Association of prostate cancer risk variants with gene expression in normal and tumor tissue.
Association of prostate cancer risk variants with gene expression in normal and tumor tissue.
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DOI：
10.1158/1055-9965.epi-14-0694-t
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发表时间：
2015-01
期刊：
影响因子：
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通讯作者：
Stampfer MJ
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文献类型：
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作者：
Penney KL;Sinnott JA;Tyekucheva S;Gerke T;Shui IM;Kraft P;Sesso HD;Freedman ML;Loda M;Mucci LA;Stampfer MJ
许多生殖系遗传变异与前列腺癌风险相关，但其生物学作用尚不清楚。一种可能性是这些变异影响前列腺组织中的基因表达。因此，我们研究了前列腺癌风险变异与附近和全基因组基因表达的关联。我们使用AffysseGeneChip Human Gene 1.0 ST微阵列生成了来自医生健康研究和健康专业人员随访研究参与者的正常前列腺（N=160）和前列腺肿瘤（N=264）组织的20，254个基因的mRNA表达数据。使用线性模型，我们测试了39个风险变体与附近基因和所有基因的关联，以及使用全局测试每个变体与典型途径的关联。除了证实先前报道的关联外，我们还检测到几种新的显著（p<0.05）变异与附近基因表达的关联，包括C2orf43、ITGA 6、MLPH、CHMP2B、BMPR1B和MTL5。在全基因组范围内，四个基因（MSMB，NUDT 11，NEFM，KLHL 33）在对每个SNP进行多重比较后显着相关（p<2.5x10−6）。更多的基因的错误发现率<10%，包括SRD5A1和PSCA，我们观察到与肿瘤组织中的通路有显著的关联。这些风险变异与几个基因相关，包括有希望的前列腺癌候选基因和脂质代谢途径，表明它们对疾病的影响机制。这些基因应在生物学和流行病学研究中进一步探索。确定这些变异的生物学作用可以提高对前列腺癌病因学的理解，并确定化学预防的新靶点。
Numerous germline genetic variants are associated with prostate cancer risk, but their biological role is not well understood. One possibility is that these variants influence gene expression in prostate tissue. We therefore examined the association of prostate cancer risk variants with the expression of genes nearby and genome-wide. We generated mRNA expression data for 20,254 genes with the Affymetrix GeneChip Human Gene 1.0 ST microarray from normal prostate (N=160) and prostate tumor (N=264) tissue from participants of the Physicians’ Health Study and Health Professionals Follow-up Study. With linear models, we tested the association of 39 risk variants with nearby genes and all genes, and the association of each variant with canonical pathways using a global test. In addition to confirming previously reported associations, we detected several new significant (p<0.05) associations of variants with the expression of nearby genes including C2orf43, ITGA6, MLPH, CHMP2B, BMPR1B, and MTL5. Genome-wide, four genes (MSMB, NUDT11, NEFM, KLHL33) were significantly associated after accounting for multiple comparisons for each SNP (p<2.5x10−6). Many more genes had a false discovery rate <10%, including SRD5A1 and PSCA, and we observed significant associations with pathways in tumor tissue. The risk variants were associated with several genes, including promising prostate cancer candidates and lipid metabolism pathways, suggesting mechanisms for their impact on disease. These genes should be further explored in biological and epidemiological studies. Determining the biological role of these variants can lead to improved understanding of prostate cancer etiology and identify new targets for chemoprevention.