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A Novel Diagnostic Tool for Selecting Patients With Mesenchymal-Type Colon Cancer Reveals Intratumor Subtype
Inge Ubink1, Sjoerd G Elias2, Cathy B Moelans3
1Cancer Center, University Medical Center Utrecht, Utrecht, The Netherlands.
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.
Insights
A new RT-qPCR test accurately identifies aggressive CMS4 colon cancer, enabling selection for targeted therapies. Analyzing multiple tumor regions is crucial due to significant intratumor heterogeneity.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Consensus molecular subtype 4 (CMS4) represents an aggressive colon cancer subtype.
- Platelet-derived growth factor receptors (PDGFRs) and KIT are identified as potential therapeutic targets for CMS4.
- Developing a clinically applicable test is essential for patient selection for targeted therapies.
Purpose of the Study:
- To develop and validate a reverse transcription polymerase chain reaction (RT-qPCR) test for identifying CMS4 colon cancer.
- To enable patient selection for PDGFR/KIT-targeted therapy.
Main Methods:
- A logistic regression model was developed using microarray data to predict CMS4 status.
- The prediction rule was translated into a single-sample RT-qPCR test.
- Intratumor heterogeneity was assessed by analyzing multiple regions of colon tumors using the RT-qPCR test.
Main Results:
- The microarray-based prediction rule demonstrated high accuracy (AUC=0.95) in both training and test sets.
- The RT-qPCR test showed excellent diagnostic performance (AUC=0.97) in independent validation.
- Extensive intratumor CMS4 heterogeneity was observed in 9 out of 20 tumors, suggesting the need for multi-region analysis.
Conclusions:
- The developed CMS4 RT-qPCR test is a promising tool for clinical application.
- This test can aid in selecting individual patients for CMS4-subtype-targeted therapy.
- Understanding intratumor heterogeneity is critical for accurate patient stratification.