Genetic variation near GRB10 associated with bone growth and osteosarcoma risk in canine and human populations.

Autor: Lucas SE; Preston Robert Tisch Brain Tumor Center, Department of Neurosurgery, Duke University, Durham, NC, USA; Division of Pediatric Hematology/Oncology, Duke University Medical Center, Durham, NC, USA., Yang T; Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, MN, USA; Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; Division of Pediatric Hematology/Oncology, Duke University Medical Center, Durham, NC, USA., Wimberly CE; Preston Robert Tisch Brain Tumor Center, Department of Neurosurgery, Duke University, Durham, NC, USA; Division of Pediatric Hematology/Oncology, Duke University Medical Center, Durham, NC, USA., Parmar KV; Preston Robert Tisch Brain Tumor Center, Department of Neurosurgery, Duke University, Durham, NC, USA; Division of Pediatric Hematology/Oncology, Duke University Medical Center, Durham, NC, USA., Hansen HM; Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA; Division of Pediatric Hematology/Oncology, Duke University Medical Center, Durham, NC, USA., de Smith AJ; Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA; Division of Pediatric Hematology/Oncology, Duke University Medical Center, Durham, NC, USA., Morimoto LM; School of Public Health, University of California, Berkeley, Berkeley, CA, USA; Division of Pediatric Hematology/Oncology, Duke University Medical Center, Durham, NC, USA., Metayer C; School of Public Health, University of California, Berkeley, Berkeley, CA, USA; Division of Pediatric Hematology/Oncology, Duke University Medical Center, Durham, NC, USA., Ostrom QT; Preston Robert Tisch Brain Tumor Center, Department of Neurosurgery, Duke University, Durham, NC, USA; Duke Cancer Institute, Duke University, Durham, NC, USA; Division of Pediatric Hematology/Oncology, Duke University Medical Center, Durham, NC, USA., Eward WC; Duke Cancer Institute, Duke University, Durham, NC, USA; Department of Orthopaedic Surgery, Duke University, Durham, NC, USA; Division of Pediatric Hematology/Oncology, Duke University Medical Center, Durham, NC, USA., Graves LA; Department of Pediatrics, Duke University, Durham, NC, USA; Division of Pediatric Hematology/Oncology, Duke University Medical Center, Durham, NC, USA., Wagner LM; Duke Cancer Institute, Duke University, Durham, NC, USA; Department of Pediatrics, Duke University, Durham, NC, USA; Division of Pediatric Hematology/Oncology, Duke University Medical Center, Durham, NC, USA., Wiemels JL; Center for Genetic Epidemiology, Department of Population and Public Health Sciences, University of Southern California, Los Angeles, CA, USA; Division of Pediatric Hematology/Oncology, Duke University Medical Center, Durham, NC, USA., Spector LG; Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA; Division of Pediatric Hematology/Oncology, Duke University Medical Center, Durham, NC, USA., Walsh KM; Preston Robert Tisch Brain Tumor Center, Department of Neurosurgery, Duke University, Durham, NC, USA; Duke Cancer Institute, Duke University, Durham, NC, USA; Department of Pediatrics, Duke University, Durham, NC, USA; Division of Pediatric Hematology/Oncology, Duke University Medical Center, Durham, NC, USA. Electronic address: Kyle.Walsh@Duke.edu.
Jazyk: angličtina
Zdroj: Cancer epidemiology [Cancer Epidemiol] 2024 Oct; Vol. 92, pp. 102599. Date of Electronic Publication: 2024 Jun 12.
DOI: 10.1016/j.canep.2024.102599
Abstrakt: Background: Canine and human osteosarcoma are similar in clinical presentation and tumor genomics. Giant breed dogs experience elevated osteosarcoma incidence, and taller stature remains a consistent risk factor for human osteosarcoma. Whether evolutionarily conserved genes contribute to both human and canine osteosarcoma predisposition merits evaluation.
Methods: A multi-center sample of childhood osteosarcoma patients and controls underwent genome-wide genotyping and imputation. Ancestry-adjusted SNP associations were calculated within each dataset using logistic regression, then meta-analyzed across the three datasets, totaling 1091 patients and 3026 controls. Ten regions previously associated with canine osteosarcoma risk were mapped to the human genome, spanning ∼6 Mb. We prioritized association testing of 5985 human SNPs mapping to candidate osteosarcoma risk regions detected in Irish wolfhounds, the largest dog breed studied. Secondary analyses explored 6289 additional human SNPs mapping to candidate osteosarcoma risk regions identified in Rottweilers and greyhounds.
Results: Fourteen SNPs were associated with human osteosarcoma risk after adjustment for multiple comparisons, all within a 42 kb region of human Chromosome 7p12.1. The lead variant was rs17454681 (OR=1.25, 95 %CI: 1.12-1.39; P=4.1×10 -5 ), and independent risk variants were not observed in conditional analyses. While the associated region spanned 2.1 Mb and contained eight genes in Irish wolfhounds, associations were localized to a 50-fold smaller region of the human genome and strongly implicate GRB10 (growth factor receptor-bound protein 10) in canine and human osteosarcoma predisposition. PheWAS analysis in UK Biobank data identified noteworthy associations of the rs17454681 risk allele with varied measures of height and pubertal timing.
Conclusions: Our comparative oncology analysis identified a novel human osteosarcoma risk allele near GRB10, a growth inhibitor that suppresses activated receptor tyrosine kinases including IGF1R, PDGFRB, and EGFR. Epidemiologists may benefit from leveraging cross-species comparisons to identify haplotypes in highly susceptible but genetically homogenous populations of domesticated animals, then fine-mapping these associations in diverse human populations.
Competing Interests: Declaration of Competing Interest The authors have no relevant financial or personal interests to report or disclose.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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