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Proteogenomic analysis of lung adenocarcinoma reveals tumor heterogeneity, survival determinants and therapeutically-relevant pathways

ABSTRACT: To characterize the etiology of lung adenocarcinoma (LUAD) in the United States, we performed deep proteogenomic profiling of 87 tumors integrating whole genome sequencing, transcriptome sequencing, proteomics and phosphoproteomics by mass spectrometry and reverse phase protein arrays. Somatic genome signature analysis revealed three subtypes including a structurally altered subtype enriched with former smokers, genomic inversions and deletions and TP53 alteration, a transition-high subtype enriched with never-smokers, and a transversion-high enriched with current smokers. We discovered that within-tumor correlations of RNA expression and protein expression were associated with tumor purity, grade, immune cell heterogeneity, and expression subtype. We detected and independently validated RNA and protein expression signatures predicting patient survival. A greater number of proteins than RNA transcripts had association with patient survival. Integrative analysis characterized three expression subtypes with divergent mutations, proteomic regulatory networks and therapeutic vulnerabilities. This proteogenomic characterization provides a new foundation for molecularly-informed medicine in LUAD.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung, Epithelial Cell

DISEASE(S): Lung Adenocarcinoma

SUBMITTER: Thomas Conrads

LAB HEAD: Thomas P Conrads, PhD

PROVIDER: PXD036025 | Pride | 2022-11-16

REPOSITORIES: Pride

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Project description:MicroRNAs are important regulatory molecules in most eukaryotes and the identification of their mRNA targets is essential for their functional analysis. From inflorescence tissue of Arabidopsis, >28,000,000 signatures were sequenced from 5’ ends of polyadenylated products of mRNA decay. Within the set of ~27,000 transcripts included in the 3,500,000 non-redundant signatures, several previously predicted but non-validated miRNA targets were found. Like validated targets, most showed a single abundant signature at the miRNA cleavage site, particularly in libraries from a mutant deficient in the 5’ to 3’ exonuclease AtXRN4. Among the most unexpected miRNA targets discovered were miRNA precursor transcripts that are self-targeted by their own mature miRNA. Although the miRNAs of Arabidopsis have been extensively investigated, working in reverse from the cleaved targets, additional novel miRNAs were identified and validated. This deep and versatile approach will impact the study of other aspects of RNA processing beyond miRNA-target RNA pair analyses. Keywords: miRNA-target RNA pairs, Palallel analysis of RNA ends, PARE, SBS RNA from inflorescence tissue from wildtype Arabidopsis and xrn4 mutants was extracted. Following polyA RNA extraction, libraries for PARE were constructed. RNA from inflorescence tissue from wildtype Arabidopsis (Col-0), and rdr2 and dcl2,3,4 mutants was extracted. The material was submitted to Illumina and libraries were constructed for small RNAs. Individual small RNA libraries from inflorescences of Arabidopsis wildtype, rdr2, and dcl2/dcl3/dcl4 were sequenced with SBS at Illumina, Inc. The distribution of small RNA sizes in each library is in agreement with that published previously for the wild type or the respective mutants sequenced with MPSS or 454; however, the presence and abundances of some small RNAs may differ. This may be attributed to the use of different sequencing technologies with different depths, biological differences in the tissue used, or other unknown reasons. raw data requested but not provided for GSM280226 and GSM280227

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Proteogenomic analysis of lung adenocarcinoma reveals tumor heterogeneity, survival determinants and therapeutically-relevant pathways

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