Genomic Alterations in the RB Pathway Indicate Prognostic Outcomes of Early-Stage Lung Adenocarcinoma
Genomic Alterations in the RB Pathway Indicate Prognostic Outcomes of Early-Stage Lung Adenocarcinoma
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DOI：
10.1158/1078-0432.ccr-14-0519
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发表时间：
2015-06-01
影响因子：
11.5
通讯作者：
Jang, Se Jin
中科院分区：
文献类型：
--
作者：
Choi, Seongmin;Kim, Hyeong Ryul;Jang, Se Jin
目的：为了更好地理解肺腺癌的完整基因组结构，实验设计：我们使用阵列实验来确定拷贝数变异，并对247个肺腺癌肿瘤样品沿着从相同患者获得的匹配的正常细胞的完整外显子组进行测序。充分注释的临床数据也可提供，提供了一个前所未有的机会，以评估基因组改变对临床outcomes.Results的影响：我们发现，基因组改变在RB通路与显着较短的无病生存期在早期肺腺癌患者。在我们的独立验证队列中也观察到了这种关联。目前早期肺腺癌患者的治疗指南建议，除高危患者外，完全切除后应随访，无需辅助治疗。然而，我们的研究结果提出了一个有趣的可能性，即额外的临床干预可能会为RB途径基因组改变的早期肺腺癌患者提供医疗益处。当研究基因组突变和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签名。值得注意的是，固体和微乳头亚型在突变基因中表现出极大的多样性，而粘液亚型表现出最独特的景观。这表明肺腺癌患者应采用更适合的治疗方法。结论：我们对247例肺腺癌的基因组和临床数据的分析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，并导致发现可用于早期肺腺癌患者的个性化治疗的有用的预后标志物。（C）2014年AACR。
Purpose: To better understand the complete genomic architecture of lung adenocarcinoma.Experimental Design: 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.Results: 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.Conclusions: 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. (C)2014 AACR.