Finding unknown parts of a well-known intracellular pathway

In a new study led by Tobias Sjöblom (Uppsala University/SciLifeLab), a large-scale search for genetic mutations in human colorectal cancer cells made it possible to assign additional genes to intracellular pathways of clinical importance for the disease.

Around 60% of human colorectal cancers have mutations in the KRAS, BRAF or ERBB genes – all of which encode proteins coupled to the Ras pathway, a well-known way of transmitting signals within cells. Until now, it has been unknown whether the remaining cases lack mutations activating the Ras pathway or whether they have mutations in genes hitherto unknown to belong to the pathway.

To extend the compendium of Ras pathway genes, the researchers performed a genetic screen to identify genes enabling cell growth under conditions with low levels of glucose fuel, an ability facilitated by Ras pathway activity, when targeted. The three genes FOXO3, NCOA3, and TCF7L2 were found mutated in human colorectal cancers and affected several established Ras pathway manifestations. The study is a proof-of-concept that forward genetic screens in human cells can assign genes to pathways with clinical importance in cancer and the approach could henceforth be applied to investigating other cancer types and pathways.

Read the full paper in Genome Medicine