The Underlying Tumor Genomics of Predominant Histologic Subtypes in Lung Adenocarcinoma.
The Underlying Tumor Genomics of Predominant Histologic Subtypes in Lung Adenocarcinoma.
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DOI：
10.1016/j.jtho.2020.08.005
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Jones DR
中科院分区：
文献类型：
--
作者：
Caso R;Sanchez-Vega F;Tan KS;Mastrogiacomo B;Zhou J;Jones GD;Nguyen B;Schultz N;Connolly JG;Brandt WS;Bott MJ;Rocco G;Molena D;Isbell JM;Liu Y;Mayo MW;Adusumilli PS;Travis WD;Jones DR
本研究的目的是对肺腺癌(LUAD)中预后重要的主要组织学亚型的生物学特性和相关治疗机会进行基因组学特征分析。我们确定了604名I-III期LUAD患者，他们接受了完全切除，并使用MSK-IMPACT平台进行了有针对性的下一代测序。肿瘤根据主要的组织学亚型进行分类，并按结构分级(LEP)、腺泡或乳头状[ACI/PAP]、微乳头状或实性[MIP/SOL]分组。临床病理因素、基因组特征、突变特征和复发之间的关系在亚型内进行了研究，并在适当的情况下，利用竞争风险回归进行量化，并根据病理分期和切除范围进行调整。与LEP和ACI/PAP肿瘤相比，MIP/SOL肿瘤具有更高的肿瘤突变负荷(p<；0.001)、部分基因组改变(p=0.001)、拷贝数扩增(p=0.021)、全基因组倍增率(p=0.008)和致癌途径改变(p<；0.001)。在所有肿瘤中，与APOBEC活性有关的突变特征与术后复发的最高风险相关：SBS2(p=0.021)和SBS13(p=0.005)。在MIP/SOL肿瘤中，三种致癌途径(P53、Wnt、Myc)的改变具有统计学意义。与LEP和ACI/PAP肿瘤相比，MIP/SOL肿瘤具有更高的靶向性BRAF-V600E突变频率(p=0.046)。在ACI/PAP肿瘤中，细胞周期改变(p<；0.001)和PI3K通路改变(p=0.002)与复发相关；在MIP/SOL肿瘤中，只有PI3K改变与复发相关(p=0.049)。这些结果首次深入评估了主要LUAD组织学亚型的肿瘤基因组图谱，它们与复发的关系，以及它们与手术切除的LUAD患者的靶向驱动因素改变的相关性。
The purpose of the study is to genomically characterize the biology and related therapeutic opportunities of prognostically important predominant histological subtypes in lung adenocarcinoma (LUAD). We identified 604 patients with stage I-III LUAD who underwent complete resection and targeted next-generation sequencing using the MSK-IMPACT platform. Tumors were classified according to predominant histologic subtype and grouped by architectural grade (lepidic [LEP], acinar or papillary [ACI/PAP], and micropapillary or solid [MIP/SOL]). Associations between clinicopathologic factors, genomic features, mutational signatures, and recurrence were examined within subtypes and, when appropriate, quantified using competing-risks regression, with adjustment for pathologic stage and extent of resection. MIP/SOL tumors had higher tumor mutational burden (p<0.001), fraction of genome altered (p=0.001), copy number amplifications (p=0.021), rate of whole-genome doubling (p=0.008), and number of oncogenic pathways altered (p<0.001), compared with LEP and ACI/PAP tumors. Across all tumors, mutational signatures attributed to APOBEC activity were associated with the highest risk of postresection recurrence: SBS2 (p=0.021) and SBS13 (p=0.005). Three oncogenic pathways (p53, Wnt, Myc) were altered with statistical significance in MIP/SOL tumors. Compared with LEP and ACI/PAP tumors, MIP/SOL tumors had a higher frequency of targetable BRAF-V600E mutations (p=0.046). Among ACI/PAP tumors, alterations in the cell cycle (p<0.001) and PI3K (p=0.002) pathways were associated with recurrence; among MIP/SOL tumors, only PI3K alterations were (p=0.049). These results provide the first in-depth assessment of tumor genomic profiling of predominant LUAD histologic subtypes, their associations with recurrence, and their correlation with targetable driver alterations in patients with surgically resected LUAD.
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影响因子：
120.7
作者：
Korf, Bruce R.;Rehm, Heidi L.
通讯作者：
Rehm, Heidi L.
DOI：
10.1164/rccm.200801-142oc
发表时间：
2008-12-01
影响因子：
24.7
作者：
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158.5
作者：
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10.6
作者：
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Garmire LX