Abstract
Germline mutations in predisposition genes account for only 20% of all familial colorectal cancers (CRC) and the remaining genetic burden may be due to rare high- to moderate-penetrance germline variants that are not explored. With the aim of identifying such potential cancer-predisposing variants, we performed whole exome sequencing on three CRC cases and three unaffected members of a Polish family and identified two novel heterozygous variants: a coding variant in APC downregulated 1 gene (APCDD1, p.R299H) and a non-coding variant in the 5′ untranslated region (UTR) of histone deacetylase 5 gene (HDAC5). Sanger sequencing confirmed the variants segregating with the disease and Taqman assays revealed 8 additional APCDD1 variants in a cohort of 1705 familial CRC patients and no further HDAC5 variants. Proliferation assays indicated an insignificant proliferative impact for the APCDD1 variant. Luciferase reporter assays using the HDAC5 variant resulted in an enhanced promoter activity. Targeting of transcription factor binding sites of SNAI-2 and TCF4 interrupted by the HDAC5 variant showed a significant impact of TCF4 on promoter activity of mutated HDAC5. Our findings contribute not only to the identification of unrecognized genetic causes of familial CRC but also underline the importance of 5’UTR variants affecting transcriptional regulation and the pathogenesis of complex disorders.
Highlights
Whole exome sequencing (WES) is gaining relevance for molecular genetic research of familial cancer and the identification of new cancer-predisposing variants
Cancer-predisposing germline mutations of APC, MUTYH and mismatch repair genes are already known to be associated with familial colorectal cancer (CRC) and to lead to: phenotypes of well-defined Mendelian CRC syndromes, familial adenomatous polyposis (FAP), resulting from APC gene mutations; MUTYH-associated polyposis (MAP); and Lynch syndrome, a hereditary non-polyposis colon cancer (HNPCC) syndrome caused by mismatch repair gene mutations (MLH1, MSH2, MSH6, PMS2 and EPCAM) [2]
The APC downregulated 1 (APCDD1) variant was identified in 8 additional familial CRC cases, 1 CRC case without family history and in 2 healthy elderly individuals without cancer family history, leading to a 4.9-fold increased CRC risk for the variant carriers (p = 0.04), while no other histone deacetylase 5 gene (HDAC5) variants were identified among the 1705 familial CRC cases
Summary
Whole exome sequencing (WES) is gaining relevance for molecular genetic research of familial cancer and the identification of new cancer-predisposing variants. Colorectal cancer (CRC) shows one of the highest proportions of familial cases and heritable factors have been estimated to account for about 35% of CRC risk, according to twin studies [1]. CRC fulfilling the diagnostic criteria of Lynch syndrome but not linked to pathogenic mismatch repair gene mutations or the resulting microsatellite instability has been classified as Familial Colorectal Cancer Type X (FCCTX). Sequencing studies have further identified germline variants in HNRNPA0 and WIF1 genes in a family with susceptibility to multiple early onset cancers including CRC [4] as well as a germline mutation in NTHL1 gene in three unrelated families with adenomatous polyposis and various cancer types including CRC [5,6]. Since the genetic background of most familial CRC cases has still not been sufficiently explored, the application of WES on these patients within pedigree-based studies bears great potential for the exploration of the remaining genetic burden
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