Investigation of colorectal cancer in accordance with consensus molecular subtype classification

Shinmoto, Hiroshi; Miyamoto, Yuji; Ogawa, Katsuhiro; Yoshida, Naoya

doi:10.1002/ags3.12362

Cited by 39 publications

(31 citation statements)

References 56 publications

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“…The CMS classification system for CRC has proven effective in understanding disease prognosis and tumor biology, with distinct gene sets and oncogenic pathways significantly associated with each of the four different subtypes (CMSs) [19,20,22,60]. However, having been developed using bulk transcriptomic data, there is now increasing recognition that there are distinct contributions to bulk CMS from both tumor and non-tumor cells and that CMS may not be adequate to capture intra-tumor heterogeneity [24,[61][62][63]. Specifically, the classification of CMS4 tumors has been identified as primarily influenced by genes expressed in cancer-associated fibroblasts (CAFs) and other stromal cell subtypes [64][65][66][67].…”

Section: Discussionmentioning

confidence: 99%

Implications of Intratumor Heterogeneity on Consensus Molecular Subtype (CMS) in Colorectal Cancer

Chowdhury

Hofree

Lin

et al. 2021

Cancers

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The implications of intratumor heterogeneity on the four consensus molecular subtypes (CMS) of colorectal cancer (CRC) are not well known. Here, we use single-cell RNA sequencing (scRNASeq) to build an algorithm to assign CMS classification to individual cells, which we use to explore the distributions of CMSs in tumor and non-tumor cells. A dataset of colorectal tumors with bulk RNAseq (n = 3232) was used to identify CMS specific-marker gene sets. These gene sets were then applied to a discovery dataset of scRNASeq profiles (n = 10) to develop an algorithm for single-cell CMS (scCMS) assignment, which recapitulated the intrinsic biology of all four CMSs. The single-cell CMS assignment algorithm was used to explore the scRNASeq profiles of two prospective CRC tumors with mixed CMS via bulk sequencing. We find that every CRC tumor contains individual cells of each scCMS, as well as many individual cells that have enrichment for features of more than one scCMS (called mixed cells). scCMS4 and scCMS1 cells dominate stroma and immune cell clusters, respectively, but account for less than 3% epithelial cells. These data imply that CMS1 and CMS4 are driven by the transcriptomic contribution of immune and stromal cells, respectively, not tumor cells.

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Section: Discussionmentioning

confidence: 99%

Implications of Intratumor Heterogeneity on Consensus Molecular Subtype (CMS) in Colorectal Cancer

Chowdhury

Hofree

Lin

et al. 2021

Cancers

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“…They incorporated molecular subtyping with phenotypic signatures displayed by each subtypes to aid in disease stratification in routine pathology. Nevertheless, CMS was still limited due to the intratumoral heterogeneity (ITH) detected and unreliability in the tissue biopsy samples (43% unknown) [ 44 , 45 ]. In short, the lack of a standardized MSI-based classification system, the use of tissue biopsy samples, the presence of ITH and the variations of MSI status across different subtypes complicates CRC diagnosis and treatment.…”

Section: Pros and Cons Of Current Tissue Biopsy-based Msi Testingmentioning

confidence: 99%

Microsatellite Instability in Colorectal Cancer Liquid Biopsy—Current Updates on Its Potential in Non-Invasive Detection, Prognosis and as a Predictive Marker

et al. 2021

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Colorectal cancer (CRC) is the third most commonly-diagnosed cancer in the world and ranked second for cancer-related mortality in humans. Microsatellite instability (MSI) is an indicator for Lynch syndrome (LS), an inherited cancer predisposition, and a prognostic marker which predicts the response to immunotherapy. A recent trend in immunotherapy has transformed cancer treatment to provide medical alternatives that have not existed before. It is believed that MSI-high (MSI-H) CRC patients would benefit from immunotherapy due to their increased immune infiltration and higher neo-antigenic loads. MSI testing such as immunohistochemistry (IHC) and PCR MSI assay has historically been a tissue-based procedure that involves the testing of adequate tissue with a high concentration of cancer cells, in addition to the requirement for paired normal tissues. The invasive nature and specific prerequisite of such tests might hinder its application when surgery is not an option or when the tissues are insufficient. The application of next-generation sequencing, which is highly sensitive, in combination with liquid biopsy, therefore, presents an interesting possibility worth exploring. This review aimed to discuss the current body of evidence supporting the potential of liquid biopsy as a tool for MSI testing in CRC.

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“…The prognostic and predictive factors of CMS classes were demonstrated in retrospective analysis of multiple phase III clinical trials [8,9,[14][15][16][17][18][19]. The prognostic role of CMS classification was well established in most of the studies, with prognosis of each CMS class varying from early-stage to advanced-stage tumors [8][9][10]14,15,20].…”

Section: Introductionmentioning

confidence: 99%

APC and TP53 Mutations Predict Cetuximab Sensitivity across Consensus Molecular Subtypes

Thota

Yang

Pflieger

et al. 2021

Cancers

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Recently, it was suggested that consensus molecular subtyping (CMS) may aide in predicting response to EGFR inhibitor (cetuximab) therapies. We recently identified that APC and TP53 as two tumor suppressor genes, when mutated, may enhance cetuximab sensitivity and may represent easily measured biomarkers in tumors or blood. Our study aimed to use APC and TP53 mutations (AP) to refine the CMS classification to better predict responses to cetuximab. In total, 433 CRC tumors were classified into CMS1-4 subtypes. The cetuximab sensitivity (CTX-S) signature scores of AP vs. non-AP tumors were determined across each of the CMS classes. Tumors harboring combined AP mutations were predominantly enriched in the CMS2 class, and to a lesser degree, in the CMS4 class. On the other hand, AP mutated CRCs had significantly higher CTX-S scores compared to non-AP CRCs across all CMS classes. Similar results were also obtained in independent TCGA tumor collections (n = 531) and in PDMR PDX/PDO/PDC models (n = 477). In addition, the in vitro cetuximab growth inhibition was preferentially associated with the CMS2 cell lines harboring A/P genotypes. In conclusion, the AP mutation signature represents a convenient biomarker that refines the CMS classification to identify CRC subpopulations predicted to be sensitive to EGFR targeted therapies.

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Investigation of colorectal cancer in accordance with consensus molecular subtype classification

Cited by 39 publications

References 56 publications

Implications of Intratumor Heterogeneity on Consensus Molecular Subtype (CMS) in Colorectal Cancer

Implications of Intratumor Heterogeneity on Consensus Molecular Subtype (CMS) in Colorectal Cancer

Microsatellite Instability in Colorectal Cancer Liquid Biopsy—Current Updates on Its Potential in Non-Invasive Detection, Prognosis and as a Predictive Marker

APC and TP53 Mutations Predict Cetuximab Sensitivity across Consensus Molecular Subtypes

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