Blandino Alice, Scherer Dominique, Rounge Trine B, Umu Sinan U, Boekstegers Felix, Barahona Ponce Carol, Marcelain Katherine, Gárate-Calderón Valentina, Waldenberger Melanie, Morales Erik, Rojas Armando, Munoz César, Retamales Javier, de Toro Gonzalo, Barajas Olga, Rivera María Teresa, Cortés Analía, Loader Denisse, Saavedra Javiera, Gutiérrez Lorena, Ortega Alejandro, Bertrán Maria Enriqueta, Gabler Fernando, Campos Mónica, Alvarado Juan, Moisán Fabrizio, Spencer Loreto, Nervi Bruno, Carvajal-Hausdorf Daniel E, Losada Héctor, Almau Mauricio, Fernández Plinio, Gallegos Ivan, Olloquequi Jordi, Fuentes-Guajardo Macarena, Gonzalez-Jose Rolando, Bortolini Maria Cátira, Gallo Carla, Linares Andres Ruiz, Rothhammer Francisco, Lorenzo Bermejo Justo
Statistical Genetics Research Group, Institute of Medical Biometry, Heidelberg University, 69120 Heidelberg, Germany.
Department of Research, Cancer Registry of Norway, 0379 Oslo, Norway.
Cancers (Basel). 2022 Jan 27;14(3):634. doi: 10.3390/cancers14030634.
Long noncoding RNAs (lncRNAs) play key roles in cell processes and are good candidates for cancer risk prediction. Few studies have investigated the association between individual genotypes and lncRNA expression. Here we integrate three separate datasets with information on lncRNA expression only, both lncRNA expression and genotype, and genotype information only to identify circulating lncRNAs associated with the risk of gallbladder cancer () using robust linear and logistic regression techniques. In the first dataset, we preselect lncRNAs based on expression changes along the sequence "gallstones → dysplasia → ". In the second dataset, we validate associations between genetic variants and serum expression levels of the preselected lncRNAs (cis-lncRNA-eQTLs) and build lncRNA expression prediction models. In the third dataset, we predict serum lncRNA expression based on individual genotypes and assess the association between genotype-based expression and risk. AC084082.3 and LINC00662 showed increasing expression levels (-value = 0.009), while C22orf34 expression decreased in the sequence from gallstones to (-value = 0.04). We identified and validated two cis-LINC00662-eQTLs (r = 0.26) and three cis-C22orf34-eQTLs (r = 0.24). Only LINC00662 showed a genotyped-based serum expression associated with risk (OR = 1.25 per log2 expression unit, 95% CI 1.04-1.52, -value = 0.02). Our results suggest that preselection of lncRNAs based on tissue samples and exploitation of cis-lncRNA-eQTLs may facilitate the identification of circulating noncoding RNAs linked to cancer risk.
长链非编码RNA（lncRNAs）在细胞过程中发挥关键作用，是癌症风险预测的良好候选指标。很少有研究调查个体基因型与lncRNA表达之间的关联。在此，我们整合了三个单独的数据集，分别仅包含lncRNA表达信息、lncRNA表达和基因型信息以及仅基因型信息，使用稳健的线性和逻辑回归技术来识别与胆囊癌风险相关的循环lncRNAs。在第一个数据集中，我们根据沿“胆结石→发育异常→”序列的表达变化预先选择lncRNAs。在第二个数据集中，我们验证遗传变异与预先选择的lncRNAs（顺式lncRNA - eQTLs）的血清表达水平之间的关联，并构建lncRNA表达预测模型。在第三个数据集中，我们根据个体基因型预测血清lncRNA表达，并评估基于基因型的表达与胆囊癌风险之间的关联。AC084082.3和LINC00662的表达水平呈上升趋势（P值 = 0.009），而C22orf34的表达在从胆结石到胆囊癌的序列中下降（P值 = 0.04）。我们鉴定并验证了两个顺式LINC00662 - eQTLs（r = 0.26）和三个顺式C22orf34 - eQTLs（r = 0.24）。只有LINC00662显示出基于基因型的血清表达与胆囊癌风险相关（每log2表达单位的OR = 1.25，95% CI 1.04 - 1.52，P值 = 0.02）。我们的结果表明，基于组织样本对lncRNAs进行预先选择以及利用顺式lncRNA - eQTLs可能有助于识别与癌症风险相关的循环非编码RNA。
