Long-read sequencing for non-small-cell lung cancer genomes.
Yoshitaka SakamotoLiu XuMasahide SekiToshiyuki T YokoyamaMasahiro KasaharaYukie KashimaAkihiro OhashiYoko ShimadaNoriko MotoiKatsuya TsuchiharaSusumu S KobayashiTakashi KohnoYuichi ShiraishiAyako SuzukiYutaka SuzukiPublished in: Genome research (2020)
Here, we report the application of a long-read sequencer, PromethION, for analyzing human cancer genomes. We first conducted whole-genome sequencing on lung cancer cell lines. We found that it is possible to genotype known cancerous mutations, such as point mutations. We also found that long-read sequencing is particularly useful for precisely identifying and characterizing structural aberrations, such as large deletions, gene fusions, and other chromosomal rearrangements. In addition, we identified several medium-sized structural aberrations consisting of complex combinations of local duplications, inversions, and microdeletions. These complex mutations occurred even in key cancer-related genes, such as STK11, NF1, SMARCA4, and PTEN The biological relevance of those mutations was further revealed by epigenome, transcriptome, and protein analyses of the affected signaling pathways. Such structural aberrations were also found in clinical lung adenocarcinoma specimens. Those structural aberrations were unlikely to be reliably detected by conventional short-read sequencing. Therefore, long-read sequencing may contribute to understanding the molecular etiology of patients for whom causative cancerous mutations remain unknown and therapeutic strategies are elusive.
Keyphrases
- copy number
- single molecule
- single cell
- signaling pathway
- papillary thyroid
- end stage renal disease
- genome wide
- pi k akt
- endothelial cells
- chronic kidney disease
- dna methylation
- ejection fraction
- newly diagnosed
- rna seq
- cell proliferation
- oxidative stress
- squamous cell
- gene expression
- peritoneal dialysis
- immune response
- lymph node metastasis
- young adults
- toll like receptor
- patient reported outcomes
- protein protein