INTRODUCTION 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). METHODS 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. RESULTS 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). CONCLUSIONS 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.

中文翻译：

---

肺腺癌主要组织学亚型的潜在肿瘤基因组学

引言 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和相关治疗机会进行基因组表征。方法 我们确定了 604 名 I-III 期 LUAD 患者，他们使用 MSK-IMPACT 平台进行了完全切除和靶向二代测序。肿瘤根据主要的组织学亚型进行分类，并按结构分级（鳞屑型 [LEP]、腺泡或乳头状 [ACI/PAP] 和微乳头状或实性 [MIP/SOL]）进行分组。在亚型内检查临床病理因素、基因组特征、突变特征和复发之间的关联，并在适当时使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。结果 MIP/SOL 肿瘤具有较高的肿瘤突变负荷 (p<0.001)、基因组改变比例 (p=0.001)、拷贝数扩增 (p=0.021)、全基因组倍增率 (p=0.008) 和与 LEP 和 ACI/PAP 肿瘤相比，致癌途径发生了改变 (p<0.001)。在所有肿瘤中，归因于 APOBEC 活性的突变特征与切除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）发生了具有统计学意义的改变。与 LEP 和 ACI/PAP 肿瘤相比，MIP/SOL 肿瘤的可靶向 BRAF-V600E 突变频率更高（p=0.046）。在 ACI/PAP 肿瘤中，细胞周期 (p<0.001) 和 PI3K (p=0.002) 通路的改变与复发相关；在 MIP/SOL 肿瘤中，只有 PI3K 改变是 (p=0.049)。结论 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分析、它们与复发的关联，以及它们与手术切除 LUAD 患者可靶向驱动改变的相关性。