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Genomic Landscape and Immune Microenvironment Features of Preinvasive and Early Invasive Lung Adenocarcinoma.

ABSTRACT: BACKGROUND:Understanding the genomic landscape and immune microenvironment features of preinvasive and early invasive lung adenocarcinoma may provide critical insight and facilitate development of novel strategies for early detection and intervention. METHODS:A total of 80 tumor tissue samples and 30 paired histologically normal lung tissue samples from 30 patients with adenocarcinoma in situ (AIS) (n = 8), minimally invasive adenocarcinoma (MIA) (n = 8), and invasive adenocarcinoma (IAC) (n = 14) were subjected to multiregion whole exome sequencing and immunohistochemistry staining for CD8 and programmed death ligand 1 (PD-L1). RESULTS:All tumors, including AIS, exhibited evidence of genomic intratumor heterogeneity. Canonical cancer gene mutations in EGFR, erb-b2 receptor tyrosine kinase 2 gene (ERBB2), NRAS, and BRAF were exclusively trunk mutations detected in all regions within each tumor, whereas genes associated with cell mobility, gap junction, and metastasis were all subclonal mutations. EGFR mutation represented the most common driver alterations across AIS, MIA, and IAC, whereas tumor protein p53 gene (TP53) was identified in MIA and IAC but not in AIS. There was no difference in PD-L1 expression among AIS, MIA, and IAC, but the CD8 positivity rate was higher in IAC. Tumors positive for both PD-L1 and CD8 had a larger proportion of subclonal mutations. CONCLUSIONS:Mutations in EGFR, ERBB2, NRAS, and BRAF are early clonal genomic events during carcinogenesis of lung adenocarcinoma, whereas TP53 and cell mobility, gap junction, and metastasis-related genes may be late events associated with subclonal diversification and neoplastic progression. Genomic intratumor heterogeneity and immunoediting are common and early phenomena that may have occurred before the acquisition of invasion.

SUBMITTER: Zhang C

PROVIDER: S-EPMC6986039 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Genomic Landscape and Immune Microenvironment Features of Preinvasive and Early Invasive Lung Adenocarcinoma.

Zhang Chao C Zhang Jianjun J Xu Fang-Ping FP Wang Yin-Guang YG Xie Zhi Z Su Jian J Dong Song S Nie Qiang Q Shao Yang Y Zhou Qing Q Yang Jin-Ji JJ Yang Xue-Ning XN Zhang Xu-Chao XC Li Zhi Z Wu Yi-Long YL Zhong Wen-Zhao WZ

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 20190822 11

<h4>Background</h4>Understanding the genomic landscape and immune microenvironment features of preinvasive and early invasive lung adenocarcinoma may provide critical insight and facilitate development of novel strategies for early detection and intervention.<h4>Methods</h4>A total of 80 tumor tissue samples and 30 paired histologically normal lung tissue samples from 30 patients with adenocarcinoma in situ (AIS) (n = 8), minimally invasive adenocarcinoma (MIA) (n = 8), and invasive adenocarcino ...[more]

PMID: 31446140

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Project description:Lung adenocarcinoma (LUAD) is a heterogeneous disease. Our study aimed to understand the unique molecular features of preinvasive to invasive LUAD subtypes. We retrospectively analyzed the clinical, histopathological, and molecular data of 3,254 Chinese patients with preinvasive lesions (n = 252), minimally invasive adenocarcinomas (n = 479), and invasive LUAD (n = 2,523). Molecular data were elucidated using a targeted 68-gene next-generation sequencing panel. Our findings revealed four preinvasive lesion-predominant gene mutations, including MAP2K1 insertion-deletions (indels), BRAF non-V600E kinase mutations, and exon 20 insertions (20ins) in both EGFR and ERBB2, which we referred to as mutations enriched in AIS (MEA). The detection rate of MEA in invasive tumors was relatively lower. MAP2K1 missense mutations, which were likely passenger mutations, co-occurred with oncogenic driver mutations, while small indels were mutually exclusive from other genes regardless of the invasion level. BRAF non-V600E kinase-mutant invasive adenocarcinomas (IAC) had significantly higher mutation rates in tumor suppressor genes but lower frequency of co-occurring oncogenic driver mutations than non-kinase-mutant IAC, suggesting the potential oncogenic activity of BRAF non-V600E kinase mutations albeit weaker than BRAF V600E. Moreover, similar to the extremely low frequency of MAP2K1 indels in IAC, BRAF non-V600E kinase domain mutations co-occurring with TSC1 mutations were exclusively found in preinvasive lesions. Compared with EGFR L858R and exon 19 deletion, patients with preinvasive lesions harboring 20ins in either EGFR or ERBB2 were significantly younger, while those with IAC had similar age. Furthermore, our study demonstrated distinct mutational features for subtypes of oncogene mutations favored by different invasion patterns in adenocarcinomas. In conclusion, our data demonstrate distinct mutational features between preinvasive lesions and invasive tumors with MEA, suggesting the involvement of MEA in the early stages of tumorigenesis. Further pre-clinical studies are required to establish the role of these genes in the malignant transformation of LUAD.

Dataset Information

Genomic Landscape and Immune Microenvironment Features of Preinvasive and Early Invasive Lung Adenocarcinoma.

Publications

Genomic Landscape and Immune Microenvironment Features of Preinvasive and Early Invasive Lung Adenocarcinoma.

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