Scientists find new genetic risks for colon cancer

NEW DELHI: Researchers have found new genes that put people at higher risk for colon and rectal cancer, an advance that may aid efforts towards prevention and treatment of this prevalent malignancy.

The researchers from Vanderbilt-Ingram Cancer Center in the US conducted a large transcriptomic-wide association study (TWAS), along with an alternative approach called splicing-TWAS, to strengthen gene discovery.

TWAS is a genetic methodology that can be used to compare the genetic components of gene expression and those of a trait to determine if an association is present between the two components.

The study, published in the Journal of the National Cancer Institute, found that oncogenic roles for two previously unreported genes, TRPSI and METRNL, and confirmed cancer susceptibility with another recently reported gene, C14orfl66.

“In our study, we utilised new large RNA-seq data and employed the TWAS approach along with splicing-TWAS to enhance novel gene discovery," said the study’s senior author, Xingyi Guo, an associate professor of Medicine and of Biomedical Informatics.

"By combining these population-based analyses with functional investigations, we can gain further insights into the biological mechanisms responsible for colorectal cancer development, which could aid in the translation of genetic findings for the prevention and treatment of this prevalent malignancy," Guo said.

Although more than 200 common genetic variants have been found to be associated with colorectal cancer through genome-wide association studies (GWAS), the target genes and the underlying biological mechanisms for the vast majority of these risk regions remain unclear, the researchers said.

The GWAS-identified risk variants explain only about half of the heritability of colorectal cancer. TWAS studies can further pinpoint susceptibility, they said.

The alternative approach the researchers utilised, splicing-TWAS, remains largely unexplored for colorectal cancer.

The researchers performed RNA-sequencing in normal colon tissues and incorporated genotyping data from 423 European descendants to build genetic prediction models of gene expression and alternative splicing.

In total, the researchers identified 57 genes associated with colorectal cancer risk after combining findings from the TWAS and splicing-TWAS studies. Sixteen of them had not been reported in GWAS studies.

Future TWAS analyses utilizing these advanced approaches are likely to reveal additional significant genes for cancer risk, the researchers said.

They noted that a limitation of the study is that it was limited to European ancestry and that further investigations are needed to assess the relevance of these genes in non-European populations.