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000305221 1001_ $$00000-0002-9806-0217$$aOak, Ninad$$b0
000305221 245__ $$aInvestigation of DNA damage response genes validates the role of DNA repair in pediatric cancer risk and identifies SMARCAL1 as novel osteosarcoma predisposition gene.
000305221 260__ $$aAlexandria, Va.$$bAmerican Society of Clinical Oncology$$c2025
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000305221 520__ $$aRecent 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.
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000305221 7001_ $$00000-0003-0379-2368$$aChen, Wenan$$b1
000305221 7001_ $$00000-0002-1336-7106$$aBlake, Alise$$b2
000305221 7001_ $$00000-0001-7595-080X$$aHarrison, Lynn$$b3
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000305221 7001_ $$0P:(DE-He78)e5bb26ffbde307745ae396c2e829dac5$$aBalasubramanian, Gnanaprakash$$b6$$udkfz
000305221 7001_ $$0P:(DE-He78)5100059e746b377e2e0a37c0e24f6bf7$$aMaass, Kendra$$b7$$udkfz
000305221 7001_ $$aHirsch, Steffen$$b8
000305221 7001_ $$00000-0002-1375-507X$$aPenkert, Judith$$b9
000305221 7001_ $$0P:(DE-He78)fae1bf941c5fd76cf5356ecfa1243cc4$$aJones, Barbara$$b10$$udkfz
000305221 7001_ $$aSchramm, Kathrin$$b11
000305221 7001_ $$00000-0002-1584-1115$$aNathrath, Michaela$$b12
000305221 7001_ $$0P:(DE-He78)a7c1bbac024fa232d9c6b78443328d9d$$aPajtler, Kristian$$b13$$udkfz
000305221 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David$$b14$$udkfz
000305221 7001_ $$0P:(DE-He78)143af26de9d57bf624771616318aaf7c$$aWitt, Olaf$$b15$$udkfz
000305221 7001_ $$00000-0002-5435-7860$$aDirksen, Uta$$b16
000305221 7001_ $$00000-0002-2017-3377$$aLi, Jiaming$$b17
000305221 7001_ $$00000-0001-5943-9454$$aSapkota, Yadav$$b18
000305221 7001_ $$00000-0002-2084-1507$$aNess, Kirsten K$$b19
000305221 7001_ $$00000-0002-5906-7504$$aGuenther, Lillian M$$b20
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000305221 7001_ $$00000-0003-4120-5873$$aKratz, Christian$$b22
000305221 7001_ $$00000-0001-7556-3869$$aWang, Zhaoming$$b23
000305221 7001_ $$aArmstrong, Greg T$$b24
000305221 7001_ $$00000-0001-6984-2407$$aHudson, Melissa M$$b25
000305221 7001_ $$00000-0002-1678-5864$$aWu, Gang$$b26
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000305221 7001_ $$00000-0002-5581-6555$$aNichols, Kim E$$b28
000305221 7001_ $$00000-0003-0462-661X$$aSharma, Richa$$b29
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