A novel low-risk germline variant in the SH2 domain of the SRC gene affects multiple pathways in familial colorectal cancer
| Autor: | Beiping Miao, Jan Lubinski, Diamanto Skopelitou, Matthias Schlesner, Magdalena Kuświk, Nagarajan Paramasivam, Abhishek Kumar, Kari Hemminki, Asta Försti, Aayushi Srivastava, Obul Reddy Bandapalli, Dagmara Dymerska |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Colorectal cancer
In silico Medicine (miscellaneous) familial colorectal cancer Biology SH2 domain Article germline variant Germline 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation medicine Missense mutation biochemistry ddc:610 Gene 030304 developmental biology 0303 health sciences whole genome sequencing medicine.disease 3. Good health 030220 oncology & carcinogenesis Cancer research SRC Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Journal of Personalized Medicine Volume 11 Issue 4 |
| Popis: | Colorectal cancer (CRC) shows one of the largest proportions of familial cases among different malignancies, but only 5–10% of all CRC cases are linked to mutations in established predisposition genes. Thus, familial CRC constitutes a promising target for the identification of novel, high- to moderate-penetrance germline variants underlying cancer susceptibility by next generation sequencing. In this study, we performed whole genome sequencing on three members of a family with CRC aggregation. Subsequent integrative in silico analysis using our in-house developed variant prioritization pipeline resulted in the identification of a novel germline missense variant in the SRC gene (V177M), a proto-oncogene highly upregulated in CRC. Functional validation experiments in HT-29 cells showed that introduction of SRCV177M resulted in increased cell proliferation and enhanced protein expression of phospho-SRC (Y419), a potential marker for SRC activity. Upregulation of paxillin, β-Catenin, and STAT3 mRNA levels, increased levels of phospho-ERK, CREB, and CCND1 proteins and downregulation of the tumor suppressor p53 further proposed the activation of several pathways due to the SRCV177M variant. The findings of our pedigree-based study contribute to the exploration of the genetic background of familial CRC and bring insights into the molecular basis of upregulated SRC activity and downstream pathways in colorectal carcinogenesis. |
| Databáze: | OpenAIRE |
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