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000168696 1001_ $$0P:(DE-He78)cea283034a4f6c64994f85d4444e7494$$aSkopelitou, Diamanto$$b0$$eFirst author$$udkfz
000168696 245__ $$aA Novel Low-Risk Germline Variant in the SH2 Domain of the SRC Gene Affects Multiple Pathways in Familial Colorectal Cancer.
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000168696 520__ $$aColorectal cancer (CRC) shows one of the largest proportions of familial cases among different malignancies, but only 5-10% of all CRC cases are linked to mutations in established predisposition genes. Thus, familial CRC constitutes a promising target for the identification of novel, high- to moderate-penetrance germline variants underlying cancer susceptibility by next generation sequencing. In this study, we performed whole genome sequencing on three members of a family with CRC aggregation. Subsequent integrative in silico analysis using our in-house developed variant prioritization pipeline resulted in the identification of a novel germline missense variant in the SRC gene (V177M), a proto-oncogene highly upregulated in CRC. Functional validation experiments in HT-29 cells showed that introduction of SRCV177M resulted in increased cell proliferation and enhanced protein expression of phospho-SRC (Y419), a potential marker for SRC activity. Upregulation of paxillin, β-Catenin, and STAT3 mRNA levels, increased levels of phospho-ERK, CREB, and CCND1 proteins and downregulation of the tumor suppressor p53 further proposed the activation of several pathways due to the SRCV177M variant. The findings of our pedigree-based study contribute to the exploration of the genetic background of familial CRC and bring insights into the molecular basis of upregulated SRC activity and downstream pathways in colorectal carcinogenesis.
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000168696 650_7 $$2Other$$aSRC
000168696 650_7 $$2Other$$afamilial colorectal cancer
000168696 650_7 $$2Other$$agermline variant
000168696 650_7 $$2Other$$awhole genome sequencing
000168696 7001_ $$0P:(DE-He78)b5b786a7a28d851956ba90aa9451887a$$aMiao, Beiping$$b1$$udkfz
000168696 7001_ $$0P:(DE-He78)43b43c5f20ed70299251a446ad8ec973$$aSrivastava, Aayushi$$b2
000168696 7001_ $$aKumar, Abhishek$$b3
000168696 7001_ $$00000-0001-9070-747X$$aKuświk, Magdalena$$b4
000168696 7001_ $$00000-0001-8097-8014$$aDymerska, Dagmara$$b5
000168696 7001_ $$aParamasivam, Nagarajan$$b6
000168696 7001_ $$0P:(DE-He78)f2a782242acf94a3114d75c45dc75b37$$aSchlesner, Matthias$$b7$$udkfz
000168696 7001_ $$aLubiński, Jan$$b8
000168696 7001_ $$0P:(DE-He78)19b0ec1cea271419d9fa8680e6ed6865$$aHemminki, Kari$$b9$$udkfz
000168696 7001_ $$0P:(DE-He78)f26164c08f2f14abcf31e52e13ee3696$$aFörsti, Asta$$b10$$udkfz
000168696 7001_ $$0P:(DE-He78)b11ccde1801d45d32a6a60f7b396d7dc$$aBandapalli, Obul Reddy$$b11$$eLast author$$udkfz
000168696 773__ $$0PERI:(DE-600)2662248-8$$a10.3390/jpm11040262$$gVol. 11, no. 4, p. 262 -$$n4$$p262$$tJournal of Personalized Medicine$$v11$$x2075-4426$$y2021
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