Highlights d We build the genomic and transcriptomic landscape of 465 primary TNBCs d Chinese TNBC cases demonstrate more PIK3CA mutations and LAR subtype d Transcriptomic data classify TNBCs into four subtypes d Multi-omics profiling identifies potential targets within specific TNBC subtypes

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.

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As an indispensable tool for transcriptome-wide analysis of differential gene expression, RNA sequencing (RNAseq) has demonstrated great potential in clinical applications. However, the lack of multi-group RNA reference materials of biological relevance and the corresponding reference datasets for assessing the reliability of RNAseq hampers its wide clinical applications wherein the underlying biological differences among study groups are often small. As part of the Quartet Project for quality control and data integration of multiomic profiling, we established four RNA reference materials derived from immortalized B-lymphoblastoid cell lines from four members of a monozygotic twin family. Additionally, we constructed ratio-based transcriptome-wide reference datasets using multi-batch RNAseq datasets, providing "ground truth" for benchmarking. Moreover, Quartet-sample-based quality metrics were developed for assessing reliability of RNAseq technology in terms of intra-batch proficiency and cross-batch reproducibility. The small intrinsic biological differences among the Quartet samples enable sensitive assessment of performance of transcriptomic measurements. The Quartet RNA reference materials combined with the reference datasets can be served as unique resources for assessing data quality and improving reliability of transcriptomic profiling.