Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 4, Pages -Publisher
MDPI
DOI: 10.3390/ijms22041837
Keywords
APCDD1; HDAC5; 5´ UTR; germline variant; familial colorectal cancer; whole exome sequencing; promoter activity
Funding
- COST (European Cooperation in Science and Technology) [CA17118]
- German Federal Ministry of Education and Research (BMBF)
- EU Horizon 2020 program [856620]
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Germline mutations in predisposition genes only contribute to 20% of familial colorectal cancers, with rare potential cancer-predisposing variants remaining poorly explored. A study identified two novel variants in a Polish family, one showing no significant impact on cell proliferation and the other enhancing promoter activity. The findings shed light on unrecognized genetic causes of familial CRC and highlight the importance of 5' UTR variants affecting transcriptional regulation.
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.
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