NEW YORK – An international team led by investigators in the UK, Spain, Denmark, and the US has tracked down new germline contributors to colorectal cancer (CRC) development in individuals of European or Asian ancestry, highlighting potential roles for previously unappreciated biological pathways.
"Our findings provide new insights into colorectal cancer and substantially expand our knowledge of the role gene variation plays in inherited colorectal cancer," co-first author Li Hsu, a Fred Hutchinson Cancer Research Center public health sciences researcher and biostatistician, said in a statement.
As they reported in Nature Genetics on Tuesday, Hsu and colleagues brought together data from prior genome-wide association studies for a GWAS meta-analysis that included more than 100,200 CRC cases and almost 150,600 unaffected controls, all with European or Asian ancestry.
"Knowing these hereditary factors and which groups are at greatest risk from them can guide clinicians in recommending preventive measures and more frequent screenings which can lead to earlier diagnosis and treatment and better survival outcomes for patients," co-first author Minta Thomas, a public health sciences researcher at Fred Hutchinson Cancer Research Center, said in a statement.
Their search led to 155 SNPs linked to CRC risk in the past, they reported, along with more than three dozen SNPs at previously unappreciated risk loci and 13 SNPs associated with the disease in their conditional analyses.
The team tracked down another 53 new CRC risk variants with transcriptome-wide association and transcript isoform-wide association analyses that included new and publicly available expression profiles for more than 1,100 colorectal mucosal samples; TWAS done with new and existing expression data for more than 16,800 samples spanning 49 tissue types; and a methylation-wide association study based on quantitative methylation profiles for nearly 500 colorectal mucosa samples.
"We're excited about our study's discoveries, including the addition of 100-plus genetic risk variants for this severe disease," co-senior and co-corresponding author Ulrike Peters, a molecular and genetic epidemiologist affiliated with Fred Hutchinson Cancer Research Center and the University of Washington, said in a statement, adding that "[s]everal of the genes and pathways we identified are potential targets for preventive therapy."
Together, the new and known risk variant set appeared to impact 155 genes, the researchers reported, with variant- and gene-level analyses pointing to known risk pathways, along with biological processes not previously linked to the disease.
"Cross-tissue analyses indicated that the colorectal mucosa was the most probable site of action of many effector genes, but some genes are more likely to act in different tissue types," the authors reported, adding that "several credible effector genes have primary roles in neurogenesis, raising the intriguing possibility that the enteric nervous system is involved in CRC risk."
While a slew of CRC candidate genes fell in pathways involved in cellular proliferation, stemness, or differentiation, for example, others were involved in intestinal homeostasis, cellular adhesion or migration, epigenetics, immunity and tissue interactions with microbes, and other processes.
Their cross-trait analyses pointed to at least a dozen ties between CRC risk and genetic contributors to several traits or lifestyle risk factors already linked to CRC, including body mass index, insulin resistance, and smoking.
In addition, the study's authors explained, the findings provided clues to potential treatment targets or for markers to help find at-risk individuals who may benefit from early or preventive treatment.
"Overall, our findings demonstrate the power of multiomics to provide new insights into the biological basis of CRC, including both the identification of candidate effector genes and the support for previously unsuspected functional mechanisms," they wrote, noting that "several of the genes and pathways we have identified are potential targets of CRC treatment or chemoprevention."