Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

A Novel Low-Risk Germline Variant in the SH2 Domain of the SRC Gene Affects Multiple Pathways in Familial Colorectal Cancer

Version 1 : Received: 2 March 2021 / Approved: 3 March 2021 / Online: 3 March 2021 (09:52:06 CET)

A peer-reviewed article of this Preprint also exists.

Skopelitou, D.; Miao, B.; Srivastava, A.; Kumar, A.; Kuświk, M.; Dymerska, D.; Paramasivam, N.; Schlesner, M.; Lubiński, J.; Hemminki, K.; Försti, A.; Bandapalli, O.R. A Novel Low-Risk Germline Variant in the SH2 Domain of the SRC Gene Affects Multiple Pathways in Familial Colorectal Cancer. J. Pers. Med. 2021, 11, 262. Skopelitou, D.; Miao, B.; Srivastava, A.; Kumar, A.; Kuświk, M.; Dymerska, D.; Paramasivam, N.; Schlesner, M.; Lubiński, J.; Hemminki, K.; Försti, A.; Bandapalli, O.R. A Novel Low-Risk Germline Variant in the SH2 Domain of the SRC Gene Affects Multiple Pathways in Familial Colorectal Cancer. J. Pers. Med. 2021, 11, 262.

Journal reference: J. Pers. Med. 2021, 11, 262
DOI: 10.3390/jpm11040262

Abstract

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 3 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 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.

Subject Areas

Familial colorectal cancer; SRC; germline variant; whole genome sequencing

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.