Cited by 677Colorectal Cancer Treatments and StudiesGenetic factors in colorectal cancerColorectal Cancer Surgical Treatments

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From tumour heterogeneity to advances in precision treatment of colorectal cancer

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Punt, Cornelis J. A., Koopman, Miriam, Vermeulen, Louis·2017·Nature Reviews Clinical Oncology

DOI 10.1038/nrclinonc.2016.171

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Abstract

In recent years, the high heterogeneity of colorectal cancer (CRC) has become evident. Hence, biomarkers need to be developed that enable the stratification of patients with CRC into different prognostic subgroups and in relation to response to therapies, according to the distinctive tumour biology. Currently, only RAS-mutation status is used routinely as a negative predictive marker to avoid treatment with anti-EGFR agents in patients with metastatic CRC, and mismatch-repair status can guide the use of adjuvant chemotherapy in patients with early stage colon cancer. Advances in molecular biology over the past decade have enabled a better understanding of the development of CRC, as well as the more-precise use of innovative targeted therapies for this disease, and include three fundamental achievements. First, the availability of large databases to capture and store the genomic landscape of patients with CRC, providing information on the genes that are frequently deregulated in CRC. Second, the possibility of using gene-expression profiling to differentiate the subtypes of CRC into prognostic groups. Third, results from highly sensitive next-generation sequencing analyses have led to an appreciation of the extensive intratumoural heterogeneity of CRC. Herein, we discuss these advances and place them into the clinical context, and present the novel targets and therapeutic opportunities that are on the horizon.

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Hypoxia‐Responsive Platinum Supernanoparticles for Urinary Microfluidic Monitoring of Tumors
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Systematic literature review and network meta-analysis of pembrolizumab versus other interventions for previously untreated, unresectable or metastatic, MSI-high or MMR-deficient CRC
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BackgroundMethodInfluential
Molecular Modeling and Functional Analysis of Exome Sequencing–Derived Variants of Unknown Significance Identify a Novel, Constitutively Active FGFR2 Mutant in Cholangiocarcinoma
Egan, J. B., Marks, D. L., Hogenson, T. L., Vrabel, A. M., Sigafoos, A. N., Tolosa, E. J., Carr, R. M., Safgren, S. L., Enriquez-Hesles, E., Almada, L. L., et al. (2017) · JCO Precision Oncology · doi:10.1200/po.17.00018 · Cited by 9
Molecular subtypes based on metabolic genes are potential biomarkers for predicting prognosis and immune responses of clear cell renal cell carcinoma
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Construction of an immune predictive model and identification of TRIP6 as a prognostic marker and therapeutic target of CRC by integration of single-cell and bulk RNA-seq data
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Biological Activity of Peptide Fraction Derived from Hermetia illucens L. (Diptera: Stratiomyidae) Larvae Haemolymph on Gastric Cancer Cells
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Personalized risk stratification in colorectal cancer via PIANOS system
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LncRNA NEAT1 Promotes the Malignant Progression of Colorectal Cancer by Targeting ZEB1 via miR-448
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Identification of genes with high heterogeneity of expression as a predictor of different prognosis and therapeutic responses in colorectal cancer: a challenge and a strategy
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“Many studies have shown that tumor specimens with the same clinical symptoms have a range of differences in many gene levels, and this issue is associated with pathogenic complexities and difficult patient perception [19].”
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Unraveling dynamic interactions between tumor-associated macrophages and consensus molecular subtypes in colorectal cancer: An integrative analysis of single-cell and bulk RNA transcriptome
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“Nevertheless, individual prognosis prediction remains challenging due to the high heterogeneity and complex molecular biological characteristics of CRC (18).”
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Reduced expression of microRNA-432-5p by DNA methyltransferase 3B leads to development of colorectal cancer through upregulation of CCND2
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Subtypes analysis and prognostic model construction based on lysosome-related genes in colon adenocarcinoma
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Harnessing the Potential of Real-World Evidence in the Treatment of Colorectal Cancer: Where Do We Stand?
van Nassau, S. C. M. W., Bol, G. M., van der Baan, F. H., Roodhart, J. M. L., Vink, G. R., Punt, C. J. A., May, A. M., Koopman, M., & Derksen, J. W. G. (2024) · Current Treatment Options in Oncology · doi:10.1007/s11864-024-01186-4 · Cited by 8
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Plasma ctDNA enhances the tissue-based detection of oncodriver mutations in colorectal cancer
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Background
N7-methyladenosine-induced SLC7A7 serves as a prognostic biomarker in pan-cancer and promotes CRC progression in colorectal cancer
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Innovative Applications of Nucleic Acid Aptamers in Colorectal Cancer Diagnosis and Therapy: From Selection Optimization to Clinical Translation
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Background
Ethoxychelerythrine as a potential therapeutic strategy targets PI3K/AKT/mTOR induced mitochondrial apoptosis in the treatment of colorectal cancer
Meng, Y., Si, Y., Guo, T., Zhao, W., Zhang, L., Wang, Y. Q., Wang, L., Sun, K., & Feng, S. (2025) · Scientific Reports · doi:10.1038/s41598-025-91251-1 · Cited by 9
Stroma-normalised vessel density predicts benefit from adjuvant fluorouracil-based chemotherapy in patients with stage II/III colon cancer
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Investigation of sirtuin 1 polymorphisms in relation to the risk of colorectal cancer by molecular subtype
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Weighted Gene Co-expression Network Analysis Identified a Novel Thirteen-Gene Signature Associated With Progression, Prognosis, and Immune Microenvironment of Colon Adenocarcinoma Patients
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Intra-Tumor Heterogeneity of Colorectal Cancer Necessitates the Multi-Regional Sequencing for Comprehensive Mutational Profiling
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“Discussion The Status of Heterogeneity in CRC Tissues and Its Indication for Cancer Therapy and Prognosis The heterogeneity of cancers has always been a focus in cancer research, and many studies have reported the status of heterogeneity in various cancers and its implications for targeted therapy.(4,9) Heterogeneity…”
Background
Construction of a Novel MYC-Associated ceRNA Regulatory Network to Identify Prognostic Biomarkers in Colon Adenocarcinoma
Xin, R., Tang, X.-M., Jiang, Y., Yu, F., Li, S., Jia, C., Wang, G., Fu, D., Liu, J.-B., & Ma, Y. (2022) · Journal of Oncology · doi:10.1155/2022/3216285 · Cited by 7
“To date, even combination therapy has been unable to improve the prognosis of CRC patients [5, 6].”
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Characterization of the microenvironment in different immune-metabolism subtypes of cervical cancer with prognostic significance
Lai, W., Liao, J., Li, X., Liang, P., He, L., Huang, K., Liang, X., & Wang, Y. (2023) · Frontiers in Genetics · doi:10.3389/fgene.2023.1067666 · Cited by 8
“It has been observed that there are significant individual differences in the prognosis of cancer patients despite controlling for factors such as age and clinical stage, which is likely due to tumor heterogeneity (Punt et al., 2017).”
Background
Polypeptide‑GalNAc‑T6 expression predicts better overall survival in patients with colon cancer
Ubillos, L., Berriel, E., Mazal, D., Victoria, S., Barrios, E., Osinaga, E., & Berois, N. (2018) · Oncology Letters · doi:10.3892/ol.2018.8686 · Cited by 7
“Precision oncology is becoming increasingly important in CRC management since the great molecular heterogeneity determines large variations in prognosis and response to chemotherapy of individual patients (58,59).”
Late gadolinium MRI enhancement of colorectal liver metastases is associated with overall survival among nonsurgical patients
Cheung, H., Kim, J. K., Hudson, J. M., Coburn, N. G., Karanicolas, P. J., Law, C. H. L., & Milot, L. M. (2019) · European Radiology · doi:10.1007/s00330-019-06177-w · Cited by 7
Modeling precision genomic-based radiation dose response in rectal cancer
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Chemical Space of Fluorinated Nucleosides/Nucleotides in Biomedical Research and Anticancer Drug Discovery
Kothapalli, Y., Lesperance, T. A., Jones, R. A., Chu, C. K., & Singh, U. S. (2025) · Chemistry · doi:10.3390/chemistry7010007 · Cited by 6
“Furthermore it transports into cells by nucleoside transporters, where it Fludarabine phosphate (F-ara-AMP, 51 ) is the monophosphate prodrug of ﬂ udara-bine (F-ara-A, 59 , Figure 7).”
Peptide Fractions Extracted from the Hemolymph of Hermetia illucens Inhibit Growth and Motility and Enhance the Effects of Traditional Chemotherapeutics in Human Colorectal Cancer Cells
Lucchetti, D., Rinaldi, R., Artemi, G., Salvia, R., Stefano, F. D., Scieuzo, C., Falabella, P., & Sgambato, A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26051891 · Cited by 6
“New approaches that are able to tackle both the toxicity issues of chemotherapy and resistance are of primary relevance for CRC [35].”
Precision, Prediction and Progress: A New Era in Pharmacology
Singh, J. P., Gaur, V., & Dubey, P. (2025) · doi:10.38124/ijisrt/25apr1322 · Cited by 6
Application of the Adaptive Validation Substudy Design to Colorectal Cancer Recurrence
Collin, L. J., Riis, A. H., MacLehose, R. F., Ahern, T. P., Erichsen, R., Thorlacius‐Ussing, O., & Lash, T. L. (2020) · Clinical Epidemiology · doi:10.2147/clep.s230314 · Cited by 6
“Treatments for local or regional (stage I–III) disease include surgery alone or combinations of surgery, chemotherapy, and radiation therapy, with the intent of curing the patient of their disease.(12) Following curative treatment and an apparent disease-free period, a recurrence is a necessary preceding condition bef…”
Background

Authors: Punt, C. J. A., Koopman, M., & Vermeulen, L.
Affiliations: Amsterdam UMC Location University of Amsterdam (NL)
University Medical Center Utrecht (NL)
Corresponding author: Punt, Cornelis J. A.
ORCID: Punt, Cornelis J. A.
Koopman, Miriam
Vermeulen, Louis
Venue: Nature Reviews Clinical Oncology
Publisher: Springer Science and Business Media LLC
Published: 2016-12-06
Volume: 14
Issue: 4
Pages: 235-246
ISSN: 1759-4774 (ISSN-L)
1759-4782
DOI: 10.1038/nrclinonc.2016.171
OpenAlex: W2560375214
Cited by: 654
References: 177
Citations by year: 2026: 38 · 2025: 41 · 2024: 87 · 2023: 79 · 2022: 88 · 2021: 96 · 2020: 83 · 2019: 57 · 2018: 56 · 2017: 28
FWCI: 4.73
Type: journal article
Language: en
Open access: green
pure.amsterdamumc.nl
Licence: other-oa
www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature Reviews Clinical Oncology (publishedVersion)
PubMed (publishedVersion)
Pure Amsterdam UMC (submittedVersion, other-oa)
Data Archiving and Networked Services (DANS) (submittedVersion)
Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
Utrecht University Repository (Utrecht University) (submittedVersion)
Funders: Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Maag Lever Darm Stichting (MLDS-CDG 14-03)
H2020 European Research Council (638193)
Topics: Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
Health Sciences › Medicine › Oncology › Colorectal Cancer Surgical Treatments
Keywords: colorectal cancer, intratumoral heterogeneity, precision medicine, targeted therapy, gene expression profiling, tumor subtypes, prognostic factors, predictive biomarkers, RAS mutations, DNA mismatch repair, anti-EGFR therapy, adjuvant chemotherapy, next-generation sequencing
MeSH terms: Antineoplastic Combined Chemotherapy Protocols, Forecasting, Humans, Immunotherapy, Neoplasm Metastasis, Neoplasm Proteins, Neoplasm Staging, Prognosis, Quality of Health Care, Colorectal Neoplasms, Treatment Outcome, Genetic Heterogeneity, Therapies, Investigational, Proto-Oncogene Proteins B-raf, DNA Mismatch Repair, Early Detection of Cancer, Precision Medicine, Molecular Targeted Therapy

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From tumour heterogeneity to advances in precision treatment of colorectal cancer

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