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.
Highlights
While estimates indicate that approximately 14% of all colorectal cancer (CRC) patients have at least one first-degree relative affected with the same tumor type [1,2], 4–8% of all CRC patients carry germline pathogenic variants in one of the known high penetrance genes for this tumor [3,4,5,6], with a relevant proportion of the familial aggregation of CRC remaining unexplained
Germline alterations in other genes involved in the DNA damage response (DDR) have been proposed as genes potentially involved in CRC predisposition [5,12,13,14]
Cell cycle dysregulation may drive tumorigenesis; it is not surprising that germline variants in genes coding for cell cycle checkpoint proteins, including factors involved in the proper formation and segregation of chromosomes, have been identified in CRC patients
Summary
While estimates indicate that approximately 14% of all colorectal cancer (CRC) patients have at least one first-degree relative affected with the same tumor type [1,2], 4–8% of all CRC patients carry germline pathogenic variants in one of the known high penetrance genes for this tumor [3,4,5,6], with a relevant proportion of the familial aggregation of CRC remaining unexplained. The identification of a germline pathogenic variant in a colorectal cancer-predisposing gene has important consequences for the patients and their relatives, as they can be counseled and managed based on gene-specific guidelines This is the main reason why large efforts have been and are still being made to identify the genetic cause of the increased CRC risk observed in some families. 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].
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