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

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.

Identification of colon cancer subtypes based on multi-omics data—construction of methylation markers for immunotherapy

“…A decrease in the expression level of PCDH20 can disrupt the integrity of the intestinal mucosa, which can contribute to the development of colitis and Crohn’s disease ( 48 ). APCDD1 (adenomatosis polyposis down-regulated 1), a negative regulator of Wnt/β-catenin pathway, its expression was regulated by promotor methylation ( 49 ). It has been demonstrated that the methylation of WNT target genes (including APCDD1) could be serve as reliable biomarkers for predicting recurrence in colon cancers ( 50 ).…”

Personalized Immunotherapy in Colorectal Cancers: Where Do We Stand?

“…Despite the efforts to study CRC heterogeneity, our current knowledge in this field is just the tip of the iceberg. Expanding next-generation sequencing (NGS), single-cell sequencing, and whole-exome sequencing techniques along with the application of omics data at various levels, including genomics, epigenomics, transcriptomics, peptidomics, proteinomics, and metabolomics, could give us valuable information on the heterogeneity of CRCs (116)(117)(118)(119)(120)(121)(122)(123).…”

Whole exome sequencing identifies novel germline variants of SLC15A4 gene as potentially cancer predisposing in familial colorectal cancer

“…For this purpose, we performed whole exome sequencing (WES) on a Polish family with CRC aggregation over three generations. Sequencing data of four CRC cases and two unaffected family members were subsequently analyzed using our in-house developed Familial Cancer Variant Prioritization Pipeline (FCVPPv2) which was used earlier in identification of variants and pathways involved in several familial cancers (Bandapalli et al 2018 ; Kumar et al 2018 ; Srivastava et al 2019 ; Srivastava et al 2020a ; Srivastava et al 2020b ; Skopelitou et al 2021 ; Srivastava et al 2021 ). Further in silico analyses resulted in the prioritization of a novel missense variant in the solute carrier family 15 member 4 gene ( SLC15A4 ), encoding a proton-dependent peptide/histidine transporter.…”