PDF(Pubmed)
Abstract：
A unique approach with rare resources was used to identify candidate variants predisposing to familial nonsquamous nonsmall-cell lung cancers (NSNSCLC). We analyzed sequence data from NSNSCLC-affected cousin pairs belonging to high-risk lung cancer pedigrees identified in a genealogy of Utah linked to statewide cancer records to identify rare, shared candidate predisposition variants. Variants were tested for association with lung cancer risk in UK Biobank. Evidence for linkage with lung cancer was also reviewed in families from the Genetic Epidemiology of Lung Cancer Consortium. Protein prediction modeling compared the mutation with reference. We sequenced NSNSCLC-affected cousin pairs from eight high-risk lung cancer pedigrees and identified 66 rare candidate variants shared in the cousin pairs. One variant in the FGF5 gene also showed significant association with lung cancer in UKBiobank. This variant was observed in 3/163 additional sampled Utah lung cancer cases, 2 of whom were related in another independent pedigree. Modeling of the predicted protein predicted a second binding site for SO4 that may indicate binding differences. This unique study identified multiple candidate predisposition variants for NSNSCLC, including a rare variant in FGF5 that was significantly associated with lung cancer risk and that segregated with lung cancer in the two pedigrees in which it was observed. FGF5 is an oncogenic factor in several human cancers, and the mutation found here (W81C) changes the binding ability of heparan sulfate to FGF5, which might lead to its deregulation. These results support FGF5 as a potential NSNSCLC predisposition gene and present additional candidate predisposition variants.
摘要：
一种具有稀有资源的独特方法用于鉴定易患家族性非鳞状非小细胞肺癌（NSNSCLC）的候选变体。我们分析了来自受NSNSCLC影响的表亲对的序列数据，这些表亲对属于在犹他州的家谱中与全州癌症记录相关的高风险肺癌谱系，共享候选易感性变体。在UKBiobank中测试了变体与肺癌风险的关联。在肺癌遗传流行病学联盟的家族中也审查了与肺癌相关的证据。蛋白质预测模型将突变与参考进行比较。我们对来自8个高风险肺癌家系的NSNSCLC影响的表亲对进行了测序，并鉴定了表亲对中共有的66个罕见候选变体。FGF5基因中的一个变异也显示与UKBiobank中的肺癌显著相关。在另外3/163例犹他州肺癌样本中观察到这种变异，其中2人与另一个独立的血统有关。预测蛋白质的建模预测了SO4的第二个结合位点，这可能表明结合差异。这项独特的研究确定了NSNSCLC的多种候选易感性变体，包括FGF5中的一个罕见变异,该变异与肺癌风险显著相关,并且在观察到的两个家系中与肺癌分离.FGF5是几种人类癌症的致癌因子，此处发现的突变（W81C）改变了硫酸乙酰肝素与FGF5的结合能力，这可能导致其失调。这些结果支持FGF5作为潜在的NSNSCLC易感性基因,并呈现另外的候选易感性变体。
