Two new mutations associated with risk of bowel cancer

Whole genome sequencing has brought to light two previously unknown genetic mutations strongly associated with colorectal cancer, in a study led by Professor Ian Tomlinson of the WTCHG. The discoveries offer families with a predisposition to the disease new opportunities for early testing and diagnosis, and shed light on the mechanism by which the disease develops. 

In some families, non-malignant growths and cancers of the large bowel recur in succeeding generations, suggesting that the disease is inherited. Previous studies looking for links between genes and disease have revealed mutations in at least 10 genes that are commonly associated with bowel cancer. Prof Tomlinson and his colleagues identified 15 families with strong histories of bowel tumours that did not carry any of the known genetic variants.

As part of the WGS500 study, a joint project between the University of Oxford and the company Illumina Inc, the team sequenced the entire genomes of 20 individuals from these families, all of whom had large numbers of precancerous growths or malignant tumours in their large intestines. Comparing these sequences with those of unaffected people revealed mutations in two genes, known as POLE and POLD1. All the family members with tumours had one or other of these mutations, and all of those with mutations had tumours. The results were published in the online edition of the journal Nature Genetics on 23 December 2012.

The team then searched for these mutations in 3805 people with a history of colorectal cancer, and in 6721 people with no history of cancer. They found 12 further carriers of the POLE mutation, and one with the POLD1 mutation. ‘These are two rare faults, but if you inherit them your chance of bowel cancer is high’, says Professor Tomlinson. ‘By testing people with a strong family history of the disease for these, we can identify those who are at high risk and try to prevent the disease by using colonoscopy and other methods.’

Both affected genes play a role in ‘proof reading’ copies of the DNA strands that are made every time a cell reproduces itself. The mutated versions produce enzymes that are unable to correct spelling errors in the sequence, which can lead the cell to reproduce uncontrollably and form a tumour.

PALLES C, CAZIER JB, HOWARTH KM, DOMINGO E, JONES AM, BRODERICK P, KEMP Z, SPAIN SL et al. 2012. Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet, 23 December.

See also:

Rare genetic faults identified in families with bowel cancer. Cancer Research UK

Faulty genes linked to high bowel cancer risk, The Daily Telegraph, p. 2, 24/12/12

Two bowel cancer genes discovered, BBC News online, 24/12/2012