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@ARTICLE{Skopelitou:168696,
      author       = {D. Skopelitou$^*$ and B. Miao$^*$ and A. Srivastava$^*$ and
                      A. Kumar and M. Kuświk and D. Dymerska and N. Paramasivam
                      and M. Schlesner$^*$ and J. Lubiński and K. Hemminki$^*$
                      and A. Försti$^*$ and O. R. Bandapalli$^*$},
      title        = {{A} {N}ovel {L}ow-{R}isk {G}ermline {V}ariant in the {SH}2
                      {D}omain of the {SRC} {G}ene {A}ffects {M}ultiple {P}athways
                      in {F}amilial {C}olorectal {C}ancer.},
      journal      = {Journal of Personalized Medicine},
      volume       = {11},
      number       = {4},
      issn         = {2075-4426},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {DKFZ-2021-01004},
      pages        = {262},
      year         = {2021},
      note         = {#EA:C050#LA:C050#},
      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 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.},
      keywords     = {SRC (Other) / familial colorectal cancer (Other) / germline
                      variant (Other) / whole genome sequencing (Other)},
      cin          = {C050 / B062 / B240},
      ddc          = {610},
      cid          = {I:(DE-He78)C050-20160331 / I:(DE-He78)B062-20160331 /
                      I:(DE-He78)B240-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:33916261},
      pmc          = {pmc:PMC8066297},
      doi          = {10.3390/jpm11040262},
      url          = {https://inrepo02.dkfz.de/record/168696},
}