The most comprehensive genome-wide association study (GWAS) of colorectal cancer (CRC) risk to date has discovered 40 new genetic variants that signal an increased risk of CRC. The study, published in Nature Genetics, has also identified the first rare protective variant for sporadic CRC.
Whole-genome sequencing was performed on 1,439 cases and 720 controls. The association between variants and CRC was tested in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls.
In a combined meta-analysis of 125,478 individuals, 40 new independent signals were identified, bringing the number of known independent signals for CRC to approximately 100. The analysis discovered a strongly protective variant signal at CHD1, which had a 0.3 per cent frequency.
The study authors report that new signals implicated lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and supported a role for immune function.
They say the findings show "a missed opportunity" in drug development. The study identified several loci near proposed drug targets and genes in pathways not previously known to be causally linked to colorectal cancer. Using GWAS results to inform drug development could even lead to chemoprevention drugs for high-risk individuals, they say.