Scarless genome editing reveals risk SNP rs6983267-G and lncRNA CCAT2 dictate targetable PI3K signaling dependence in WNT-dysregulated CRC
Abstract Genome-wide association studies have identified numerous loci associated with increased risk for colorectal cancer (CRC), including 8q24.21 which contains a known enhancer of proto-oncogene MYC . However, the role of candidate functional SNP rs6983267 within this locus remains unclear. Here, we generate isogenic cellular models of risk SNP rs6983267 in human CRC line, HCT-116. Comprehensive molecular characterization reveals risk allele-G drives enhancer DNA contacts with downstream regions that include MYC . Absence of risk allele leads to activation of lncRNA CCAT2 . Rather than changes in MYC expression, we observe activation of alternative growth factor signaling pathways with loss of both risk allele and CCAT2 expression. Analysis of TCGA CRC cases demonstrates low CCAT2 expression combined with non-risk rs6983267 genotype correlate with higher frequency of PI3K mutations in CRC patients displaying WNT dysregulation. Together, these provide a potential biomarker for therapeutically targetable PI3K dysregulation in CRC and application in cancer precision medicine.