The consensus molecular subtypes of colorectal cancer

Guinney, Justin; Dienstmann, Rodrigo; Wang, Xin; Reyniès, Aurélien de; Schlicker, Andreas; Soneson, Charlotte; Marisa, Laëtitia; Roepman, Paul; Nyamundanda, Gift; Angelino, Paolo; Bot, Brian M.; Morris, Jeffrey S.; Simón, Iris; Gerster, Sarah; Fessler, Evelyn; Melo, Felipe de Sousa e; Missiaglia, Edoardo; Ramay, Hena R.; Barras, David; Homicsko, Krisztian; Maru, Dipen M.; Manyam, Ganiraju C.; Broom, Bradley M.; Boige, Valérie; Pérez-Villamil, Beatriz; Laderas, Ted; Salazar, Ramón; Gray, Joe W.; Hanahan, Douglas; Tabernero, Josep; Bernards, René; Friend, Stephen H.; Laurent‐Puig, Pierre; Medema, Jan Paul; Sadanandam, Anguraj; Wessels, Lodewyk; Delorenzi, Mauro; Kopetz, Scott; Vermeulen, Louis; Tejpar, Sabine

doi:10.1038/nm.3967

Cited by 3,969 publications

(5,370 citation statements)

References 74 publications

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“…The recent definition of four CMS groups has provided a rational framework to refine classification and stratification of CRC (Guinney et al ., 2015). In our datasets, we observe strong correlation between loss of CDX2 and the CMS1 and CMS4 subtypes, in accordance with the strong association of CDX2 loss with MSI (CMS1) and worse prognosis (CMS4), and loss of differentiation, a hallmark of CDX2 loss in cancer (Suh et al ., 1994).…”

Section: Discussionmentioning

confidence: 99%

“…The data have partly been published ( n = 236; NCBI's Gene Expression Omnibus (GEO) accession numbers http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE24550, http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE29638, http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE69182, and http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE79959), and the remaining data will be published elsewhere (Sveen et al ., manuscript). The samples were classified according to CMS using the random forest predictor implemented in the R library CMSclassifier with a default posterior probability of 0.5 (Guinney et al ., 2015). …”

Section: Methodsmentioning

confidence: 99%

“…Recently, four gene expression‐based consensus molecular subtypes (CMS) of CRC were defined (Guinney et al ., 2015). This classification has prognostic value independent of cancer stage, recognizing a mesenchymal subtype (CMS4) associated with poor prognosis and poor response to standard oncological treatment with chemotherapy (Song et al ., 2016; Trinh et al ., 2017).…”

Section: Introductionmentioning

confidence: 99%

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Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer

et al. 2018

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We aimed to refine the value of CDX2 as an independent prognostic and predictive biomarker in colorectal cancer (CRC) according to disease stage and chemotherapy sensitivity in preclinical models. CDX2 expression was evaluated in 1045 stage I–IV primary CRCs by gene expression (n = 403) or immunohistochemistry (n = 642) and in relation to 5‐year relapse‐free survival (RFS), overall survival (OS), and chemotherapy. Pharmacogenomic associations between CDX2 expression and 69 chemotherapeutics were assessed by drug screening of 35 CRC cell lines. CDX2 expression was lost in 11.6% of cases and showed independent poor prognostic value in multivariable models. For individual stages, CDX2 was prognostic only in stage IV, independent of chemotherapy. Among stage I–III patients not treated in an adjuvant setting, CDX2 loss was associated with a particularly poor survival in the BRAF‐mutated subgroup, but prognostic value was independent of microsatellite instability status and the consensus molecular subtypes. In stage III, the 5‐year RFS rate was higher among patients with loss of CDX2 who received adjuvant chemotherapy than among patients who did not. The CDX2‐negative cell lines were significantly more sensitive to chemotherapeutics than CDX2‐positive cells, and the multidrug resistance genes MDR1 and CFTR were significantly downregulated both in CDX2‐negative cells and in patient tumors. Loss of CDX2 in CRC is an adverse prognostic biomarker only in stage IV disease and appears to be associated with benefit from adjuvant chemotherapy in stage III. Early‐stage patients not qualifying for chemotherapy might be reconsidered for such treatment if their tumor has loss of CDX2 and mutated BRAF.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer

et al. 2018

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“…Furthermore, it would be interesting to investigate if there is a relationship and/or synergism with mutational status of K‐ras, as this is already associated with CAT in colorectal cancer 43. Finally, future work may demonstrate that there is a link between the expression profiles in CAT and different subtypes of colon cancer,61 as Magnus et al. previously reported glioblastoma subtype‐specific phenotypes and altered coagulation‐related genes.…”

Section: Unbiased Screen For Risk Factors In Catmentioning

confidence: 96%

Cancer‐associated thrombosis: The search for the holy grail continues

Ünlü

Versteeg

2018

Research and Practice in Thrombosis and Haemostasis

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Cancer patients have an increased risk of developing venous thromboembolism (VTE), a condition that is associated with increased morbidity and mortality. Although risk assessment tools have been developed, it is still very challenging to predict which cancer patients will suffer from VTE. The scope of this review is to summarize and discuss studies focusing on the link between genetic alterations and risk of cancer‐associated thrombosis (CAT). Thus far, classical risk factors that contribute to VTE have been tried as risk factors of CAT, with low success. In support, hypercoagulant plasma profiles in patients with CAT differ from those with only VTE, indicating other risk factors that contribute to VTE in cancer. As germline mutations do not significantly contribute to elevated risk of VTE, somatic mutations in tumors may significantly associate with and contribute to CAT. As it is very time‐consuming to investigate each and every mutation, an unbiased approach is warranted. In this light we discuss our own recent unbiased proof‐of‐principle study using RNA sequencing in isolated colorectal cancer cells. Our work has uncovered candidate genes that associate with VTE in colorectal cancer, and these gene profiles associated with VTE more significantly than classical parameters such as platelet counts, D‐dimer, and P‐selectin levels. Genes associated with VTE could be linked to pathways being involved in coagulation, inflammation and methionine degradation. We conclude that tumor cell‐specific gene expression profiles and/or mutational status has superior potential as predictors of VTE in cancer patients.

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“…This novel classification takes into account various molecular and histological features such as microsatellite instability, immune activation status, morphological appearance (epithelial vs. mesenchymal), activation of Wnt, c‐Myc and TGF‐β signaling circuits, and metabolic dysregulation. In addition, prototypical CRC genes such as TP53 , APC , CTNNB1 , SMAD4 , PI3KCA , NRAS , PTEN , KRAS, and BRAF , which are not strictly associated with the CMS classification system 17, further diversify the clinical presentation spectrum of CRC. Nevertheless, particular aberrations can provide a basis for personalized treatment decisions, such as activating mutations in KRAS , which serve as contraindications for epidermal growth factor receptor (EGFR)‐targeted therapy 18.…”

Section: Stemness Programs and Emt Govern Crc Heterogeneity And Progrmentioning

confidence: 99%

Concise Review: Aggressive Colorectal Cancer: Role of Epithelial Cell Adhesion Molecule in Cancer Stem Cells and Epithelial-to-Mesenchymal Transition

Boesch

Spizzo

Seeber

2018

Stem Cells Translational Medicine

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Colorectal cancer (CRC) is one of the most common malignancies worldwide. In spite of various attempts to ameliorate outcome by escalating treatment, significant improvement is lacking particularly in the adjuvant setting. It has been proposed that cancer stem cells (CSCs) and the epithelial‐to‐mesenchymal transition (EMT) are at least partially responsible for therapy resistance in CRC. The epithelial cell adhesion molecule (EpCAM) was one of the first CSC antigens to be described. Furthermore, an EpCAM‐specific antibody (edrecolomab) has the merit of having launched the era of monoclonal antibody treatment in oncology in the 1990s. However, despite great initial enthusiasm, monoclonal antibody treatment has not proven successful in the adjuvant treatment of CRC patients. In the meantime, new insights into the function of EpCAM in CRC have emerged and new drugs targeting various epitopes have been developed. In this review article, we provide an update on the role of EpCAM in CSCs and EMT, and emphasize the potential predictive selection criteria for novel treatment strategies and refined clinical trial design. stem cells translational medicine 2018;7:495–501

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The consensus molecular subtypes of colorectal cancer

Cited by 3,969 publications

References 74 publications

Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer

Prognostic, predictive, and pharmacogenomic assessments of CDX2 refine stratification of colorectal cancer

Cancer‐associated thrombosis: The search for the holy grail continues

Concise Review: Aggressive Colorectal Cancer: Role of Epithelial Cell Adhesion Molecule in Cancer Stem Cells and Epithelial-to-Mesenchymal Transition

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