Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2025
Investigation of DNA Damage Response Genes Validates the Role of DNA Repair in Pediatric Cancer Risk and Identifies SMARCAL1 as a Novel Osteosarcoma Predisposition Gene.
СтатьяПоддержка исследования: вне правительства СШАПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Oak Ninad, Chen Wenan, Blake Alise, Harrison Lynn, O'Brien Martha, Previti Christopher, Balasubramanian Gnanaprakash, Maass Kendra, Hirsch Steffen, Penkert Judith, Jones Barbara C, Schramm Kathrin, Nathrath Michaela, Pajtler Kristian W, Jones David T W, Witt Olaf, Dirksen Uta, Li Jiaming, Sapkota Yadav, Ness Kirsten K, Guenther Lillian M, Pfister Stefan M, Kratz Christian, Wang Zhaoming, Armstrong Greg T, Hudson Melissa M, Wu Gang, Autry Robert J, Nichols Kim E, Sharma Richa
Аннотация
PURPOSE: 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.
METHODS: 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 noncancer controls (discovery cohort). PV were determined using a tiered approach incorporating ClinVar annotations, InterVar classification, and in silico tools (REVEL, CADD, and MetaSVM). Using logistic and firth regression, we identified genes with PV statistically enriched in the germline of children with tumors and replicated findings among 1,497 additional childhood cancer cases across three independent cohorts.
RESULTS: Analysis across all cases with cancer 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%, false discovery rate [FDR]logistic = 0.0189) as well as all three replication cohorts (Childhood Cancer Survivor Study: 8/275, 2.9%; PFisher < .0001; Cancer Predisposition Syndrome-German Childhood Cancer Registry: 4/135, 3%, PFisher = .002; Individualized Therapy for Relapsed Malignancies in Childhood: 4/217, 1.8%, PFisher = .012). The remaining wild-type SMARCAL1 allele was deleted in three of four OS tumors with available data.
CONCLUSION: 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.
METHODS: 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 noncancer controls (discovery cohort). PV were determined using a tiered approach incorporating ClinVar annotations, InterVar classification, and in silico tools (REVEL, CADD, and MetaSVM). Using logistic and firth regression, we identified genes with PV statistically enriched in the germline of children with tumors and replicated findings among 1,497 additional childhood cancer cases across three independent cohorts.
RESULTS: Analysis across all cases with cancer 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%, false discovery rate [FDR]logistic = 0.0189) as well as all three replication cohorts (Childhood Cancer Survivor Study: 8/275, 2.9%; PFisher < .0001; Cancer Predisposition Syndrome-German Childhood Cancer Registry: 4/135, 3%, PFisher = .002; Individualized Therapy for Relapsed Malignancies in Childhood: 4/217, 1.8%, PFisher = .012). The remaining wild-type SMARCAL1 allele was deleted in three of four OS tumors with available data.
CONCLUSION: 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.