Associations between Gene Expression Variations and Ovarian Cancer Risk Alleles Identified from Genome Wide Association Studies

Functional genetic variations play important roles in shaping phenotypic differences among individuals through affecting gene expression, and thus, very likely to influence disease susceptibility, such as cancer susceptibility. One critical question in this era of post-genome wide association studies (GWAS) is how to assess the functional significance of the genetic variations identified from GWAS. In the current study, with lymphoblastoid cell lines (LCLs) from 74 non-related women with familial ovarian cancer and 47 unrelated controls matched on gender and race, we explored the associations between seven ovarian cancer risk variants identified from GWAS (rs3814113 on 9p22.2, rs2072590 on 2q31, rs2665390 on 3q25, rs10088218, rs1516982, rs10098821 on 8q24.21, and rs2363956 on 19p13) and whole genome mRNA expression profiles. We observed 95 significant trans-associations at a permutation level of 0.001. Compared to the other risk variants, rs10088218, rs1516982, and rs10098821 on 8q24.21 had the greatest number of significant associations (25, 16, and 38, respectively). Two possible cis-associations were observed between rs10098821 and c-Myc, and rs2072590 and HS.565379 (Permutated P = 0.0198 and 0.0399, respectively). Pathway enrichment analysis showed that several key biological pathways, such as cell cycle (P = 2.59×10−06), etc, were significantly overrepresented. Further characterization of significant associations between mRNAs and risk alleles might facilitate understanding the functions of GWAS discovered risk alleles in the genetic etiology of ovarian cancer.

功能性遗传变异通过调控基因表达，在塑造个体间表型差异的过程中发挥关键作用，因此极有可能影响疾病易感性，例如癌症易感性。在后全基因组关联研究（Genome-Wide Association Study, GWAS）时代，一个核心议题是如何评估通过GWAS鉴定得到的遗传变异的功能重要性。本研究利用74例家族性卵巢癌女性患者的淋巴母细胞系（Lymphoblastoid Cell Line, LCLs），以及47例性别、种族匹配的无关健康对照，探究了经GWAS鉴定出的7个卵巢癌风险变异（9p22.2区域rs3814113、2q31区域rs2072590、3q25区域rs2665390、rs10088218、rs1516982、8q24.21区域rs10098821以及19p13区域rs2363956）与全基因组mRNA表达谱之间的关联。在置换检验阈值为0.001的条件下，本研究共检测到95个显著的反式关联（trans-association）。与其余风险变异相比，8q24.21区域的rs10088218、rs1516982及rs10098821所对应的显著关联数量最多，分别为25个、16个及38个。此外还观察到2组潜在的顺式关联（cis-association）：分别为rs10098821与c-Myc、rs2072590与HS.565379，二者的置换检验P值分别为0.0198与0.0399。通路富集分析结果显示，细胞周期（P=2.59×10⁻⁶）等若干关键生物学通路存在显著富集现象。进一步对mRNA与风险等位基因间的显著关联进行解析，将有助于阐明经GWAS鉴定的风险等位基因在卵巢癌遗传病因学中的功能机制。