Center for RNA Research, Institute for Basic Science, Seoul National University, Seoul, South Korea. School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul, South Korea.
Department of Thoracic and Cardiovascular Surgery, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
Clin Cancer Res. 2015 Jun 1;21(11):2613-23. doi: 10.1158/1078-0432.CCR-14-0519. Epub 2014 Oct 7.
To better understand the complete genomic architecture of lung adenocarcinoma.
We used array experiments to determine copy number variations and sequenced the complete exomes of the 247 lung adenocarcinoma tumor samples along with matched normal cells obtained from the same patients. Fully annotated clinical data were also available, providing an unprecedented opportunity to assess the impact of genomic alterations on clinical outcomes.
We discovered that genomic alternations in the RB pathway are associated with significantly shorter disease-free survival in early-stage lung adenocarcinoma patients. This association was also observed in our independent validation cohort. The current treatment guidelines for early-stage lung adenocarcinoma patients recommend follow-up without adjuvant therapy after complete resection, except for high-risk patients. However, our findings raise the interesting possibility that additional clinical interventions might provide medical benefits to early-stage lung adenocarcinoma patients with genomic alterations in the RB pathway. When examining the association between genomic mutation and histologic subtype, we uncovered the characteristic genomic signatures of various histologic subtypes. Notably, the solid and the micropapillary subtypes demonstrated great diversity in the mutated genes, while the mucinous subtype exhibited the most unique landscape. This suggests that a more tailored therapeutic approach should be used to treat patients with lung adenocarcinoma.
Our analysis of the genomic and clinical data for 247 lung adenocarcinomas should help provide a more comprehensive genomic portrait of lung adenocarcinoma, define molecular signatures of lung adenocarcinoma subtypes, and lead to the discovery of useful prognostic markers that could be used in personalized treatments for early-stage lung adenocarcinoma patients.
更好地了解肺腺癌的完整基因组结构。
我们使用阵列实验来确定拷贝数变异，并对 247 例肺腺癌肿瘤样本的完整外显子进行测序，同时对来自同一患者的匹配正常细胞进行测序。还获得了完全注释的临床数据，这为评估基因组改变对临床结果的影响提供了前所未有的机会。
我们发现 RB 通路中的基因组改变与早期肺腺癌患者无病生存期显著缩短有关。这一关联在我们的独立验证队列中也得到了观察。目前，对于早期肺腺癌患者，建议在完全切除后进行随访而无需辅助治疗，除非是高危患者。然而，我们的发现提出了一个有趣的可能性，即对于 RB 通路中有基因组改变的早期肺腺癌患者，额外的临床干预可能会带来医疗益处。在检查基因组突变与组织学亚型之间的关联时，我们发现了各种组织学亚型的特征性基因组特征。值得注意的是，实体和微乳头状亚型在突变基因方面表现出很大的多样性，而粘液性亚型则表现出最独特的景观。这表明，应该采用更具针对性的治疗方法来治疗肺腺癌患者。
我们对 247 例肺腺癌的基因组和临床数据分析应该有助于提供更全面的肺腺癌基因组图谱，定义肺腺癌亚型的分子特征，并发现有用的预后标志物，可用于早期肺腺癌患者的个体化治疗。
