Abstract

Adenocarcinoma in situ and minimally invasive adenocarcinoma are the pre-invasive forms of lung adenocarcinoma. The genomic and immune profiles of these lesions are poorly understood. Here we report exome and transcriptome sequencing of 98 lung adenocarcinoma precursor lesions and 99 invasive adenocarcinomas. We have identified EGFR, RBM10, BRAF, ERBB2, TP53, KRAS, MAP2K1 and MET as significantly mutated genes in the pre/minimally invasive group. Classes of genome alterations that increase in frequency during the progression to malignancy are revealed. These include mutations in TP53, arm-level copy number alterations, and HLA loss of heterozygosity. Immune infiltration is correlated with copy number alterations of chromosome arm 6p, suggesting a link between arm-level events and the tumor immune environment.

Highlights

  • Adenocarcinoma in situ and minimally invasive adenocarcinoma are the pre-invasive forms of lung adenocarcinoma

  • We identified eight significantly mutated genes in adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) specimens, including EGFR, RBM10, BRAF, ERBB2, TP53, KRAS, MAP2K1, and MET, all previously reported as recurrently mutated in Lung adenocarcinoma (LUAD) from The Cancer Genome Atlas (TCGA) cohort[11,12]

  • EGFR, TP53, RB1, and KRAS were significantly mutated in the tested LUAD cases (Fig. 1a, b)

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Summary

Introduction

Adenocarcinoma in situ and minimally invasive adenocarcinoma are the pre-invasive forms of lung adenocarcinoma. The pre-invasive stages of LUAD, such as adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA), are associated with a nearly 100% survival rate, after surgical resection[3,4,5]. Some focused studies have identified mutations in lung cancer drivers in AIS and MIA7–10, there remains a lack of deep insight into the molecular events driving progression of these lesions to invasive LUAD. To address this gap in our knowledge of AIS/MIA pathogenesis, we undertook a systematic investigation of the genomic and immune profiles of pre/minimally invasive lung lesions. By comparing the genomic landscapes of the preinvasive and invasive samples, we suggest the potential molecular events underlying the invasiveness of LUAD

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