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Background  The Ras pathway genes  KRAS ,  BRAF , or  ERBBs  have somatic mutations in ~ 60% of human colorectal carcinomas. At present, it is unknown whether the remaining cases lack mutations activating the Ras pathway or whether they have acquired mutations in genes hitherto unknown to belong to the pathway.    Methods  To address the second possibility and extend the compendium of Ras pathway genes, we used genome-wide transposon mutagenesis of two human colorectal cancer cell systems deprived of their activating  KRAS  or  BRAF  allele to identify genes enabling growth in low glucose, a Ras pathway phenotype, when targeted.    Results  Of the 163 recurrently targeted genes in the two different genetic backgrounds, one-third were known cancer genes and one-fifth had links to the EGFR/Ras/MAPK pathway. When compared to cancer genome sequencing datasets, nine genes also mutated in human colorectal cancers were identified. Among these, stable knockdown of  FOXO3 ,  NCOA3 , and  TCF7L2  restored growth in low glucose but reduced MEK/MAPK phosphorylation, reduced anchorage-independent growth, and modulated expressions of  GLUT1  and Ras pathway related proteins. Knockdown of  NCOA3  and  FOXO3  significantly decreased the sensitivity to cetuximab of KRAS mutant but not wild-type cells.    Conclusions  This work establishes a proof-of-concept that human cell-based genome-wide forward genetic screens can assign genes to pathways with clinical importance in human colorectal cancer.    Electronic supplementary material  The online version of this article (doi:10.1186/s13073-017-0511-4) contains supplementary material, which is available to authorized users.

Linking FOXO3, NCOA3, and TCF7L2 to Ras pathway phenotypes through a genome-wide forward genetic screen in human colorectal cancer cells