Integrative genomics analysis identifies ancestral-related eQTLs on POLB, and supports the association of genetic ancestry with survival disparity in HNSCC

Abstract

BACKGROUND

African-Americans (Afr-Amr) with head and neck squamous cell carcinoma (HNSCC) have a lower survival rate than Caucasians (Cau). This study investigates the functional importance of ancestry-informative SNPs in HNSCC and also examines the effect of functionally important genetic elements on racial disparities in HNSCC survival.

METHODS

Ancestry-informative SNPs, RNAseq, methylation, and copy number variation data for 316 oral cavity and laryngeal cancer patients were analyzed across 178 DNA repair genes. The results of eQTL analyses were also replicated using a Gene Expression Omnibus (GEO) dataset. The effects of eQTLs on overall survival (OS) and disease-free survival (DFS) were evaluated.

RESULTS

Five ancestry-related SNPs were identified as cis-eQTLs in the POLB gene (FDR<0.01). The homozygous/ heterozygous genotypes containing the Afr-allele showed higher POLB expression relative to the homozygous Cau-allele genotype (P<0.001). A replication study using a GEO dataset validated all five eQTLs, also showing a statistically significant difference in POLB expression based on genetic ancestry (P=0.002). An association was observed between these eQTLs and OS (P<0.037; FDR<0.0363) as well as DFS of oral cavity and laryngeal cancer patients treated with platinum-based chemotherapy and/or radiotherapy (P=0.018 to 0.0629; FDR<0.079). Genotypes containing the Afr-allele were associated with poor OS/DFS compared to homozygous genotypes harboring the Cau-allele.

CONCLUSIONS

Our analyses show that ancestry-related alleles could act as eQTLs in HNSCC and support the association of ancestry-related genetic factors with survival disparity in patients diagnosed with oral cavity and laryngeal cancer.