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      author       = {A. Srivastava$^*$ and S. Giangiobbe$^*$ and D.
                      Skopelitou$^*$ and B. Miao$^*$ and N. Paramasivam and C.
                      Diquigiovanni and E. Bonora and K. Hemminki$^*$ and A.
                      Försti$^*$ and O. R. Bandapalli$^*$},
      title        = {{W}hole {G}enome {S}equencing {P}rioritizes {CHEK}2,
                      {EWSR}1, and {TIAM}1 as {P}ossible {P}redisposition {G}enes
                      for {F}amilial {N}on-{M}edullary {T}hyroid {C}ancer.},
      journal      = {Frontiers in endocrinology},
      volume       = {12},
      issn         = {1664-2392},
      address      = {Lausanne},
      publisher    = {Frontiers Research Foundation},
      reportid     = {DKFZ-2021-00603},
      pages        = {600682},
      year         = {2021},
      note         = {#EA:B062#LA:B062#},
      abstract     = {Familial inheritance in non-medullary thyroid cancer (NMTC)
                      is an area that has yet to be adequately explored. Despite
                      evidence suggesting strong familial clustering of
                      non-syndromic NMTC, known variants still account for a very
                      small percentage of the genetic burden. In a recent whole
                      genome sequencing (WGS) study of five families with several
                      NMTCs, we shortlisted promising variants with the help of
                      our in-house developed Familial Cancer Variant
                      Prioritization Pipeline (FCVPPv2). Here, we report
                      potentially disease-causing variants in checkpoint kinase 2
                      (CHEK2), Ewing sarcoma breakpoint region 1 (EWSR1) and
                      T-lymphoma invasion and metastasis-inducing protein 1
                      (TIAM1) in one family. Performing WGS on three cases, one
                      probable case and one healthy individual in a family with
                      familial NMTC left us with 112254 variants with a minor
                      allele frequency of less than $0.1\%,$ which was reduced by
                      pedigree-based filtering to 6368. Application of the
                      pipeline led to the prioritization of seven coding and nine
                      non-coding variants from this family. The variant identified
                      in CHEK2, a known tumor suppressor gene involved in DNA
                      damage-induced DNA repair, cell cycle arrest, and apoptosis,
                      has been previously identified as a germline variant in
                      breast and prostate cancer and has been functionally
                      validated by Roeb et al. in a yeast-based assay to have an
                      intermediate effect on protein function. We thus
                      hypothesized that this family may harbor additional
                      disease-causing variants in other functionally related
                      genes. We evaluated two further variants in EWSR1 and TIAM1
                      with promising in silico results and reported interaction in
                      the DNA-damage repair pathway. Hence, we propose a polygenic
                      mode of inheritance in this family. As familial NMTC is
                      considered to be more aggressive than its sporadic
                      counterpart, it is important to identify such susceptibility
                      genes and their associated pathways. In this way, the
                      advancement of personalized medicine in NMTC patients can be
                      fostered. We also wish to reopen the discussion on monogenic
                      vs polygenic inheritance in NMTC and instigate further
                      development in this area of research.},
      keywords     = {CHEK2 (Other) / EWSR1 (Other) / TIAM1 (Other) / familial
                      non-medullary thyroid cancer (Other) / germline variant
                      (Other) / non-syndromic (Other) / whole-genome sequencing
      cin          = {C050 / B062},
      ddc          = {610},
      cid          = {I:(DE-He78)C050-20160331 / I:(DE-He78)B062-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:33692755},
      pmc          = {pmc:PMC7937922},
      doi          = {10.3389/fendo.2021.600682},
      url          = {https://inrepo02.dkfz.de/record/167869},