Exome genotyping arrays to identify rare and low frequency variants associated with epithelial ovarian cancer risk.

Rare and low frequency variants are not well covered in most germline genotyping arrays and are understudied in relation to epithelial ovarian cancer (EOC) risk. To address this gap, we used genotyping arrays targeting rarer protein-coding variation in 8,165 EOC cases and 11,619 controls from the international Ovarian Cancer Association Consortium (OCAC). Pooled association analyses were conducted at the variant and gene level for 98,543 variants directly genotyped through two exome genotyping projects. Only common variants that represent or are in strong linkage disequilibrium (LD) with previously-identified signals at established loci reached traditional thresholds for exome-wide significance (P < 5.0 × 10 - 7). One of the most significant signals (Pall histologies = 1.01 × 10 - 13;Pserous = 3.54 × 10 - 14) occurred at 3q25.31 for rs62273959, a missense variant mapping to the LEKR1 gene that is in LD (r2 = 0.90) with a previously identified 'best hit' (rs7651446) mapping to an intron of TIPARP. Suggestive associations (5.0 × 10 - 5 > P≥5.0 ×10 - 7) were detected for rare and low-frequency variants at 16 novel loci. Four rare missense variants were identified (ACTBL2 rs73757391 (5q11.2), BTD rs200337373 (3p25.1), KRT13 rs150321809 (17q21.2) and MC2R rs104894658 (18p11.21)), but only MC2R rs104894668 had a large effect size (OR = 9.66). Genes most strongly associated with EOC risk included ACTBL2 (PAML = 3.23 × 10 - 5; PSKAT-o = 9.23 × 10 - 4) and KRT13 (PAML = 1.67 × 10 - 4; PSKAT-o = 1.07 × 10 - 5), reaffirming variant-level analysis. In summary, this large study identified several rare and low-frequency variants and genes that may contribute to EOC susceptibility, albeit with possible small effects. Future studies that integrate epidemiology, sequencing, and functional assays are needed to further unravel the unexplained heritability and biology of this disease.

A functional polymorphism in the pre-miR-146a gene is associated with risk and prognosis in adult glioma.

MicroRNAs (miRNAs) are non-coding RNAs that function as post-transcriptional regulators of tumor suppressors and oncogenes. Single nucleotide polymorphisms (SNPs) in miRNAs may contribute to carcinogenesis by altering expression of miRNAs and their targets. A G>C polymorphism (rs2910164) in the miR-146a precursor sequence leads to a functional change associated with the risk for numerous malignancies. A role for this SNP in glioma pathogenesis has not yet been examined. We investigated whether rs2910164 genotypes influence glioma risk and prognosis in a multi-center case-control study comprised of 593 Caucasian glioma cases and 614 community-based controls. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for rs2910164 genotypes according to case status. Cox proportional hazards regression modeling was used to estimate hazards ratios (HR) and 95% CIs according to genotype among glioblastomas, the most lethal glioma subtype. An increased glioma risk was observed among rs2910164 minor allele (C) carriers (per allele OR (95% CI) = 1.22 (1.01-1.46, p (trend) = 0.039)). The association was stronger among older subjects carrying at least one copy of the C allele (OR (95% CI) = 1.38 (1.04-1.83, P = 0.026). Mortality was increased among minor allele carriers (HR (95% CI) = 1.33 (1.03-1.72, P = 0.029)), with the association largely restricted to females (HR (95% CI) = 2.02 (1.28-3.17, P = 0.002)). We provide novel data suggesting rs2910164 genotype may contribute to glioma susceptibility and outcome. Future studies are warranted to replicate these findings and characterize mechanisms underlying these associations.

Cancer susceptibility variants and the risk of adult glioma in a US case-control study.

Malignant gliomas are the most common and deadly brain tumors. Although their etiology remains elusive, recent studies have narrowed the search for genetic loci that influence risk. We examined variants implicated in recent cancer genome-wide association studies (GWAS) for associations with glioma risk in a US case-control study. Cases were identified from neurosurgical and neuro-oncology clinics at major academic centers in the Southeastern US. Controls were identified from the community or were friends or other associates of cases. We examined a total of 191 susceptibility variants in genes identified in published cancer GWAS including glioma. A total of 639 glioma cases and 649 controls, all Caucasian, were included in analysis. Cases were enrolled a median of 1 month following diagnosis. Among glioma GWAS-identified variants, we detected associations in CDKN2B, RTEL1, TERT and PHLDB1, whereas we did not find overall associations for CCDC26. Results showed clear heterogeneity according to histologic subtypes of glioma, with TERT and RTEL variants a feature of astrocytic tumors and glioblastoma (GBM), CCDC26 and PHLDB1 variants a feature of astrocytic and oligodendroglial tumors, and CDKN2B variants most prominent in GBM. No examined variant in other cancer GWAS was found to be related to risk after adjustment for multiple comparisons. These results suggest that GWAS-identified SNPs in glioma mark different molecular etiologies in glioma. Stratification by broad histological subgroups may shed light on molecular mechanisms and assist in the discovery of novel loci in future studies of genetic susceptibility variants in glioma.