European genetic ancestry associated with risk of childhood ependymoma.

BACKGROUND: Ependymoma is a histologically defined central nervous system tumor most commonly occurring in childhood. Population-level incidence differences by race/ethnicity are observed, with individuals of European ancestry at highest risk. We aimed to determine whether extent of European genetic ancestry is associated with ependymoma risk in US populations. METHODS: In a multi-ethnic study of Californian children (327 cases, 1970 controls), we estimated the proportions of European, African, and Native American ancestry among recently admixed Hispanic and African American subjects and estimated European admixture among non-Hispanic white subjects using genome-wide data. We tested whether genome-wide ancestry differences were associated with ependymoma risk and performed admixture mapping to identify associations with local ancestry. We also evaluated race/ethnicity-stratified ependymoma incidence data from the Central Brain Tumor Registry of the United States (CBTRUS). RESULTS: CBTRUS data revealed that African American and Native American children have 33% and 36%, respectively, reduced incidence of ependymoma compared with non-Hispanic whites. In genetic analyses, a 20% increase in European ancestry was associated with a 1.31-fold higher odds of ependymoma among self-reported Hispanics and African Americans (95% CI: 1.08-1.59, Pmeta = 6.7 × 10-3). Additionally, eastern European ancestral substructure was associated with increased ependymoma risk in non-Hispanic whites (P = 0.030) and in Hispanics (P = 0.043). Admixture mapping revealed a peak at 20p13 associated with increased local European ancestry, and targeted fine-mapping identified a lead variant at rs6039499 near RSPO4 (odds ratio = 1.99; 95% CI: 1.45-2.73; P = 2.2 × 10-5) but which was not validated in an independent set of posterior fossa type A patients. CONCLUSIONS: Interethnic differences in ependymoma risk are recapitulated in the genomic ancestry of ependymoma patients, implicating regions to target in future association studies.

Common genetic variation and risk of osteosarcoma in a multi-ethnic pediatric and adolescent population.

Osteosarcoma, a malignant primary bone tumor most commonly diagnosed in children and adolescents, has a poorly understood genetic etiology. Genome-wide association studies (GWAS) and candidate-gene analyses have identified putative risk variants in subjects of European ancestry. However, despite higher incidence among African-American and Hispanic children, little is known regarding common heritable variation that contributes to osteosarcoma incidence and clinical presentation across racial/ethnic groups. In a multi-ethnic sample of non-Hispanic white, Hispanic, African-American and Asian/Pacific Islander children (537 cases, 2165 controls), we performed association analyses assessing previously-reported loci for osteosarcoma risk and metastasis, including meta-analysis across racial/ethnic groups. We also assessed a previously described association between genetic predisposition to longer leukocyte telomere length (LTL) and osteosarcoma risk in this independent multi-ethnic dataset. In our sample, we were unable to replicate previously-reported loci for osteosarcoma risk or metastasis detected in GWAS of European-ancestry individuals in either ethnicity-stratified analyses or meta-analysis across ethnic groups. Our analyses did confirm that genetic predisposition to longer LTL is a risk factor for osteosarcoma (ORmeta: 1.22; 95% CI: 1.09-1.36; P = 3.8 × 10-4), and the strongest effect was seen in Hispanic subjects (OR: 1.32; 95% CI: 1.12-1.54, P = 6.2 × 10-4). Our findings shed light on the replicability of osteosarcoma risk loci across ethnicities and motivate further characterization of these genetic factors in diverse clinical cohorts.

Genetic determinants of childhood and adult height associated with osteosarcoma risk.

BACKGROUND: Although increased height has been associated with osteosarcoma risk in previous epidemiologic studies, to the authors' knowledge the relative contribution of stature during different developmental timepoints remains unclear. Furthermore, the question of how genetic determinants of height impact osteosarcoma etiology remains unexplored. Genetic variants associated with stature in previous genome-wide association studies may be biomarkers of osteosarcoma risk. METHODS: The authors tested the associations between osteosarcoma risk and polygenic scores for adult height (416 variants), childhood height (6 variants), and birth length (5 variants) in 864 osteosarcoma cases and 1879 controls of European ancestry. RESULTS: Each standard deviation increase in the polygenic score for adult height, corresponding to a 1.7-cm increase in stature, was found to be associated with a 1.10-fold increase in the risk of osteosarcoma (95% confidence interval [95% CI], 1.01-1.19; P =.027). Each standard deviation increase in the polygenic score for childhood height, corresponding to a 0.5-cm increase in stature, was associated with a 1.10-fold increase in the risk of osteosarcoma (95% CI, 1.01-1.20; P =.023). The polygenic score for birth length was not found to be associated with osteosarcoma risk (P =.11). When adult and childhood height scores were modeled together, they were found to be independently associated with osteosarcoma risk (P =.037 and P = .043, respectively). An expression quantitative trait locus for cartilage intermediate layer protein 2 (CILP2), rs8103992, was significantly associated with osteosarcoma risk after adjustment for multiple comparisons (odds ratio, 1.35; 95% CI, 1.16-1.56 [P = 7.93×10-5 and Padjusted =.034]). CONCLUSIONS: A genetic propensity for taller adult and childhood height attainments contributed independently to osteosarcoma risk in the current study data. These results suggest that the biological pathways affecting normal bone growth may be involved in osteosarcoma etiology.

Two HLA Class II Gene Variants Are Independently Associated with Pediatric Osteosarcoma Risk.

Background: The genetic etiology of osteosarcoma remains poorly understood despite the publication of a genome-wide association study. Association between HLA genetic variants and risk of several cancers has been observed, but HLA variation is not well captured by standard SNP arrays.Methods: We genotyped 207 Californian pediatric osteosarcoma cases and 696 controls of European ancestry using a custom genome-wide array supplemented with approximately 6,000 additional probes across the MHC region. We subsequently imputed 4-digit classical HLA alleles using a reference panel of 5,225 individuals who underwent high-resolution HLA typing via next-generation sequencing. Case-control comparisons were adjusted for ancestry-informative principal components, and top associations from the discovery analysis underwent replication in an independent dataset of 657 cases and 1,183 controls.Results: Three highly correlated HLA class II variants (r 2 = 0.33-0.98) were associated with osteosarcoma risk in discovery analyses, including HLA-DRB1*0301 (OR = 0.52; P = 3.2 × 10-3), HLA-DQA1*0501 (OR = 0.74; P = 0.031), and HLA-DQB1*0201 (OR = 0.51; P = 2.7 × 10-3). Similar associations were observed in the replication data (P range = 0.011-0.037). Meta-analysis of the two datasets identified HLA-DRB1*0301 as the most significantly associated variant (ORmeta = 0.62; P meta = 1.5 × 10-4), reaching Bonferroni-corrected statistical significance. The meta-analysis also revealed a second significant independent signal at HLA-DQA1*01:01 (ORmeta = 1.33, P meta = 1.2 × 10-3), and a third suggestive association at HLA-DQB1*0302 (ORmeta = 0.73, P meta = 6.4 × 10-3).Conclusions: Multiple independent HLA class II alleles may influence osteosarcoma risk.Impact: Additional work is needed to extend our observations to other patient populations and to clarify the potential causal mechanisms underlying these associations. Understanding immunologic contributions to the etiology of osteosarcoma may inform rational therapeutic targets. Cancer Epidemiol Biomarkers Prev; 27(10); 1151-8. ©2018 AACR.