Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed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

Diamanto Skopelitou
,
Beiping Miao
,
Aayushi Srivastava
,
Abhishek Kumar
,
Magdalena Kuświk
,
Dagmara Dymerska
ORCID logo ,
Nagarajan Paramasivam
,
Matthias Schlesner
,
Jan Lubiński
,
Kari Hemminki
,
Asta Försti
ORCID logo ,
Obul Reddy Bandapalli
* ORCID logo
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.

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.

Keywords

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

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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