Genomic and immune profiling of pre-invasive lung adenocarcinoma

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.

Fig. 1

Somatic alterations in pre-invasive and invasive lung adenocarcinomas. a Co-mutation plots for AIS/MIA and b LUAD. Stars indicate significantly mutated genes in each group. c Lung cancer genes with focal amplification in AIS/MIA and LUAD. d Somatic alterations with higher frequencies in LUAD, compared to AIS and MIA. Color bar represents log₁₀-transformed p value calculated from two-sided Fisher’s exact test. Source data are provided as a source data file.

Fig. 2

Correlation of somatic alterations with genomic features. TP53, EGFR, RB1 mutations and EGFR amplification in correlation with a TMB and APOBEC signature, and b arm and focal CNA. Student’s t test was used to calculate the log₁₀-transformed p value. Samples in all stages were included to calculate the alteration frequency. Source data are provided as a source data file.

Fig. 3

Tumor immune environment in association with arm-level CNA. a Frequency of loss of HLA heterozygosity and the co-occurrence of HLA LOH with 6p loss. Significantly more HLA LOH events are found in the LUAD group compared to the AIS/MIA group. b Comparison of inferred T cell infiltration in FUSCC LUAD samples and c leukocyte infiltration in TCGA LUAD samples with 6p CNA loss, gain, or no change. P values are calculated from Mann–Whitney U test. Significantly decreased level of T cell or leukocyte infiltrations are found in 6p gain samples compared to 6p neutral samples. In the box plots, the upper and lower hinges represent the first and third quartile, the whiskers span the first and third quartile, and center lines represent the median. d Correlation of arm-level CNA with leukocyte infiltration for the TCGA LUAD samples. P values are calculated from multivariate linear regression, while each arm is assigned 1 if gained, −1 if lost and 0 if unchanged, and adding the aneuploidy score and TMB as covariates. Source data are provided as a source data file.