Abstract 4623: piRNA and glioma risk: Evidence from a post-GWAS analysis of the GliomaScan Cohort
Authors: Jacobs Daniel I. , Lerro Michael C. , Fu Alan , Qin Qin , DeWan Andrew T. , Dubrow Robert , Claus Elizabeth B. , Zhu Yong 
Published: August 2015

Background: Piwi-interacting RNAs (piRNAs) comprise a large but relatively understudied class of small non-coding RNAs that are transcribed from &gt;600,000 loci and act in the silencing of transposable elements in the germline. While a single piRNA sequence may be encoded in thousands of genomic locations, our previous research has demonstrated that piRNAs of moderate copy number (100 or fewer) may also have the capacity to regulate protein-coding genes including oncogenes and/or tumor suppressors in somatic cells. The objective of this study was to explore the association of inherited variants in moderate copy-number piRNA sequences and glioma risk.

Methods: Genotype data from 1,840 predominantly high grade glioma cases and 2,401 controls of European ancestry in the GliomaScan Cohort-Based GWAS were downloaded from the dbGaP database. After QC of the Illumina660-QuadV1-generated data, 550,600 SNPs were used to impute the genotypes of 2,361 piRNA SNPs with minor allele frequency ≥ 0.01 identified from a search of all 48,478 moderate copy-number piRNA sequences. Imputation was performed with IMPUTE2 using 1,000 Genomes Phase 3 haplotypes as the reference panel. Odds ratios and 95% confidence intervals for SNP-glioma risk associations were estimated using unconditional logistic regression under an additive model while controlling for gender, age, study design (case/control or cohort), and the first two principal components as estimated by EIGENSTRAT (genomic inflation λ = 1.00). An expression array covering 23,677 piRNAs was used to profile expression in seven grade IV glioma and seven normal brain specimens obtained from the Cooperative Human Tissue Network (CHTN), pooled by tissue type.

Results: After exclusion of poorly-imputed SNPs, 1,384 piRNA SNPs were examined for association with glioma risk. Five SNPs were associated with glioma at FDR-adjusted P &lt; 0.10 (rs149336947 in piR-2799, rs62435800 in piR-18913, rs147061479 in piR-598, rs142742690 in piR-11714, and rs35712968 in piR-3266). Rare variant rs149336947 in piR-2799 was most strongly associated with glioma risk, yielding an odds ratio of 2.54 (95% CI: 1.65-3.91, P = 2.34 × 10-5, significant after Bonferroni correction). The potential functional role of this SNP is supported by the finding that piR-2799 was expressed in both grade IV glioma and normal brain specimens (piR-18913, piR-598, and piR-11714 were also expressed; piR-3266 was not included on the array). Intriguingly, rs149336947 is located in a region encoding both piR-2799 and an alternative exon of CASP8 and FADD-like apoptosis regulator (CFLAR), however the functional interrelatedness of these genetic elements in glioma has yet to be elucidated.

Conclusions: Together, these results draw a novel link between inherited piRNA variants and the risk of glioma development. Functional analyses are ongoing to specify the biological mechanisms underlying the observed associations.

Citation Format: Daniel I. Jacobs, Michael C. Lerro, Alan Fu, Qin Qin, Andrew T. DeWan, Robert Dubrow, Elizabeth B. Claus, Yong Zhu. piRNA and glioma risk: Evidence from a post-GWAS analysis of the GliomaScan Cohort. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4623. doi:10.1158/1538-7445.AM2015-4623