Single-cell and bulk transcriptome sequencing identifies two epithelial tumor cell states and refines the consensus molecular classification of colorectal cancer.
Ignasius JoanitoPratyaksha WirapatiNancy Q ZhaoZahid NawazGrace Hui Ting YeoYi Xin Fiona LeeChristine L P EngDominique Camat MacalinaoMerve KahramanHarini SrinivasanVairavan LakshmananSara VerbandtPetros K TsantoulisNicole GunnPrasanna Nori VenkateshZhong Wee PohRahul NaharHsueh Ling Janice OhJia Min LooShumei ChiaLih Feng CheowElsie CherubaMichael Thomas WongLindsay KuaClarinda ChuaAndrew NguyenJustin GolovanAnna GanWan-Jun LimYu Amanda GuoChoon Kong YapBrenda TayYourae HongDawn Qingqing ChongAik-Yong ChokWoong-Yang ParkShuting HanMei Huan ChangIsaac Seow-EnCherylin FuRonnie MathewEe-Lin TohLewis Z HongAnders Jacobsen SkanderupRamanuj DasGuptaChin-Ann Johnny OngKiat Hon LimEmile K W TanSi-Lin KooWei Qiang LeowSabine TejparShyam PrabhakarIain Beehuat TanPublished in: Nature genetics (2022)
The consensus molecular subtype (CMS) classification of colorectal cancer is based on bulk transcriptomics. The underlying epithelial cell diversity remains unclear. We analyzed 373,058 single-cell transcriptomes from 63 patients, focusing on 49,155 epithelial cells. We identified a pervasive genetic and transcriptomic dichotomy of malignant cells, based on distinct gene expression, DNA copy number and gene regulatory network. We recapitulated these subtypes in bulk transcriptomes from 3,614 patients. The two intrinsic subtypes, iCMS2 and iCMS3, refine CMS. iCMS3 comprises microsatellite unstable (MSI-H) cancers and one-third of microsatellite-stable (MSS) tumors. iCMS3 MSS cancers are transcriptomically more similar to MSI-H cancers than to other MSS cancers. CMS4 cancers had either iCMS2 or iCMS3 epithelium; the latter had the worst prognosis. We defined the intrinsic epithelial axis of colorectal cancer and propose a refined 'IMF' classification with five subtypes, combining intrinsic epithelial subtype (I), microsatellite instability status (M) and fibrosis (F).
Keyphrases
- single cell
- rna seq
- copy number
- gene expression
- high throughput
- genome wide
- end stage renal disease
- machine learning
- deep learning
- ejection fraction
- newly diagnosed
- dna methylation
- mitochondrial dna
- single molecule
- bone marrow
- induced apoptosis
- cell therapy
- oxidative stress
- patient reported outcomes
- cell proliferation
- endoplasmic reticulum stress
- patient reported
- young adults
- nucleic acid