Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Whole Exome Sequencing Identifies APCDD1 and HDAC5 Genes as Potentially Cancer Predisposing in Familial Colorectal Cancer

Version 1 : Received: 29 January 2021 / Approved: 1 February 2021 / Online: 1 February 2021 (14:04:24 CET)

A peer-reviewed article of this Preprint also exists.

Skopelitou, D.; Miao, B.; Srivastava, A.; Kumar, A.; Kuswick, M.; Dymerska, D.; Paramasivam, N.; Schlesner, M.; Lubinski, J.; Hemminki, K.; Försti, A.; Bandapalli, O.R. Whole Exome Sequencing Identifies APCDD1 and HDAC5 Genes as Potentially Cancer Predisposing in Familial Colorectal Cancer. Int. J. Mol. Sci. 2021, 22, 1837. Skopelitou, D.; Miao, B.; Srivastava, A.; Kumar, A.; Kuswick, M.; Dymerska, D.; Paramasivam, N.; Schlesner, M.; Lubinski, J.; Hemminki, K.; Försti, A.; Bandapalli, O.R. Whole Exome Sequencing Identifies APCDD1 and HDAC5 Genes as Potentially Cancer Predisposing in Familial Colorectal Cancer. Int. J. Mol. Sci. 2021, 22, 1837.

Journal reference: Int. J. Mol. Sci. 2021, 22, 1837
DOI: 10.3390/ijms22041837

Abstract

Germline mutations in predisposition genes account for only 20% of all familial colorectal cancer (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 down-regulated 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 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.

Subject Areas

APCDD1; HDAC5; germline variants; familial colorectal cancer; whole exome sequencing; promoter activity

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our diversity statement.

Leave a public comment
Send a private comment to the author(s)
Views 0
Downloads 0
Comments 0
Metrics 0


×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here.