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Tracing OncogeneRearrangements in the Mutational History of Lung Adenocarcinoma
Lee JJ, Park S,Park H, Kim S, Lee J, et.al
Cell.2019
Lungadenocarcinoma (LADC) is the most common type of lung cancer, which is theleading cause of cancer-related death worldwide. Mutational processes givingrise to lung adenocarcinomas (LADCs) in non-smokers remain elusive. The authorsanalyzed 138 LADC whole genomes, including 83 cases with minimal contributionof smoking-associated mutational signature. Complex genomic rearrangements,including chromothripsis and chromoplexy, generated 74% of known fusiononcogenes, including EML4-ALK, CD74-ROS1, and KIF5B-RET. Fusions often arise inearly decades of life, leaving long latency to diagnosis and SETD2 inactivationis cooperative with fusion oncogenes in TP53-wild-type LADCs. Their study highlightsLADC oncogenesis driven by endogenous mutational processes and demonstratesthat driver fusion oncogenes in human lung adenocarcinoma of non-smokers are generatedfrom complex genomic rearrangements and often arise in early decades of life,long before diagnosable disease.
https://www.cell.com/cell/fulltext/S0092-8674(19)30511-2
High-throughput single-cellChIP-seq identifies heterogeneity of chromatin states in breast cancer
GrosselinK, Durand A, Marsolier J, Poitou A, Marangoni E, Nemati F,Dahmani A, et.al
NatGenet. 2019
The emergence ofresistance to chemotherapy and targeted therapies is a major challenge for thetreatment of cancer. Recent studies, using single-cell RNA sequencing(scRNA-seq), indicate that emergence of transcriptional subclones on treatmentmay account for the adaptation of cancer cells to therapeutic pressure.Modulation of chromatin structure via histone modification is a majorepigenetic mechanism and regulator of gene expression. Here the authorsdescribe a high-throughput droplet microfluidics platform to profile chromatinlandscapes of thousands of cells at single-cell resolution. Usingpatient-derived xenograft models of acquired resistance to chemotherapy andtargeted therapy in breast cancer, they found that a subset of cells withinuntreated drug-sensitive tumors share a common chromatin signature with resistantcells, undetectable using bulk approaches. Loss of repressive chromatin markssuch as H3K27me3 could change the chromatin to a permissive state and mightcorrespond to a priming event preceding changes in transcription. In summary, theirscChIP-seq system can probe the role of heterogeneity and dynamics of chromatinstates within any complex biological system; in addition to cancer, it can beapplied to other diseases and healthy systems, notably to study cellulardifferentiation and development.
https://www.nature.com/articles/s41588-019-0424-9
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