In the immunotherapy era, a better understanding of heterogeneity in MSI cancers is required. We evaluated gene expression profiles of MSI colorectal (CRC), gastric (GC) and endometrial cancer (EC) samples with our cell-of-origin signature (CRCassigner), which is able to classify samples in differentiated (goblet-like; CMS3), differentiating (transit-amplifying – TA; CMS2) and less differentiated/mesenchymal (stem-like; CMS4 and inflammatory; CMS1) subtypes to identify whether MSI transcriptional heterogeneity exists.
Normalised RNAseq/microarrays gene expression profiles and microsatellite status were downloaded from TCGA. CRCassigner classification of samples was performed using Pearson correlation. Samples with low classification confidence were classified as “mixed” subtype. Gene selection enrichment analysis (using published immune markers) and differential protein expression analysis (of PDL1 from Cancer Proteome Atlas data) was performed between inflammatory and goblet-like MSI samples.
The majority of MSI-H in all the 3 cancer types expressed the inflammatory profile. While in MSI-H CRC only two subtypes were present (inflammatory - 91% and goblet-like - 9%), 5 subtypes in MSI-H GC (inflammatory - 45%, goblet-like - 24%, stem-like - 21%, TA - 6%, enterocyte - 3%) and 4 subtypes in EC (inflammatory - 36%, stem-like - 36%, goblet-like - 14%, TA - 14%) were present. Inflammatory MSI tumours from all the three cancer types were significantly (p
MSI tumours are heterogeneous and can be stratified by virtue of differentiation states (or cell-of-origin) and different immune phenotypes. With further studies, this heterogeneity may help select MSI cancer patients for immune checkpoint combination therapies.
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Legal entity responsible for the study
NIHR Biomedical Research Centre at the Royal Marsden Hospital and Institute of Cancer Research, London, UK; Cancer Research UK.
A. Sadanandam: Entitled to a share of royalties received by the licensor for a patent patent number PCT/IB2013/060416. Received research funding from Bristol-Myers Squibb for pancreatic cancer. All other authors have declared no conflicts of interest.