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

Abstract

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. 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. Three highly correlated HLA class II variants ( = 0.33-0.98) were associated with osteosarcoma risk in discovery analyses, including (OR = 0.52; = 3.2 × 10), (OR = 0.74; = 0.031), and (OR = 0.51; = 2.7 × 10). Similar associations were observed in the replication data ( = 0.011-0.037). Meta-analysis of the two datasets identified as the most significantly associated variant (OR = 0.62; = 1.5 × 10), reaching Bonferroni-corrected statistical significance. The meta-analysis also revealed a second significant independent signal at (OR = 1.33, = 1.2 × 10), and a third suggestive association at (OR = 0.73, = 6.4 × 10). Multiple independent HLA class II alleles may influence osteosarcoma risk. 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. .

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

“…A separate case-only GWAS of osteosarcoma clinical characteristics among patients of European, African, and Brazilian ancestry identified a single nucleotide polymorphism (SNP) associated with osteosarcoma metastasis 5 . Common germline variants involved in DNA repair 6 , growth regulation 7,8 , antigen processing and presentation 9 , and telomere maintenance 10,11 pathways have also been implicated in osteosarcoma risk.…”

Divergent HLA variations and heterogeneous expression but recurrent HLA loss-of- heterozygosity and common HLA-B and TAP transcriptional silencing across advanced pediatric solid cancers

“…Of note, a study in osteosarcoma (with > 90% of primary diagnosis tumor cases) reported putative HLA associations, with several class II alleles claimed to be negatively ( DRB1*03:01 , DQB1*02:01 ) or positively ( DQA1*01:01 ) associated with disease risk; however, only odd ratio values were described but not allele frequencies ( 89 ). Furthermore, a genome-wide association study in one cohort did not identify a susceptibility locus within the HLA ( 90 ).…”

Identification of potential crucial genes and key pathways in osteosarcoma

“…The function enrichment analysis results revealed that HLA class II alleles may be a main impactive factor in osteosarcoma. HLA-DQA1 is also an HLA class II variant that has been reported to be associated with the osteosarcoma risks [ 31 ]. Profound understanding of those genes’ immunologic contribution to the etiology of osteosarcoma may be helpful for selecting rational therapeutic targets.…”