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@ARTICLE{Oak:305221,
      author       = {N. Oak and W. Chen and A. Blake and L. Harrison and M.
                      O'Brien$^*$ and C. Previti$^*$ and G. Balasubramanian$^*$
                      and K. Maass$^*$ and S. Hirsch and J. Penkert and B.
                      Jones$^*$ and K. Schramm and M. Nathrath and K. Pajtler$^*$
                      and D. Jones$^*$ and O. Witt$^*$ and U. Dirksen$^*$ and J.
                      Li and Y. Sapkota and K. K. Ness and L. M. Guenther and S.
                      Pfister$^*$ and C. Kratz and Z. Wang and G. T. Armstrong and
                      M. M. Hudson and G. Wu and R. Autry$^*$ and K. E. Nichols
                      and R. Sharma},
      title        = {{I}nvestigation of {DNA} damage response genes validates
                      the role of {DNA} repair in pediatric cancer risk and
                      identifies {SMARCAL}1 as novel osteosarcoma predisposition
                      gene.},
      journal      = {Journal of clinical oncology},
      volume       = {nn},
      issn         = {0732-183X},
      address      = {Alexandria, Va.},
      publisher    = {American Society of Clinical Oncology},
      reportid     = {DKFZ-2025-02067},
      pages        = {nn},
      year         = {2025},
      note         = {epub},
      abstract     = {Recent studies reveal that $5-18\%$ of children with cancer
                      harbor pathogenic variants in known cancer predisposing
                      genes. However, DNA damage repair (DDR) genes, which are
                      frequently somatically altered in pediatric tumors, have not
                      been systematically examined as a source of novel cancer
                      predisposing signals.To address this gap, we interrogated
                      189 DDR genes for presence of germline predisposing variants
                      (PV) among 5,993 childhood cancer cases and 14,477 adult
                      non-cancer controls (discovery cohort). PV were determined
                      using a tiered approach incorporating ClinVar annotations,
                      InterVar classification, and in silico tools (REVEL, CADD,
                      MetaSVM). Using logistic and firth regression, we identified
                      genes with PV statistically enriched in tumors and
                      replicated findings among 1,497additional childhood cancer
                      cases across three independent cohorts.Analysis across all
                      cancers revealed enrichment of TP53 PV. Cancer-specific
                      analyses confirmed known associations including germline
                      TP53 PV in adrenocortical carcinoma, high-grade glioma
                      (HGG), and medulloblastoma (MB), PMS2 in HGG and non-Hodgkin
                      lymphoma (NHL), MLH1 in HGG, BRCA2 in NHL, and BARD1 in
                      neuroblastoma. In addition, four novel associations were
                      uncovered, including BRCA1 in ependymoma, SPIDR in HGG, SMC5
                      in MB, and SMARCAL1 in osteosarcoma (OS). Importantly, the
                      SMARCAL1:OS association was significant in the discovery
                      (6/230, $2.6\%,$ FDRlogistic=0.0189) as well as all three
                      replication cohorts (Childhood Cancer Survivor Study: 8/275,
                      $2.9\%;$ PFisher<0.0001; German Childhood Cancer Registry:
                      4/135, $3\%,$ PFisher=0.002; INdividualized Therapy FOr
                      Relapsed Malignancies in Childhood: 4/217, $1.8\%,$
                      PFisher=0.012). The remaining wildtype SMARCAL1 allele was
                      deleted in three of four OS tumors with available data.Our
                      study confirms the relevance DDR genetic variation in
                      pediatric cancer risk and establishes SMARCAL1 as a novel OS
                      predisposing gene, providing insights into tumor biology and
                      creating opportunities to optimize care for patients with
                      this challenging tumor.},
      cin          = {B062 / HD01 / B360 / B310 / ED01},
      ddc          = {610},
      cid          = {I:(DE-He78)B062-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)B360-20160331 / I:(DE-He78)B310-20160331 /
                      I:(DE-He78)ED01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:41066719},
      doi          = {10.1200/JCO-25-01114},
      url          = {https://inrepo02.dkfz.de/record/305221},
}