Candidate genes for hereditary colorectal cancer: Mutational screening and systematic review

Genome-wide approaches applied for the identification of new hereditary colorectal cancer (CRC) genes, identified several potential causal genes, includingRPS20,IL12RB1,LIMK2,POLE2,MRE11,POT1,FAN1,WIF1,HNRNPA0,SEMA4A,FOCAD,PTPN12,LRP6,POLQ,BLM,MCM9, and the epigenetic inactivation ofPTPRJ. Here we attempted to validate the association between variants in these genes and nonpolyposis CRC by performing a mutational screening of the genes andPTPRJpromoter methylation analysis in 473 familial/early-onset CRC cases, a systematic review of the published cases, and assessment of allele frequencies in control population. In the studied cohort, 24 (5%) carriers of (predicted) deleterious variants in the studied genes and no constitutionalPTPRJepimutations were identified. Assessment of allele frequencies in controls compared with familial/early-onset patients with CRC showed association with increased nonpolyposis CRC risk of disruptive variants inRPS20,IL12RB1,POLE2,MRE11andPOT1, and ofFAN1c.149T>G (p.Met50Arg). Lack of association was demonstrated forLIMK2,PTPN12,LRP6,PTPRJ,POLQ,BLM,MCM9andFOCADvariants. Additional studies are required to provide conclusive evidence forSEMA4A,WIF1,HNRNPA0 c.-110G>C, andFOCADlarge deletions.