Lung cancer (LC) continues to be an important public health problem, being the most common form of cancer and a major cause of cancer deaths worldwide. Despite the great bulk of research to identify genetic susceptibility genes by genome-wide association studies, only few loci associated to nicotine dependence have been consistently replicated. Our previously published study in few phenotypically discordant sib-pairs identified a combination of germline truncating mutations in known cancer susceptibility genes in never-smoker early-onset LC patients, which does not present in their healthy sib. These results firstly demonstrated the presence of an oligogenic combination of disrupted cancer-predisposing genes in non-smokers patients, giving experimental support to a model of a “private genetic epidemiology”. Here, we used a combination of whole-exome and RNA sequencing coupled with a discordant sib’s model in a novel cohort of pairs of never-smokers early-onset LC patients and in their healthy sibs used as controls. We selected rare germline variants predicted as deleterious by CADD and SVM bioinformatics tools and absent in the healthy sib. Overall, we identified an average of 200 variants per patient, about 10 of which in cancer-predisposing genes. In most of them, RNA sequencing data reinforced the pathogenic role of the identified variants showing: (i) downregulation in LC tissue (indicating a “second hit” in tumor suppressor genes); (ii) upregulation in cancer tissue (likely oncogene); and (iii) downregulation in both normal and cancer tissue (indicating transcript instability). The combination of the two techniques demonstrates that each patient has an average of six (with a range from four to eight) private mutations with a functional effect in tumor-predisposing genes. The presence of a unique combination of disrupting events in the affected subjects may explain the absence of the familial clustering of non-small-cell lung cancer. In conclusion, these findings indicate that each patient has his/her own “predisposing signature” to cancer development and suggest the use of personalized therapeutic strategies in lung cancer.
肺癌（LC）作为全球最常见的癌症类型及癌症死亡的主要原因，始终是公共卫生领域的重要议题。尽管全基因组关联研究已投入大量工作以识别遗传易感基因，但仅有少数与尼古丁依赖相关的基因位点得到一致性验证。我们先前针对少数表型不一致的同胞对开展的研究发现，非吸烟早发肺癌患者携带已知癌症易感基因的种系截短突变组合，而其健康同胞则未携带。这些结果首次证实了非吸烟患者中存在癌症易感基因破坏性变异的多基因组合，为"个体化遗传流行病学"模型提供了实验依据。本研究采用全外显子组测序与RNA测序相结合的技术，并基于新构建的非吸烟早发肺癌患者与其健康同胞（作为对照）的配对队列，采用表型不一致同胞模型进行分析。我们筛选出经CADD和SVM生物信息学工具预测为有害、且在健康同胞中不存在的罕见种系变异。总体而言，每位患者平均携带200个变异，其中约10个位于癌症易感基因。RNA测序数据在多数病例中强化了这些变异的致病作用，表现为：（1）肺癌组织中表达下调（提示抑癌基因存在"二次打击"）；（2）癌组织中表达上调（可能为原癌基因）；（3）正常与癌组织均表达下调（提示转录本不稳定）。两种技术的联合分析表明，每位患者平均携带6个（范围4-8个）对肿瘤易感基因产生功能性影响的个体特异性突变。这种仅存在于患病个体中的破坏性事件独特组合，可能解释了非小细胞肺癌缺乏家族聚集性的现象。综上所述，这些发现表明每位患者都具有其独特的癌症发展"易感特征谱"，提示在肺癌治疗中应采用个体化治疗策略。
The Personalized Inherited Signature Predisposing to Non-Small-Cell Lung Cancer in Non-Smokers
肿瘤(癌症)患者之家