Comprehensive Molecular and Clinicopathologic Analysis of 200 Pulmonary Invasive Mucinous Adenocarcinomas Identifies Distinct Characteristics of Molecular Subtypes.
Comprehensive Molecular and Clinicopathologic Analysis of 200 Pulmonary Invasive Mucinous Adenocarcinomas Identifies Distinct Characteristics of Molecular Subtypes.
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DOI：
10.1158/1078-0432.ccr-21-0423
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发表时间：
2021-07-15
期刊：
影响因子：
--
通讯作者：
Rekhtman N
中科院分区：
文献类型：
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作者：
Chang JC;Offin M;Falcon C;Brown D;Houck-Loomis BR;Meng F;Rudneva VA;Won HH;Amir S;Montecalvo J;Desmeules P;Kadota K;Adusumilli PS;Rusch VW;Teed S;Sabari JK;Benayed R;Nafa K;Borsu L;Li BT;Schram AM;Arcila ME;Travis WD;Ladanyi M;Drilon A;Rekhtman N
侵袭性粘液腺癌 (IMA) 是肺腺癌的一种独特亚型，其基因组特征为频繁的 KRAS 突变或特定基因融合，最常见的是 NRG1。目前仍缺乏利用广泛的 DNA 和 RNA 测序方法对大量 IMA 进行综合分析，并且尚不清楚 IMA 的分子亚型在临床病理学上是否存在差异。通过 410 基因 DNA 下一代测序（MSK-IMPACT；n=136）或热点 8 癌基因基因分型（n=64）对总共 200 个 IMA 进行了分析。通过 62 基因 RNA 测序 (MSK-Fusion) 进一步分析驱动阴性病例，通过全外显子组和全转录组测序进一步测试缺乏融合的病例。 MSK-IMPACT 和 MSK-Fusion 组合测试在 96% 的 IMA 中发现了相互排斥的驱动改变，包括 KRAS 突变 (76%)、NRG1 融合 (7%)、ERBB2 改变 (6%) 和其他不太常见的事件。此外，全转录组测序还发现了一种新型 NRG2 融合体 (F11R-NRG2)。总体而言，在 51% 的 KRAS 野生型 IMA 中发现了靶向基因融合，导致一些患者对靶向治疗产生持久反应。与 KRAS 突变 IMA 相比，NRG1 重排肿瘤表现出多种更具侵袭性的特征，包括更差的无复发生存率 (p<0.0001)。这是迄今为止最大规模的 IMA 分子研究，我们证明了几乎所有情况下都存在主要致癌驱动因素。这项研究首次记录了 NRG1 重排 IMA 的更具侵袭性的特征，ERBB2 作为第三种最常见的改变，以及这些肿瘤中的新型 NRG2 融合。鉴于该子集中已建立的和正在研究的靶向疗法的改变发生率很高，因此对 KRAS 野生型 IMA 进行全面的分子测试（包括融合测试）至关重要。
Invasive mucinous adenocarcinoma (IMA) is a unique subtype of lung adenocarcinoma, characterized genomically by frequent KRAS mutations or specific gene fusions, most commonly involving NRG1. Comprehensive analysis of a large series of IMAs utilizing broad DNA and RNA sequencing methods is still lacking, and it remains unclear whether molecular subtypes of IMA differ clinicopathologically. A total of 200 IMAs were analyzed by 410-gene DNA next-generation sequencing (MSK-IMPACT; n=136) or hotspot 8-oncogene genotyping (n=64). Driver-negative cases were further analyzed by 62-gene RNA sequencing (MSK-Fusion) and those lacking fusions were further tested by whole-exome and whole-transcriptome sequencing. Combined MSK-IMPACT and MSK-Fusion testing identified mutually-exclusive driver alterations in 96% of IMAs, including KRAS mutations (76%), NRG1 fusions (7%), ERBB2 alterations (6%), and other less common events. Additionally, whole-transcriptome sequencing identified a novel NRG2 fusion (F11R-NRG2). Overall, targetable gene fusions were identified in 51% of KRAS wild-type IMAs, leading to durable responses to targeted therapy in some patients. Compared to KRAS-mutant IMAs, NRG1-rearranged tumors exhibited several more aggressive characteristics including worse recurrence-free survival (p<0.0001). This is the largest molecular study of IMAs to date, where we demonstrate the presence of a major oncogenic driver in nearly all cases. This study is the first to document more aggressive characteristics of NRG1-rearranged IMAs, ERBB2 as the third most common alteration, and a novel NRG2 fusion in these tumors. Comprehensive molecular testing of KRAS wild-type IMAs that includes fusion testing is essential given the high prevalence of alterations with established and investigational targeted therapies in this subset.