing pre-cancerous growths with an even higher number of mutations. The results of this research imply that the higher mutation rates in healthy tissues are likely responsible for the increased bowel cancer risk in these individuals.
The research, published earlier in Nature Communications, also found mutation rates were modestly increased in blood cells from affected individuals. Still, these are not known to be linked to any increase in risk of blood cancer development, highlighting that there may be other factors or mechanisms protecting these tissues.
Understanding why a mutated MUTYH gene gives an increased cancer risk, particularly of bowel cancer, could lead to new ways to prevent and treat the disease. The discovery of a link between the rate of mutations in the blood and intestine suggests this could be investigated to produce a blood test to help predict bowel cancer risk.
Bowel cancer, also known as colorectal cancer, is the fourth most common cancer in the UK, with around 42,300 people diagnosed with the disease in the UK each year1.
While the cause of cancer is due to various factors, some inherited mutations can lead to an increased risk of developing disease. The gene, MUTYH, is involved in the DNA repair pathway following oxidative damage. Inherited mutations in the MUTYH gene lead to a syndrome known as MUTYH-associated polyposis (MAP), which results in growths known as polyps in the large intestine and an elevated risk of early-onset colorectal cancer2.
The progression from inherited mutations in the MUTYH gene to the development of bowel cancer is not fully understood. In this latest study, Wellcome Sanger Institute researchers and their collaborators from Cardiff University analysed intestinal tissues and blood from 10 patients with MAP, and found a considerably increased mutation rate in the healthy intestinal cells. At one extreme, a sixteen-year-old with MAP had the same number of mutations in his healthy intestinal tissues as would be expected if someone without MAP syndrome had lived to 455 years old.
They also found an increase in mutation rate in peripheral blood cells, which are those circulating in the blood. The rate of mutations between intestinal and blood cells was positively correlated, suggesting that one day this might be used to stratify bowel cancer risk through a blood test.
In addition, they identified two patterns of mutations, known as mutational signatures, that have been found in individuals with bowel cancer that was not linked to an inherited MUTYH gene mutation, adding to current understanding about the cellular changes linked to the development of this disease.
Further research is needed to shed light on why the bowel is particularly susceptible to cancers in this condition, and if there are ways to target the MUTYH mutation or the downstream mutations in developing new treatments.
Source: Sanger Institute