RAS oncogenic activity predicts response to chemotherapy and outcome in lung adenocarcinoma.
RAS oncogenic activity predicts response to chemotherapy and outcome in lung adenocarcinoma.
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DOI：
10.1038/s41467-022-33290-0
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发表时间：
2022-09-26
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
KRAS的激活突变发生在32%的肺腺癌（LUAD）中。尽管在临床前研究中导致侵袭性疾病和对治疗的耐药性，但KRAS突变不能预测患者的结局或对治疗的反应，可能是由于调节RAS通路的其他事件。为了获得RAS通路激活的更广泛测量，我们开发了RAS 84，这是一种优化的转录特征，用于捕获LUAD中的RAS致癌活性。我们报告了84%的LUAD（包括65%的KRAS野生型肿瘤）中存在RAS途径致癌激活的证据，这些肿瘤分为四组，其特征是STK 11/LKB 1、TP 53或CDKN 2A的同时改变，这表明仅考虑KRAS时制定的分类突变肿瘤在更广泛的患者队列中具有重要意义。关键是，高RAS活性患者组显示不良临床结局和对化疗的反应降低。使用致癌RAS转录活性而不是遗传改变对患者进行分层，最终可能有助于临床决策。RAS癌基因和相关通路的突变在肺癌中是常见的。在这里，作者推导出RAS基因表达特征和机器学习分类器来预测肺腺癌和其他实体瘤的药物反应和临床结果，其性能优于单独的KRAS突变。
Activating mutations in KRAS occur in 32% of lung adenocarcinomas (LUAD). Despite leading to aggressive disease and resistance to therapy in preclinical studies, the KRAS mutation does not predict patient outcome or response to treatment, presumably due to additional events modulating RAS pathways. To obtain a broader measure of RAS pathway activation, we developed RAS84, a transcriptional signature optimised to capture RAS oncogenic activity in LUAD. We report evidence of RAS pathway oncogenic activation in 84% of LUAD, including 65% KRAS wild-type tumours, falling into four groups characterised by coincident alteration of STK11/LKB1, TP53 or CDKN2A, suggesting that the classifications developed when considering only KRAS mutant tumours have significance in a broader cohort of patients. Critically, high RAS activity patient groups show adverse clinical outcome and reduced response to chemotherapy. Patient stratification using oncogenic RAS transcriptional activity instead of genetic alterations could ultimately assist in clinical decision-making. Mutations in RAS oncogenes and related pathways are frequent in lung cancers. Here, the authors derive a RAS gene expression signature and a machine learning classifier to predict drug response and clinical outcomes in lung adenocarcinoma and other solid tumours, with improved performance over KRAS mutations alone.
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影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H
影响因子：
56.9
作者：
FLIER, JS;MUECKLER, MM;LODISH, HF
通讯作者：
LODISH, HF
DOI：
10.2147/tacg.s69210
发表时间：
2016
期刊：
The application of clinical genetics
影响因子：
--
作者：
Helgadottir H;Höiom V
通讯作者：
Höiom V
影响因子：
8.4
作者：
Cserepes, Mihaly;Ostoros, Gyula;Dome, Balazs
通讯作者：
Dome, Balazs
影响因子：
64.8
作者：
Bild, AH;Yao, G;Nevins, JR
通讯作者：
Nevins, JR