Colorectal Cancer Risk Linked to Common and Rare Variants

Colorectal cancer (CRC), also known as bowel cancer and colon cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Screening, by one of a number of methods, is recommended starting from the age of 50 to 75.

Most colorectal cancers are due to old age and lifestyle factors, with only a small number of cases due to underlying genetic disorders. An international team has identified a combination of rare and common genetic variants coinciding with colorectal cancer (CRC) susceptibility.


The international team led by investigators at the Fred Hutchinson Cancer Research Center (Seattle, WA, USA) performed whole-genome sequencing on more than 2,100 CRC cases and controls, using variants imputed from these and other data in a two-stage genome-wide association study that included nearly 125,500 individuals with or without CRC. This revealed 40 previously undocumented CRC-associated variants and 55 variants implicated in CRC risk in prior studies.

The team used HiSeq 2500 paired-end sequencing, and did whole-genome sequencing on 1,439 individuals with CRC and 720 unaffected controls. Using sequence data covering each genome to 3.8- to 8.6-fold coverage, on average, and population reference sequence data from the Haplotype Reference Consortium, they got haplotype phasing information for 31.8 million variants, including rare variants. A subset of participants were genotyped using a custom Illumina array that included known cancer-related loci as well as suspicious variants found in the first phase of the association study.

From the genome-wide association study (GWAS) meta-analysis and their subsequent conditional analysis, the team uncovered known CRC contributors, along with new associations involving common, low-frequency, and rare variants. They went on to delve into 40 new variants implicated in CRC with functional annotation, open chromatin maps, and chromatin accessibility profiling by ATAC-seq. The team also came up with a polygenic score based on 95 new and previously known risk variants, though it cautioned that the polygenic risk score is expected to be less accurate in non-European populations due to the over-representation of European participants in the current study. They discovered a strongly protective 0.3% frequency variant signal at Chromodomain Helicase DNA Binding Protein 1 (CHD1).

The authors concluded that heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development. The study was published on December 3, 2018, in the journal Nature Genetics.

Related Links:
Fred Hutchinson Cancer Research Center