A novel diagnostic tool for selecting patients with mesenchymal-type colon cancer reveals intratumor subtype heterogeneity
Open accessAbstract
Background: Consensus molecular subtype 4 (CMS4) is a recently identified aggressive colon cancer subtype for which platelet-derived growth factor receptors (PDGFRs) and KIT are potential therapeutic targets. We aimed to develop a clinically applicable CMS4 reverse transcription polymerase chain reaction (RT-qPCR) test to select patients for PDGFR/KIT-targeted therapy. Methods: We used logistic regression to develop a CMS4 prediction rule based on microarray expression values of PDGFRA , PDGFRB , PDGFC , and KIT (566 training and 1259 test samples, using the 273-gene random forest classifier as CMS4 reference standard). We next translated the prediction rule into a single-sample RT-qPCR test, which we independently validated in 29 fresh tumor samples. To study intratumor CMS4 heterogeneity, we used the RT-qPCR test to analyze five random regions of 20 colon tumors. Results: The microarray-based prediction rule diagnosed CMS4-type tumors extremely well in both training and independent test samples (training: area under the curve [AUC] = 0.95, 95% confidence interval [CI] = 0.94 to 0.97; test: AUC = 0.95, 95% CI = 0.94 to 0.96), with excellent calibration and approximately 80% overall net benefit over a large threshold range. Translation into an RT-qPCR test did not affect discrimination (AUC = 0.97, 95% CI = 0.93 to 1.00, independent validation). RT-qPCR analysis of five random tumor regions revealed extensive intratumor CMS4 heterogeneity in nine out of 20 tumors. At least two regions likely have to be analyzed to identify patients that are predominantly CMS4 positive (>50% average CMS4 chance). Conclusion: The CMS4 RT-qPCR test is a promising clinical tool for selecting individual patients for CMS4-subtype-targeted therapy.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A qRT-PCR-based test based on the expression of several effectors of the PDGF pathway and the KIT receptor has a high degree of robustness.
“the group of O. Kranenburg proposed a qRT-PCR–based test based on the expression of several effectors of the PDGF pathway as well as the KIT receptor, with a high degree of robustness (58).”
From Clinical Challenges of Consensus Molecular Subtype CMS4 Colon Cancer in the Era of Precision Medicine (2024) · cites this paper as [58]
Cites
(2016) · Springer eBooks · doi:10.1007/978-3-319-40618-3 · Cited by 17,280 · see citing works
The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments
Bustin, S. A., Benes, V., Garson, J. A., Hellemans, J., Huggett, J., Kubista, M., Mueller, R., Nolan, T., Pfaffl, M. W., Shipley, G. L., et al. (2009) · Clinical Chemistry · doi:10.1373/clinchem.2008.112797 · Cited by 16,303 · cited 2× · see citing works
“We adhere to the TRIPOD (19) and MIQE (20) guidelines in reporting this study and used R version 3.”
MethodInfluentialDecision curve analysis: a novel method for evaluating prediction models
Vickers, A. J., & Elkin, E. B. (2006) · Medical Decision Making · doi:10.1177/0272989x06295361 · Cited by 6,341 · see citing works
The consensus molecular subtypes of colorectal cancer
Guinney, J., Dienstmann, R., Wang, X., de Reyniès, A., Schlicker, A., Soneson, C., Marisa, L., Roepman, P., Nyamundanda, G., Angelino, P., et al. (2015) · Nature Medicine · doi:10.1038/nm.3967 · Cited by 5,170 · see citing works
Collins, G. S., Reitsma, J. B., Altman, D. G., & Moons, K. G. M. (2015) · Annals of Internal Medicine · doi:10.7326/m14-0697 · Cited by 3,267 · see citing works
Huang, Y., Liang, C., He, L., Tian, J., Liang, C., Chen, X., Ma, Z., & Liu, Z. (2016) · Journal of Clinical Oncology · doi:10.1200/jco.2015.65.9128 · Cited by 1,745 · see citing works
Marisa, L., de Reyniès, A., Duval, A., Selves, J., Gaub, M. P., Vescovo, L., Etienne-Grimaldi, M.-C., Schiappa, R., Guenot, D., Ayadi, M., et al. (2013) · PLoS Medicine · doi:10.1371/journal.pmed.1001453 · Cited by 1,507 · see citing works
Vickers, A. J., Van Calster, B., & Steyerberg, E. W. (2016) · BMJ · doi:10.1136/bmj.i6 · Cited by 1,163 · see citing works
Blanke, C. D., Rankin, C. J., Demetri, G. D., Ryan, C. W., von Mehren, M., Benjamin, R. S., Raymond, A. K., Bramwell, V. H. C., Baker, L. H., Maki, R. G., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.13.4452 · Cited by 1,074 · see citing works
Stromal gene expression defines poor-prognosis subtypes in colorectal cancer
Calon, A., Lonardo, E., Berenguer-Llergo, A., Espinet, E., Hernando-Momblona, X., Iglesias, M., Sevillano, M., Palomo-Ponce, S., Tauriello, D. V. F., Byrom, D., et al. (2015) · Nature Genetics · doi:10.1038/ng.3225 · Cited by 1,070 · see citing works
Dependency of Colorectal Cancer on a TGF-β-Driven Program in Stromal Cells for Metastasis Initiation
Calon, A., Espinet, E., Palomo-Ponce, S., Tauriello, D. V. F., Iglesias, M., Céspedes, M. V., Sevillano, M., Nadal, C., Jung, P., Zhang, X. H.-F., et al. (2012) · Cancer Cell · doi:10.1016/j.ccr.2012.08.013 · Cited by 1,060 · see citing works
A Big Bang model of human colorectal tumor growth
Sottoriva, A., Kang, H., Ma, Z., Graham, T. A., Salomon, M. P., Zhao, J., Marjoram, P., Siegmund, K. D., Press, M. F., Shibata, D. K., et al. (2015) · Nature Genetics · doi:10.1038/ng.3214 · Cited by 1,010 · see citing works
Stromal contribution to the colorectal cancer transcriptome
Isella, C., Terrasi, A., Bellomo, S. E., Petti, C., Galatola, G., Muratore, A., Mellano, A., Senetta, R., Cassenti, A., Sonetto, C., et al. (2015) · Nature Genetics · doi:10.1038/ng.3224 · Cited by 640 · see citing works
Autocrine PDGFR signaling promotes mammary cancer metastasis
Jechlinger, M. (2006) · Journal of Clinical Investigation · doi:10.1172/jci24652 · Cited by 371 · see citing works
Böckelman, C., Engelmann, B. E., Kaprio, T., Hansen, T. F., & Glimelius, B. L. G. (2014) · Acta Oncologica · doi:10.3109/0284186x.2014.975839 · Cited by 367 · see citing works
Pisco, A. O., & Huang, S. (2015) · British Journal of Cancer · doi:10.1038/bjc.2015.146 · Cited by 278 · see citing works
Henriksen, R., Funa, K., Wilander, E., et al. (1993) · PubMed · Cited by 220 · see citing works
ColoGuideEx: a robust gene classifier specific for stage II colorectal cancer prognosis
Ågesen, T. H., Sveen, A., Merok, M. A., Lind, G. E., Nesbakken, A., Skotheim, R. I., & Lothe, R. A. (2012) · Gut · doi:10.1136/gutjnl-2011-301179 · Cited by 192 · see citing works
Heldin, C., & Lennartsson, J. (2013) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a009100 · Cited by 176 · see citing works
Song, N., Pogue–Geile, K. L., Gavin, P. G., Yothers, G., Kim, S. R., Johnson, N. L., Lipchik, C., Allegra, C. J., Petrelli, N. J., O’Connell, M. J., et al. (2016) · JAMA Oncology · doi:10.1001/jamaoncol.2016.2314 · Cited by 172 · see citing works
Rousson, V., & Zumbrunn, T. (2011) · BMC Medical Informatics and Decision Making · doi:10.1186/1472-6947-11-45 · Cited by 165 · see citing works
Kim, T., Jung, S., An, C. H., Lee, S. H., Baek, I.-P., Kim, M. S., Park, S., Rhee, J., Lee, S.-H., & Chung, Y. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-14-2413 · Cited by 161 · see citing works
Quantifying the Added Value of a Diagnostic Test or Marker
Moons, K. G. M., de Groot, J. A. H., Linnet, K., Reitsma, J. B., & Bossuyt, P. M. M. (2012) · Clinical Chemistry · doi:10.1373/clinchem.2012.182550 · Cited by 152 · see citing works
Maak, M., Simón, I., Nitsche, U., Roepman, P., Snel, M. H. J., Glas, A. M., Schuster, T., Keller, G., Zeestraten, E. C. M., Goossens, I., et al. (2013) · Annals of Surgery · doi:10.1097/sla.0b013e31827c1180 · Cited by 120 · see citing works
Expression and prognostic value of VEGFR-2, PDGFR-β, and c-Met in advanced hepatocellular carcinoma
Chu, J., Ge, F. J., Zhang, B., et al. (2013) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/1756-9966-32-16 · Cited by 108 · see citing works
Kitadai, Y., Sasaki, T., Kuwai, T., Nakamura, T., Bucana, C. D., & Fidler, I. J. (2006) · American Journal Of Pathology · doi:10.2353/ajpath.2006.060653 · Cited by 104 · see citing works
PDGFRB Promotes Liver Metastasis Formation of Mesenchymal-Like Colorectal Tumor Cells
Steller, E. J. A., Raats, D., Köster, J., Rutten, B., Govaert, K. M., Emmink, B. L., Snoeren, N., van Hooff, S. R., Holstege, F. C. P., Maas, C., et al. (2013) · Neoplasia · doi:10.1593/neo.121726 · Cited by 101 · see citing works
Self-citationBraun, K., Sjoberg, D. D., Vickers, A. J., et al. (2015) · European Urology · doi:10.1016/j.eururo.2015.04.028 · Cited by 95 · see citing works
Shinagawa, K., Kitadai, Y., Tanaka, M., Sumida, T., Onoyama, M., Ohnishi, M., Ohara, E., Higashi, Y., Tanaka, S., Yasui, W., et al. (2012) · International Journal of Cancer · doi:10.1002/ijc.27735 · Cited by 79 · see citing works
Sulzbacher, I., Birner, P., Träxler, M., et al. (2003) · American Journal of Clinical Pathology · doi:10.1309/lq9e-mk8q-ke75-nggx · Cited by 77 · see citing works
Sulzbacher, I., Birner, P., Träxler, M., et al. (2003) · American Journal of Clinical Pathology · doi:10.1309/lq9emk8qke75nggx · Cited by 64 · see citing works
Bellone, G., Ferrero, D., Carbone, A., Quadros, M. R. D., Gramigni, C., Prati, A., Davidson, W., Mioli, P., Dughera, L., Emanuelli, G., et al. (2004) · Cancer Biology & Therapy · doi:10.4161/cbt.3.4.727 · Cited by 44 · see citing works
Chen, E. C., Karl, T. A., Tomer Kalisky, C., Gupta, S. K., O'Brien, C. A., Longacre, T. A., van de Rijn, M., Quake, S. R., Clarke, M. F., & Rothenberg, M. E. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.05.042 · Cited by 43 · see citing works
Fátrai, S., van Schelven, S. J., Ubink, I., Govaert, K. M., Raats, D., Köster, J., Verheem, A., Rinkes, I. H. M. B., & Kranenburg, O. (2015) · Gastroenterology · doi:10.1053/j.gastro.2015.05.003 · Cited by 37 · see citing works
Self-citationInter- and intra-tumor profiling of multi-regional colon cancer and metastasis
Kogita, A., Yoshioka, Y., Sakai, K., Togashi, Y., Sogabe, S., Nakai, T., Okuno, K., & Nishio, K. (2015) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2015.01.064 · Cited by 29 · see citing works
Abelson, S., Shamai, Y., Berger, L., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0083651 · Cited by 23 · see citing works
Lohmann, S., Herold, A., Bergauer, T., et al. (2012) · Methods · doi:10.1016/j.ymeth.2012.07.003 · Cited by 19 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Investigation of colorectal cancer in accordance with consensus molecular subtype classification
Sawayama, H., Miyamoto, Y., Ogawa, K., Yoshida, N., & Baba, H. (2020) · Annals of Gastroenterological Surgery · doi:10.1002/ags3.12362 · Cited by 60 · see citing works
Neoadjuvant chemotherapy affects molecular classification of colorectal tumors
Trumpi, K., Ubink, I., Trinh, A., Djafarihamedani, M., Jongen, J. M., Govaert, K. M., Elias, S. G., van Hooff, S. R., Medema, J. P., Lacle, M. M., et al. (2017) · Oncogenesis · doi:10.1038/oncsis.2017.48 · Cited by 46 · see citing works
Self-citationMouillet-Richard, S., Cazelles, A., Sroussi, M., Gallois, C., Taieb, J., & Laurent-Puig, P. (2024) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-23-3964 · Cited by 43 · see citing works
Peters, N. A., Constantinides, A., Ubink, I., van Kuik, J., Bloemendal, H. J., van Dodewaard, J. M., Brink, M. A., Schwartz, T. P., Lolkema, M. P. J. K., Lacle, M. M., et al. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.969855 · Cited by 35 · see citing works
Self-citationStrating, E., Wassenaar, E., Verhagen, M., Rauwerdink, P., van Schelven, S., de Hingh, I., Rinkes, I. B., Boerma, D., Witkamp, A., Lacle, M., et al. (2022) · British Journal of Cancer · doi:10.1038/s41416-022-01748-z · Cited by 36 · see citing works
Self-citationHaasnoot, K. J. C., Backes, Y., Moons, L. M. G., Kranenburg, O., Trinh, A., Vermeulen, L., Noë, M., Tuynman, J. B., van Lent, A. U. G., van Ginneken, R., et al. (2020) · Modern Pathology · doi:10.1038/s41379-020-0598-9 · Cited by 30 · see citing works
Self-citationKüçükköse, E., Peters, N. A., Ubink, I., van Keulen, V. A. M., Daghighian, R., Verheem, A., Laoukili, J., & Kranenburg, O. (2022) · Cell Death & Disease · doi:10.1038/s41419-022-05078-z · Cited by 18 · see citing works
Self-citation
- Authors
- Ubink, I., Elias, S. G., Moelans, C. B., Laclé, M. M., van Grevenstein, W. M. U., van Diest, P. J., Borel Rinkes, I. H. M., & Kranenburg, O.
- Affiliations
- University Medical Center Utrecht (NL)
- Corresponding author
- Kranenburg, Onno
- Venue
- JNCI: Journal of the National Cancer Institute
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-03-09
- Volume
- 109
- Issue
- 7
- ISSN
- 0027-8874 (ISSN-L)
- 1460-2105
- OpenAlex
- W2594149170
- Cited by
- 40
- References
- 37
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 2 · 2023: 5 · 2022: 10 · 2021: 1 · 2020: 5 · 2019: 1 · 2018: 6 · 2017: 4
- FWCI
- 1.97
- Type
- journal article
- Language
- en
- Open access
- green
- dspace.library.uu.nl
- Licence
- other-oa
- Locations
- JNCI Journal of the National Cancer Institute (publishedVersion)
- PubMed (publishedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- 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
- colon cancer, PDGFRA, PDGFRβ, PDGF-C, KIT, intratumoral heterogeneity, molecular subtype prediction, patient selection for targeted therapy
- MeSH terms
- Biopsy, Colon, Colonic Neoplasms, Humans, Lymphokines, Neoplasm Staging, Platelet-Derived Growth Factor, Predictive Value of Tests, ROC Curve, Survival Rate, Disease-Free Survival, Patient Selection, Genetic Heterogeneity, Proto-Oncogene Proteins c-kit, Area Under Curve, Reverse Transcriptase Polymerase Chain Reaction, Receptor, Platelet-Derived Growth Factor alpha, Receptor, Platelet-Derived Growth Factor beta, Gene Expression Profiling, Molecular Diagnostic Techniques, Microarray Analysis, Molecular Targeted Therapy
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
