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A panel of DNA methylation markers for the classification of consensus molecular subtypes 2 and 3 in patients with colorectal cancer

ABSTRACT: INTRODUCTION. Consensus molecular subtypes (CMSs) can guide precision treatment of colorectal cancer (CRC). Currently available dedicated assays can identify CMS1 and CMS4 cases very well while a dedicated test to distinguish CMS2 and 3 is lacking. This study aimed to identify a panel of methylation markers to distinguish between CMS2 and 3 in patients with CRC. METHODS. Fresh-frozen tumor tissue of 239 patients with stage I-III CRC who underwent surgery between 2007 and 2014 was included. CMS classification was performed on RNA-seq data using the single-sample prediction parameter from the “CMSclassifier” package. Methylation profiles were gathered/obtained using the Infinium HumanMethylation450 BeadChip for 146 samples (124 CMS2 and 22 CMS3) . We performed adaptive group-regularised logistic ridge regression with post-hoc group-weighted elastic net marker selection to build prediction models for classification of CMS2 and CMS3 based on 15, 10 or 5 methylation markers. Data from the Cancer Genome Atlas project was used for independent validation of our obtained models. RESULTS. Overall methylation profiles differed between CMS2 and CMS3 tumors. Group-regularisation of the methylation probes was done based on their location either relative to a CpG island or relative to a gene present in the CMS classifier. This resulted in two different prediction models and subsequently different marker panels. For both panels, even when using only 5 markers, the sensitivity, specificity, and accuracy were >90%. Independent validation of the fixed models in TCGA data showed comparable performances. CONCLUSION. Our highly sensitive and specific methylation marker panel can be used to distinguish CMS2 and 3. This enables future development of a qPCR DNA methylation assay in patients with CRC to provide a specific and non-invasive classification tool.

ORGANISM(S): Homo sapiens

PROVIDER: GSE164811 | GEO | 2021/12/08

REPOSITORIES: GEO

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Project description:Colorectal cancer (CRC) is stratified into four consensus molecular subtypes (CMS1-4). CMS3 represents the metabolic subtype, but its wiring remains largely undefined. To identify the underlying tumorigenesis of CMS3, organoids derived from 16 genetically engineered mouse models are analyzed. Upon in vitro Cre-recombinase activation, transformation is established and transcriptional profiling reveals that distinct CMSs (CMS2-4) are modeled with different organoids. CMS3-like, metabolic signature-positive, organoids are induced by KRAS mutations. Interestingly, metabolic signatures are subsequently shown to result from enterocyte-like differentiation both in organoids and human cancers. Further analysis reveals carbamoyl-phosphate synthase 1 (CPS1) and sucrase-isomaltase (SI) as signature proteins. More importantly, CPS1 is crucial for de novo pyrimidine synthesis in CMS3 and its inhibition targets proliferation and stemness, facilitating enterocyte-like differentiation, while CMS2 and CMS4 models are not affected. Our data point to an enterocyte-like differentiation of CMS3 CRCs and reveal a selective vulnerability of this subtype through CPS1 inhibition. To investigate the effect of single and combined mutations in colon and small intestine of mouse models, we have generated a large set of organoids across 16 different genotypes zooming in on microsatellite stable CRC (CMS2-4). This set of organoids includes villinCreER Apcfl/fl (A), villinCreER Apcfl/fl Trp53fl/fl (AP), villinCreER Apcfl/fl Trp53R172H/fl (AP2), villinCreER Apcfl/fl KrasG12D/+ Trp53fl/fl (AKP), villinCreER Apcfl/fl KrasG12D/+ Trp53fl/fl Smad4fl/+ (AKPS), villinCreER KrasG12D/+ (K), villinCreER KrasG12D/+ Trp53fl/fl (KP), villinCreER KrasG12D/+ Trp53fl/fl Rosa26N1ind/+ (KPN), villinCreER BrafV600E/+ Trp53fl/fl Rosa26N1ind/+ (BPN), villinCreER BrafV600E/+ Trp53fl/fl Rosa26N1ind/+ Alk5fl/fl (BPNA2), villinCreER Apcfl/fl KrasG12D/+ (AK), villinCreER Apcfl/fl KrasG12D/+ Trp53R172H/fl (AKP2), villinCreER Apcfl/fl KrasG12D/+ Trp53fl/fl Rosa26N1ind/+ (AKPN), villinCreER Apcfl/fl Trp53fl/fl Rosa26N1ind/+ (APN), villinCreER BrafV600E/+ Trp53fl/fl (BP), and villinCreER KrasG12D/+ Trp53fl/fl Rosa26N1ind/+ Alk5fl/fl (KPNA2).

Project description:The Colorectal Cancer Subtyping Consortium established four Consensus Molecular Subtypes (CMS) in colorectal cancer: CMS1 (microsatellite-instability [MSI], Immune), CMS2 (Canonical, epithelial), CMS3 (Metabolic), and CMS4 (Mesenchymal). However, in the clinical practice only patients with MSI tumors have experienced a change in the management of their disease. Proteomics has experimented significant technical advances with the implementation of data-independent acquisition (DIA) as the gold-standard for the analysis of large cohort of patients, providing a dynamic framework of the disease and direct information about the effectors of the biological processes. The aim of this study is the characterization of the proteome of colon cancer CMS by DIA–based proteomics and expand the utility of CMS in the clinical practice. CMS were assigned and differences in the protein profiles between CMS were defined and evaluated using a Systems Biology approach. One hundred fifty-eight paraffin samples from colon cancer patients with stage II-III disease treated with adjuvant chemotherapy were analyzed. After applying quality criteria, 1,940 identified and quantified proteins were used for the analyses. CMS1 had an overexpression of proteins related to immune system, specifically neutrophils, phagocytosis and antimicrobial response, and a glycolytic profile. CMS3 had an overexpression of proteins related to metabolic pathways, while CMS2 showed an intermediate protein profile between CMS1-3, but with a characteristic profile regarding translation, adhesion, and mitochondria and metabolism biological processes. Two proteomics subtypes within CMS2 with different protein characteristics and prognosis were identified. CMS4 was the most different group with an overexpression of proteins related to angiogenesis, extracellular matrix, focal adhesion, and complement activation. In conclusion, DIA LC-MS/MS proteomics characterization of CRC CMS established new features for each CMS, such as a higher mitochondrial activity in CMS2 or an overexpression of proteins related to phagocytosis in CMS1, but also confirmed previous findings established using transcriptomics such as an overexpression of proteins related to angiogenesis in CMS4. In this CMS4 subtype, several adhesion-related proteins suggested a high metastatic profile and a possible chemoresistance that may explain the worse prognosis of this subtype. CMS1 was characterized as immune and glycolitic-active subtype, being the combination of immunotherapy and glycolytic inhibitors a possible therapeutic strategy. Additionally, two different CMS2 proteomics-based subtypes with different prognosis and possible therapeutic targets were identified. These proccesses could be used as therapeutic targets in the future.

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A panel of DNA methylation markers for the classification of consensus molecular subtypes 2 and 3 in patients with colorectal cancer

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