|Title||Germline genetic variants and pediatric rhabdomyosarcoma outcomes: a report from the Children's Oncology Group.|
|Publication Type||Journal Article|
|Year of Publication||2023|
|Authors||Martin-Giacalone, BA, Richard, MA, Scheurer, ME, Khan, J, Sok, P, Shetty, PB, Chanock, SJ, Li, SAlfred, Yeager, M, Marquez-Do, DA, Barkauskas, DA, Hall, D, McEvoy, MT, Brown, AL, Sabo, A, Scheet, P, Huff, CD, Skapek, SX, Hawkins, DS, Venkatramani, R, Mirabello, L, Lupo, PJ|
|Journal||J Natl Cancer Inst|
|Date Published||2023 Jun 08|
|Keywords||Child, Genome-Wide Association Study, Germ Cells, Humans, Mediator Complex, Proportional Hazards Models, Rhabdomyosarcoma, Rhabdomyosarcoma, Alveolar, Ubiquitin-Protein Ligases|
BACKGROUND: Relative to other pediatric cancers, survival for rhabdomyosarcoma (RMS) has not improved in recent decades, suggesting the need to enhance risk stratification. Therefore, we conducted a genome-wide association study for event-free survival (EFS) and overall survival (OS) to identify genetic variants associated with outcomes in individuals with RMS.
METHODS: The study included 920 individuals with newly diagnosed RMS who were enrolled in Children's Oncology Group protocols. To assess the association of each single nucleotide polymorphism (SNP) with EFS and OS, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using multivariable Cox proportional hazards models, adjusted for clinical covariates. All statistical tests were two sided. We also performed stratified analyses by histological subtype (alveolar and embryonal RMS) and carried out sensitivity analyses of statistically significant SNPs by PAX3/7-FOXO1 fusion status and genetic ancestry group.
RESULTS: We identified that rs17321084 was associated with worse EFS (HR = 2.01, 95% CI = 1.59 to 2.53, P = 5.39 × 10-9) and rs10094840 was associated with worse OS (HR = 1.84, 95% CI = 1.48 to 2.27, P = 2.13 × 10-8). Using publicly available data, we found that rs17321084 lies in a binding region for transcription factors GATA2 and GATA3, and rs10094840 is associated with SPAG1 and RNF19A expression. We also identified that CTNNA3 rs2135732 (HR = 3.75, 95% CI = 2.34 to 5.99, P = 3.54 × 10-8) and MED31 rs74504320 (HR = 3.21, 95% CI = 2.12 to 4.86, P = 3.60 × 10-8) were associated with worse OS among individuals with alveolar RMS.
CONCLUSIONS: We demonstrated that common germline variants are associated with EFS and OS among individuals with RMS. Additional replication and investigation of these SNP effects may further support their consideration in risk stratification protocols.
|Alternate Journal||J Natl Cancer Inst|
|PubMed Central ID||PMC10248851|
|Grant List||T32 CA190194 / CA / NCI NIH HHS / United States |
U10 CA180899 / CA / NCI NIH HHS / United States
T32CA190194 / CA / NCI NIH HHS / United States
T32GM088129 / GM / NIGMS NIH HHS / United States
Germline genetic variants and pediatric rhabdomyosarcoma outcomes: a report from the Children's Oncology Group.
|Single-cell multiomics of the human retina reveals hierarchical transcription factor collaboration in mediating cell type-specific effects of genetic variants on gene regulation. Genome Biol. 2023;24(1):269..|
|PLS3 missense variants affecting the actin-binding domains cause X-linked congenital diaphragmatic hernia and body-wall defects. Am J Hum Genet. 2023;110(10):1787-1803..|
|Chimeric RNAs reveal putative neoantigen peptides for developing tumor vaccines for breast cancer. Front Immunol. 2023;14:1188831..|