Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes

Abstract

In the past two decades, multiple studies have been undertaken to elucidate the genetic cause of the predisposition to mismatch repair (MMR)-proficient nonpolyposis colorectal cancer (CRC). Here, we present the proposed candidate genes according to their involvement in specific pathways considered relevant in hereditary CRC and/or colorectal carcinogenesis. To date, only pathogenic variants in RPS20 may be convincedly linked to hereditary CRC. Nevertheless, accumulated evidence supports the involvement in the CRC predisposition of other genes, including MRE11, BARD1, POT1, BUB1B, POLE2, BRF1, IL12RB1, PTPN12, or the epigenetic alteration of PTPRJ. The contribution of the identified candidate genes to familial/early onset MMR-proficient nonpolyposis CRC, if any, is extremely small, suggesting that other factors, such as the accumulation of low risk CRC alleles, shared environmental exposures, and/or gene-environmental interactions, may explain the missing heritability in CRC.

Keywords: cancer genetics; cancer predisposition; cancer susceptibility; colorectal cancer; familial colorectal cancer type X; gene identification; hereditary cancer; mismatch repair proficiency; molecular pathways.

Figure 1

Schematic representation of colorectal cancer predisposing syndromes, causal genes, and affected molecular pathways. Genes shaded in grey correspond to the most promising proposed candidate genes. Abbreviations: BER, base excision repair; DSB, double strand breaks; meth, promoter hypermethylation; MMR, DNA mismatch repair; SAC, spindle assembly checkpoint.

Figure 2

(A) Number of disruptive (non-sense and frameshift) and (B) predicted pathogenic (disruptive, canonical splice-site, and predicted pathogenic missense) variants identified in the MMR genes MLH1, MSH2 and MSH6, RPS20, and in the most promising candidate genes for nonpolyposis CRC predisposition, in 1006 familial/early onset CRC cases. PMS2 was not included in the graph due to the possibility of miscalled variants due to the existence of multiple pseudogenes. Data obtained from Chubb et al., 2016 [28].