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

Abstract

Genome‐wide approaches applied for the identification of new hereditary colorectal cancer (CRC) genes, identified several potential causal genes, including RPS20, IL12RB1, LIMK2, POLE2, MRE11, POT1, FAN1, WIF1, HNRNPA0, SEMA4A, FOCAD, PTPN12, LRP6, POLQ, BLM, MCM9, and the epigenetic inactivation of PTPRJ. Here we attempted to validate the association between variants in these genes and nonpolyposis CRC by performing a mutational screening of the genes and PTPRJ promoter 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 constitutional PTPRJ epimutations 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 in RPS20, IL12RB1, POLE2, MRE11 and POT1, and of FAN1 c.149T>G (p.Met50Arg). Lack of association was demonstrated for LIMK2, PTPN12, LRP6, PTPRJ, POLQ, BLM, MCM9 and FOCAD variants. Additional studies are required to provide conclusive evidence for SEMA4A, WIF1, HNRNPA0 c.−110G>C, and FOCAD large deletions.

Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes

“…Very recently, we performed a mutational screening of RPS20 in 473 familial/early onset CRC cases and did not identify any predicted pathogenic variant. Taking the three studies together, we concluded that disruptive (stop-gain, frameshift, and start-loss) variants are enriched in familial/early onset CRC cases compared to controls [ 10 ]. Supporting this association with hereditary CRC, RPS20 c.177+1G>A has recently been identified in another family with four CRC-affected members, all of them carriers or obligate carriers of the RPS20 variant [ 11 ].…”

“…Aldubayan et al (2018) identified two additional carriers of MRE11 predicted pathogenic missense variants among 667 CRC patients [ 5 ], and Belhadj et al (2020) 2 more carriers in a 473-familial/early onset-CRC cohort. A meta-analysis of all reported series compared to a control population indicated that MRE11 -disruptive variants are significantly enriched in familial/early onset CRC, supporting the role of MRE11 in CRC predisposition [ 10 ]. On the other hand, it has been suggested that MRE11 and other MRN components may be used as biomarkers for predicting disease progression and treatment response.…”

“…Since then, numerous studies have been published, some of them supporting the association of heterozygous BLM pathogenic variants with various types of cancers, including CRC [ 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ], and others where no association with increased cancer risk was detected [ 5 , 51 , 52 , 53 , 54 ]. A recent meta-analysis combining our own BLM mutational screening with previous studies and publicly available sequencing data from familial and/or early onset CRC patients suggested a lack of association of BLM heterozygous disruptive and predicted pathogenic variants with CRC predisposition after comparison with the frequencies in population controls [ 10 ].…”

“…Homozygous variants in MCM9 , a DNA helicase involved in HR, DNA replication and MMR, were described in two polyposis-affected siblings [ 57 ]. However, recent case-control data suggests a lack of association of homozygous or heterozygous variants with polyposis or CRC predisposition [ 10 , 58 ]. A frameshift mutation in XRCC4 , a member of the DNA ligase 4 complex involved in the last step of NHEJ, was found in a CRC patient with familial CRC history, which, together with the lack of XRCC4 variant carriers among population controls, led the authors to propose XRCC4 as a candidate gene for CRC predisposition [ 13 ].…”

“…Nonetheless, sequencing data from cases and controls does not show over-representation of predicted pathogenic variants in familial/early onset CRC patients (8/1006) compared to controls (11/1609) [ 28 ]. Predicted pathogenic variants in POLQ , a DNA polymerase involved in the alternative DSB repair pathway θ-mediated end joining (TMEJ), were found in familial CRC and polyposis patients [ 48 , 59 ], but studies in additional cohorts and combined analysis of available data did not support this association [ 10 , 60 ].…”