Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Carcinogenesis. 2013 Dec;34(12):2767-73. doi: 10.1093/carcin/bgt294. Epub 2013 Aug 25.
Lung adenocarcinoma patients of similar clinical stage and undergoing the same treatments often have marked interindividual variations in prognosis. These clinical discrepancies may be due to the genetic background modulating an individual's predisposition to fighting cancer. Herein, we hypothesized that the lung microenvironment, as reflected by its expression profile, may affect lung adenocarcinoma patients' survival. The transcriptome of non-involved lung tissue, excised from a discovery series of 204 lung adenocarcinoma patients, was evaluated using whole-genome expression microarrays (with probes corresponding to 28 688 well-annotated coding sequences). Genes associated with survival status at 60 months were identified by Cox regression analysis (adjusted for gender, age and clinical stage) and retested in a validation series of 78 additional cases. RNA-Seq analysis from non-involved lung tissue of 12 patients was performed to characterize the different isoforms of candidate genes. Ten genes for which the loge-transformed hazard ratios expressed the same direction of effect in the discovery (P < 1.0 × 10(-3)) and validation series comprised the gene expression signature associated with survival: CNTNAP1, PKNOX1, FAM156A, FRMD8, GALNTL1, TXNDC12, SNTB1, PPP3R1, SNX10 and SERPINH1. RNA sequencing highlighted the complex expression pattern of these genes in non-involved lung tissue from different patients and permitted the detection of a read-through gene fusion between PPP3R1 and the flanking gene (CNRIP1) as well as a novel isoform of CNTNAP1. Our findings support the hypothesis that individual genetic characteristics, evidenced by the expression pattern of non-involved tissue, influence the outcome of lung adenocarcinoma patients.
肺腺癌患者在相似的临床分期和接受相同的治疗下，其预后往往存在显著的个体间差异。这些临床差异可能是由于遗传背景调节个体对癌症的易感性。在此，我们假设肺微环境（由其表达谱反映）可能会影响肺腺癌患者的生存。通过全基因组表达微阵列（对应 28688 个充分注释的编码序列）评估了 204 例肺腺癌患者的非受累肺组织的转录组。使用 Cox 回归分析（调整性别、年龄和临床分期）鉴定与 60 个月生存状态相关的基因，并在另外 78 例病例的验证系列中进行了重新测试。对 12 例患者的非受累肺组织进行了 RNA-Seq 分析，以表征候选基因的不同异构体。在发现（P < 1.0 × 10(-3))和验证系列中，有 10 个基因的对数转换风险比表达出相同的生存方向效应，这些基因组成了与生存相关的基因表达特征：CNTNAP1、PKNOX1、FAM156A、FRMD8、GALNTL1、TXNDC12、SNTB1、PPP3R1、SNX10 和 SERPINH1。RNA 测序突出了这些基因在不同患者非受累肺组织中的复杂表达模式，并检测到 PPP3R1 和相邻基因（CNRIP1）之间的读通基因融合以及 CNTNAP1 的新异构体。我们的研究结果支持这样的假设，即个体遗传特征（由非受累组织的表达模式证明）影响肺腺癌患者的结局。
