4/12/2023 0 Comments Spindle assembly checkpoint![]() identified germline mutations in BUB1 and BUB3, components of the spindle assembly checkpoint (SAC) and thus controllers of correct chromosome segregation, as cause for CRC predisposition. īased on genome-wide copy number profiling and exome sequencing in early-onset and familial CRC, De Voer et al. Despite the identification of novel candidate genes for CRC predisposition, overall, they account for a very low number of familial cases, and for many of the suggested genes, identification of additional mutated families is essential to conclusively define their actual implication in CRC predisposition. Genome-wide genetic and genomic screenings have tried to identify novel high penetrance genes for CRC. Much of the heritability associated with colorectal cancer (CRC) cannot be explained by the currently known genetic risk factors for CRC. As of today, the rarity of functionally relevant mutations identified in familial and/or early onset series does not support the inclusion of BUB1 and BUB3 testing in routine genetic diagnostics of familial CRC. BUB1 c.2473C>T (p.P825S) and BUB3 c.77C>T (p.T26I) remained as variants of uncertain significance. Evident functional effects in the heterozygous form were observed for c.1965-1G>A, but not for c.2296G>A (p.E766K), in spite of the positive co-segregation in the family. Neither variegated aneuploidy nor dysmorphic traits were observed in carriers. Four novel or rare germline variants, one splice-site and three missense, were identified in four families. We performed a mutational analysis of BUB1 and BUB3 in 456 uncharacterized mismatch repair-proficient hereditary non-polyposis CRC families and 88 polyposis cases. Germline mutations in BUB1 and BUB3 have been reported to increase the risk of developing colorectal cancer (CRC) at young age, in presence of variegated aneuploidy and reminiscent dysmorphic traits of mosaic variegated aneuploidy syndrome.
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