Major genetic cause of colorectal cancer identified

Scientists have identified one of the leading genetic causes of inherited colorectal cancer, reported in the journal Science. Research teams at the Northwestern University Feinberg School of Medicine and the Human Cancer Genetics Program at Ohio State University found that abnormal activity of the transforming growth factor-beta type 1 receptor (TGFBR1) gene is associated with a greater risk of developing colorectal cancer.

Approximately one third of colorectal cancer cases are believed to genetically inherited, though many of the genetic abnormalities have yet to be identified. 'This probably accounts for more colorectal cancers than all other gene mutations discovered thus far,' said Dr Boris Pasche of Northwestern University, who lead the study with Professor Albert de la Chapelle, Ohio State University.

The researchers compared the DNA of 242 colorectal cancer patients, and 195 healthy controls. In patients with colorectal cancer, 10-20 per cent had abnormal production of TGFRB1, compared to 1-3 per cent in the control group. This genetic abnormality was clustered in families and dominantly inherited. Patients with abnormal TGFRB1 production were nine times more likely to develop colorectal cancer than healthy controls, with an estimated overall lifetime risk of developing the cancer at fifty per cent.

'There is not a conventional mutation,' said Professor de la Chapelle. The team found that the increased risk of developing colorectal cancer was linked to differences in the activity of the TGFBR1 gene, known as Allele Specific Expression (ASE), rather than a mutation in the gene. Each person has two copies, or alleles, of every gene in their genome, one inherited from the father and the other from the mother. The researchers found that when one copy of the gene was less active, there was reduced production of TGFBR1.

TGF-beta is an important cell signalling molecule involved in inhibiting cell growth and has been linked to colorectal and other cancers. In this study the researchers have identified one major mechanism of action.

The researchers stressed that the results will need to be replicated in a larger study involving many more patients. They also noted that their findings may be different in other ethnic populations, for example in African or Asian groups. Non-genetic risk factors for colorectal cancer include a diet high in fat and calories, and low in fiber; obesity; a sedentary lifestyle; alcohol consumption and smoking.

The research group hopes to develop clinical tests to identify abnormal expression of the TGFRB1 gene in families with colorectal cancer history. 'We will be able to identify a larger number of individuals that are at risk of colorectal cancer and, in the long term, maybe decrease the cases of colorectal cancer and of people dying from it by being able to screen them more frequently,' said Dr Pasche.