Cover Image

Whole exome sequencing identifies APCDD1 and HDAC5 genes as potentially cancer predisposing in familial colorectal cancer

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,...

Full description

Saved in:
Bibliographic Details
Main Authors: Skopelitou, Diamanto (Author) , Miao, Beiping (Author) , Srivastava, Aayushi (Author) , Kumar, Abhishek (Author) , Kuswick, Magdalena (Author) , Dymerska, Dagmara (Author) , Paramasivam, Nagarajan (Author) , Schlesner, Matthias (Author) , Lubinski, Jan (Author) , Hemminki, Kari (Author) , Försti, Asta (Author) , Bandapalli, Obul Reddy (Author)
Format: Article (Journal)
Language:English
Published: 2 February 2021
In: International journal of molecular sciences
Year: 2021, Volume: 22, Issue: 4, Pages: 1-21
ISSN:1422-0067
DOI:10.3390/ijms22041837
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.3390/ijms22041837
Verlag, lizenzpflichtig, Volltext: https://www.mdpi.com/1422-0067/22/4/1837
Get full text
Author Notes:Diamanto Skopelitou, Beiping Miao, Aayushi Srivastava, Abhishek Kumar, Magdalena Kuswick, Dagmara Dymerska, Nagarajan Paramasivam, Matthias Schlesner, Jan Lubinski, Kari Hemminki, Asta Försti and Obul Reddy Bandapalli
Description
Summary: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.
Item Description:Gesehen am 27.08.2021
Physical Description:Online Resource
ISSN:1422-0067
DOI:10.3390/ijms22041837

Similar Items