Genomic Profiling and Prognostic Value Analysis of Genetic Alterations in Chinese Resected Lung Cancer With Invasive Mucinous Adenocarcinoma.
Genomic Profiling and Prognostic Value Analysis of Genetic Alterations in Chinese Resected Lung Cancer With Invasive Mucinous Adenocarcinoma.
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DOI：
10.3389/fonc.2020.603671
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发表时间：
2020
影响因子：
4.7
通讯作者：
Jiang Y
中科院分区：
文献类型：
--
作者：
Cai L;Wang J;Yan J;Zeng J;Zhu L;Liang J;Pan C;Huang X;Jin J;Xu Y;Wang F;Shao Y;Xu Q;Xia G;Xing M;Xu X;Jiang Y
肺浸润性粘液腺癌是一种具有独特临床和病理特征的组织学亚型。尽管以前对肺IMA的基因组学研究，但中国人手术切除的肺IMA的遗传特征和凋亡相关生物标志物仍不清楚。我们收集了76例手术切除的原发性浸润性肺腺癌，包括51例IMA和25例非粘液腺癌（non-IMA）。IMA进一步分为纯IMA（粘液特征≥90%）和混合IMA亚组。基于425个基因的靶向下一代测序（NGS）的综合基因组分析进行了探索，并评估了基因组特征与术后无病生存期（DFS）的相关性。IMA具有独特的遗传特征，与非IMA相比，具有更多样化的驱动突变和更多的肿瘤驱动/抑制因子共存。EGFR（72.0% vs. 40.0% vs. 23.1%，p=0.002）和ALK（未检出vs. 20.0% vs. 26.9%，p=0.015）改变的频率分别显示从非IMA到混合IMA再到纯IMA逐渐降低和增加的趋势。纯IMA中KRAS突变的频率高于混合IMA，尽管统计学上不显著（23.1% vs. 4.0%，p=0.10）。与混合IMA和非IMA相比，纯IMA中的TP 53突变显著较少（23.1% vs. 52.0% vs. 56.0%，p=0.03）。IMA组的臂水平扩增率（p=0.04）低于非IMA组，臂水平缺失率（p=0.004）高于非IMA组，且从非IMA组到混合IMA组再到纯IMA组，扩增率逐渐降低，缺失率逐渐升高。此外，III期IMA患者的预后分析显示，EGFR改变的患者（mDFS=30.3 vs. 16.0个月，HR=0.19，P=0.027）和PI 3 K通路（mDFS=36.0 vs. 16.0个月，HR=0.12，P=0.023）获得了延长的DFS，而低分化肿瘤患者，（mDFS=14.1 vs. 28.0个月，HR=3.75，p=0.037）或KRAS突变（mDFS=13.0 vs. 20.0个月，HR=6.95，p=0.027）的DFS较短。多因素分析显示KRAS突变、PI 3 K通路改变和肿瘤分化状态是影响IMA患者临床结局的独立因素。我们的研究为中国人手术切除的肺IMA提供了基因组学的见解。我们还确定了几个基因组特征，这些特征可能作为III期IMA患者术后复发的潜在生物标志物。
Invasive mucinous adenocarcinoma (IMA) of the lung is a distinct histological subtype with unique clinical and pathological features. Despite previous genomic studies on lung IMA, the genetic characteristics and the prognosis-related biomarkers in Chinese surgically resected lung IMA remain unclear. We collected 76 surgically resected primary tumors of invasive lung adenocarcinoma, including 51 IMA and 25 non-mucinous adenocarcinomas (non-IMA). IMA was further divided into pure-IMA (mucinous features≥90%) and mixed-IMA subgroups. Comprehensive genomic profiling based on targeted next-generation sequencing (NGS) of 425 genes was explored and genomic characteristics were evaluated for the correlation with postoperative disease-free survival (DFS). IMA had a unique genetic profile, with more diverse driver mutations and more tumor drivers/suppressors co-occurrence than that of non-IMA. The frequency of EGFR (72.0% vs. 40.0% vs. 23.1%, p=0.002) and ALK (undetected vs. 20.0% vs. 26.9%, p=0.015) alterations showed a trend of gradual decrease and increase from non-IMA to mixed-IMA to pure-IMA, respectively. The frequency of KRAS mutations in pure-IMA was higher than that in mixed-IMA, albeit statistically insignificant (23.1% vs. 4.0%, p=0.10). TP53 mutation was significantly less in pure-IMA compared to mixed-IMA and non-IMA (23.1% vs. 52.0% vs. 56.0%, p=0.03). Besides, IMA exhibited less arm-level amplifications (p=0.04) and more arm-level deletions (p=0.004) than non-IMA, and the frequency of amplification and deletion also showed a trend of gradual decrease and increase from non-IMA to mixed-IMA to pure-IMA, respectively. Furthermore, prognosis analysis in stage III IMA patients showed that patients harboring alterations in EGFR (mDFS=30.3 vs. 16.0 months, HR=0.19, P=0.027) and PI3K pathway (mDFS=36.0 vs. 16.0 months, HR=0.12, P=0.023) achieved prolonged DFS, while patients with poorly differentiated tumors (mDFS=14.1 vs. 28.0 months, HR=3.75, p=0.037) or with KRAS mutations (mDFS=13.0 vs. 20.0 months, HR=6.95, p=0.027) had shorter DFS. Multivariate analysis showed that KRAS mutations, PI3K pathway alterations, and tumor differentiation status were independent factors that have statistically significant influences on clinical outcomes of IMA patients. Our study provided genomic insights into Chinese surgically resected lung IMA. We also identified several genomic features that may serve as potential biomarkers on postoperative recurrence in IMA patients with stage III disease.
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影响因子：
3
作者：
Amarasinghe KC;Li J;Halgamuge SK
通讯作者：
Halgamuge SK
影响因子：
51.1
作者：
Drilon, Alexander;Rekhtman, Natasha;Arcila, Maria;Wang, Lu;Ni, Andy;Albano, Melanie;Van Voorthuysen, Martine;Somwar, Romel;Smith, Roger S.;Montecalvo, Joseph;Plodkowski, Andrew;Ginsberg, Michelle S.;Riely, Gregory J.;Rudin, Charles M.;Ladanyi, Marc;Kris, Mark G.
通讯作者：
Kris, Mark G.
影响因子：
28.2
作者：
Drilon A;Wang L;Hasanovic A;Suehara Y;Lipson D;Stephens P;Ross J;Miller V;Ginsberg M;Zakowski MF;Kris MG;Ladanyi M;Rizvi N
通讯作者：
Rizvi N
影响因子：
2.9
作者：
Lee MA;Kang J;Lee HY;Kim W;Shon I;Hwang NY;Kim HK;Choi YS;Kim J;Zo JI;Shim YM
通讯作者：
Shim YM
影响因子：
2.9
作者：
Beck KS;Sung YE;Lee KY;Han DH
通讯作者：
Han DH