scholarly journals Investigation of colorectal cancer in accordance with consensus molecular subtype classification

2020 ◽  
Vol 4 (5) ◽  
pp. 528-539
Author(s):  
Hiroshi Sawayama ◽  
Yuji Miyamoto ◽  
Katsuhiro Ogawa ◽  
Naoya Yoshida ◽  
Hideo Baba
Keyword(s):  
Colorectal Cancer ◽  
Molecular Subtype ◽  
Subtype Classification ◽  
Consensus Molecular Subtype

scholarly journals Consensus molecular subtype classification of colorectal adenomas

2018 ◽  
Vol 246 (3) ◽  
pp. 266-276 ◽  
Author(s):  
Malgorzata A Komor ◽  
Linda JW Bosch ◽  
Gergana Bounova ◽  
Anne S Bolijn ◽  
Pien M Delis-van Diemen ◽  
...  
Keyword(s):  
Molecular Subtype ◽  
Colorectal Adenomas ◽  
Subtype Classification ◽  
Consensus Molecular Subtype

scholarly journals Human Colorectal Cancer from the Perspective of Mouse Models

Genes ◽  
2019 ◽  
Vol 10 (10) ◽  
pp. 788 ◽  
Author(s):  
Monika Stastna ◽  
Lucie Janeckova ◽  
Dusan Hrckulak ◽  
Vitezslav Kriz ◽  
Vladimir Korinek
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Mouse Models ◽  
Intracellular Signaling ◽  
Transforming Growth Factor ◽  
Molecular Subtype ◽  
Transforming Growth Factor Β ◽  
Dna Mismatch ◽  
Individual Mouse ◽  
Consensus Molecular Subtype

Colorectal cancer (CRC) is a heterogeneous disease that includes both hereditary and sporadic types of tumors. Tumor initiation and growth is driven by mutational or epigenetic changes that alter the function or expression of multiple genes. The genes predominantly encode components of various intracellular signaling cascades. In this review, we present mouse intestinal cancer models that include alterations in the Wnt, Hippo, p53, epidermal growth factor (EGF), and transforming growth factor β (TGFβ) pathways; models of impaired DNA mismatch repair and chemically induced tumorigenesis are included. Based on their molecular biology characteristics and mutational and epigenetic status, human colorectal carcinomas were divided into four so-called consensus molecular subtype (CMS) groups. It was shown subsequently that the CMS classification system could be applied to various cell lines derived from intestinal tumors and tumor-derived organoids. Although the CMS system facilitates characterization of human CRC, individual mouse models were not assigned to some of the CMS groups. Thus, we also indicate the possible assignment of described animal models to the CMS group. This might be helpful for selection of a suitable mouse strain to study a particular type of CRC.

scholarly journals Stratified analysis reveals chemokine-like factor (CKLF) as a potential prognostic marker in the MSI-immune consensus molecular subtype CMS1 of colorectal cancer

Oncotarget ◽  
2016 ◽  
Vol 7 (24) ◽  
pp. 36632-36644 ◽  
Author(s):  
Philip D. Dunne ◽  
Paul G. O’Reilly ◽  
Helen G. Coleman ◽  
Ronan T. Gray ◽  
Daniel B. Longley ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Prognostic Marker ◽  
Molecular Subtype ◽  
Consensus Molecular Subtype ◽  
Stratified Analysis

scholarly journals Bi-clustering based biological and clinical characterization of colorectal cancer in complementary to CMS classification

2018 ◽  
Author(s):  
Sha Cao ◽  
Wennan Chang ◽  
Changlin Wan ◽  
Yong Zhang ◽  
Jing Zhao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Large Scale ◽  
Molecular Subtype ◽  
Resistance Mechanisms ◽  
Low Rank ◽  
Data Sets ◽  
Alternative Drug ◽  
Transcriptomics Data ◽  
Consensus Molecular Subtype

In light of the marked differences in the intrinsic biological underpinnings and prognostic outcomes among different subtypes, Consensus Molecular Subtype (CMS) classification provides a new taxonomy of colorectal cancer (CRC) solely based on transcriptomics data and has been accepted as a standard rule for CRC stratification. Even though CMS was built on highly cancer relevant features, it suffers from limitations in capturing the promiscuous mechanisms in a clinical setting. There are at least two facts about using transcriptomic data for prognosis prediction: the engagement of genes or pathways that execute the clinical response pathway are highly dynamic and interactive with others; and a predefined patient stratification not only largely decrease the statistical analysis power, but also excludes the fact that clusters of patients that confer similar clinical outcomes may or may not overlap with a pre-defined subgrouping. To enable a flexible and prospective stratified exploration, we here present a novel computational framework based on bi-clustering aiming to identify gene regulatory mechanisms associated with various biological, clinical and drug-resistance features, with full recognition of the transiency of transcriptional regulation and complicacies of patients subgrouping with regards to different biological and clinical settings. Our analysis on multiple large scale CRC transcriptomics data sets using a bi-clustering based formulation suggests that the detected local low rank modules can not only generate new biological understanding coherent to CMS stratification, but also identify predictive markers for prognosis that are general to CRC or CMS dependent, as well as novel alternative drug resistance mechanisms. Our key results include: (1) a comprehensive annotation of the local low rank module landscape of CRC; (2) a mechanistic relationship between different clinical subtypes and outcomes, as well as their characteristic biological underpinnings, visible through a novel consensus map; and (3) a few (novel) resistance mechanisms of Oxaliplatin, 5-Fluorouracil, and the FOLFOX therapy are revealed, some of which are validated on independent datasets.

scholarly journals A pre-existing population of ZEB2+ quiescent cells with stemness and mesenchymal features dictate chemoresistance in colorectal cancer

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Federica Francescangeli ◽  
Paola Contavalli ◽  
Maria Laura De Angelis ◽  
Silvia Careccia ◽  
Michele Signore ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Stem Cell ◽  
Molecular Subtype ◽  
Cancer Prognosis ◽  
Mesenchymal Transition ◽  
Tumor Xenografts ◽  
Dismal Prognosis ◽  
Large Patient ◽  
Slow Cycling ◽  
Consensus Molecular Subtype

Abstract Background Quiescent/slow cycling cells have been identified in several tumors and correlated with therapy resistance. However, the features of chemoresistant populations and the molecular factors linking quiescence to chemoresistance are largely unknown. Methods A population of chemoresistant quiescent/slow cycling cells was isolated through PKH26 staining (which allows to separate cells on the basis of their proliferation rate) from colorectal cancer (CRC) xenografts and subjected to global gene expression and pathway activation analyses. Factors expressed by the quiescent/slow cycling population were analyzed through lentiviral overexpression approaches for their ability to induce a dormant chemoresistant state both in vitro and in mouse xenografts. The correlation between quiescence-associated factors, CRC consensus molecular subtype and cancer prognosis was analyzed in large patient datasets. Results Untreated colorectal tumors contain a population of quiescent/slow cycling cells with stem cell features (quiescent cancer stem cells, QCSCs) characterized by a predetermined mesenchymal-like chemoresistant phenotype. QCSCs expressed increased levels of ZEB2, a transcription factor involved in stem cell plasticity and epithelial-mesenchymal transition (EMT), and of antiapototic factors pCRAF and pASK1. ZEB2 overexpression upregulated pCRAF/pASK1 levels resulting in increased chemoresistance, enrichment of cells with stemness/EMT traits and proliferative slowdown of tumor xenografts. In parallel, chemotherapy treatment of tumor xenografts induced the prevalence of QCSCs with a stemness/EMT phenotype and activation of the ZEB2/pCRAF/pASK1 axis, resulting in a chemotherapy-unresponsive state. In CRC patients, increased ZEB2 levels correlated with worse relapse-free survival and were strongly associated to the consensus molecular subtype 4 (CMS4) characterized by dismal prognosis, decreased proliferative rates and upregulation of EMT genes. Conclusions These results show that chemotherapy-naive tumors contain a cell population characterized by a coordinated program of chemoresistance, quiescence, stemness and EMT. Such population becomes prevalent upon drug treatment and is responsible for chemotherapy resistance, thus representing a key target for more effective therapeutic approaches.

scholarly journals The role of PDGFRA as a therapeutic target in young colorectal cancer patients

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Tae Won Kim ◽  
Hye Kyung Hong ◽  
Chung Lee ◽  
Sunmin Kim ◽  
Woo Yong Lee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Subtype ◽  
Age Groups ◽  
Young Patients ◽  
Growth Factor Receptor ◽  
Predictive Biomarker ◽  
Molecular Characteristics ◽  
Novel Therapeutic Strategies ◽  
Consensus Molecular Subtype

Abstract Background Young patients with colorectal cancer (CRC) exhibit poor prognoses compared to older patients due to the difficulty in early diagnosis and treatment. However, the underlying molecular characteristics are still unclear. Methods We conducted a comprehensive analysis of 49 CRC patients without hereditary CRC using the whole-exome and RNA sequencing with tumor and matched normal samples. A total of 594 TCGA samples and 4 patient-derived cells were utilized for validation. Results Consensus molecular subtype 4 (CMS4) (53.85%) and CMS2 (38.46%) were enriched in the young (≤ 40 years) and old (> 60 years) age groups, respectively. A CMS4-associated gene, platelet-derived growth factor receptor α (PDGFRA), was significantly upregulated in young patients with CRC (FC = 3.21, p = 0.0001) and was negatively correlated with age (p = 0.0001, R = − 0.526). Moreover, PDGFRA showed a positive co-expression with metastasis-related genes in young CRC patients. In vitro validation confirmed that young patient-derived cells (PDCs) showed an enriched expression of PDGFRA compared to old PDCs and a reduced proliferation rate by knockdown of PDGFRA. Furthermore, young CRC patients were more sensitive to regorafenib, a PDGFRA-targeting drug, than old CRC patients. Conclusions Our study suggests that CRC in young patients is associated with CMS4 and PDGFRA. In addition, PDGFRA may serve potential of novel therapeutic strategies and represent a predictive biomarker of response to regorafenib for young CRC patients.

scholarly journals Impact of Consensus Molecular Subtype on Survival in Patients With Metastatic Colorectal Cancer: Results From CALGB/SWOG 80405 (Alliance)

2019 ◽  
Vol 37 (22) ◽  
pp. 1876-1885 ◽  
Author(s):  
Heinz-Josef Lenz ◽  
Fang-Shu Ou ◽  
Alan P. Venook ◽  
Howard S. Hochster ◽  
Donna Niedzwiecki ◽  
...  
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
Molecular Subtype ◽  
Progression Free Survival ◽  
Classification Systems ◽  
Phase Iii ◽  
Primary Tumors ◽  
Phase Iii Trial ◽  
Consensus Molecular Subtype ◽  
Predictive And Prognostic Value

PURPOSE To determine the predictive and prognostic value of the consensus molecular subtypes (CMSs) of colorectal cancer (CRC) that represent a merging of gene expression–based features largely in primary tumors from six independent classification systems and provide a framework for capturing the intrinsic heterogeneity of CRC in patients enrolled in CALGB/SWOG 80405. PATIENTS AND METHODS CALGB/SWOG 80405 is a phase III trial that compared the addition of bevacizumab or cetuximab to infusional fluorouracil, leucovorin, and oxaliplatin or fluorouracil, leucovorin, and irinotecan as first-line treatment of advanced CRC. We characterized the CMS classification using a novel NanoString gene expression panel on primary CRCs from 581 patients enrolled in this study to assess the prognostic and predictive value of CMSs in these patients. RESULTS The CMSs are highly prognostic for overall survival (OS; P < .001) and progression-free survival (PFS; P < .001). Furthermore, CMSs were predictive for both OS ( P for interaction < .001) and PFS ( P for interaction = .0032). In the CMS1 cohort, patients treated with bevacizumab had a significantly longer OS than those treated with cetuximab ( P < .001). In the CMS2 cohort, patients treated with cetuximab had a significantly longer OS than patients treated with bevacizumab ( P = .0046). CONCLUSION These findings highlight the possible clinical utility of CMSs and suggests that refinement of the CMS classification may provide a path toward identifying patients with metastatic CRC who are most likely to benefit from specific targeted therapy as part of the initial treatment.

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