Based on data from the IMPACT2 clinical trial, this study systematically analyzed the concordance between DNA and RNA sequencing, revealing a significant association between TP53 genomic alterations and VEGFA overexpression, and demonstrating that high tumor transcriptional burden (≥6 genes) correlates with shorter overall survival. These findings highlight the potential clinical utility of RNA sequencing in precision oncology.
Literature Overview
This article, 'Concordance analysis of DNA and RNA profiling: The MD Anderson IMPACT2 study in precision oncology,' published in Signal Transduction and Targeted Therapy, reviews and summarizes the results of integrated DNA and RNA multi-omics analysis in patients with advanced cancers from the IMPACT2 prospective precision oncology study. The study evaluated the concordance between genomic DNA alterations and RNA expression changes, explored the relationship between tumor transcriptional burden (TTB) and overall survival (OS), and analyzed the impact of PD-L1 status on the number of abnormally expressed genes. The results indicate that RNA sequencing provides biological information independent of DNA alterations, and high TTB is significantly associated with poor prognosis. This study underscores the potential value of RNA sequencing in tumor molecular subtyping and prognostic prediction, offering clinical evidence for multi-omics-guided therapeutic strategies.Background Knowledge
In the field of precision oncology, DNA sequencing has become the standard approach for identifying driver mutations and guiding targeted therapies, with over a hundred FDA-approved targeted drugs based on DNA alterations. However, DNA alterations alone cannot fully reflect gene functional states, as transcriptional regulation, epigenetic modifications, and post-transcriptional mechanisms may prevent DNA alterations from resulting in corresponding RNA expression changes. RNA sequencing captures gene expression levels, alternative splicing, fusion transcripts, and tumor microenvironment information, providing a dynamic view of tumor biology. Although RNA-based tests are widely used in research—such as Oncotype DX in breast cancer—their role in clinical treatment decisions remains exploratory due to a lack of large-scale prospective data. Moreover, tumor transcriptional burden (TTB)—defined as the number of abnormally expressed genes—as a potential prognostic biomarker has not been systematically evaluated in prospective multi-cancer trials. This study, based on the IMPACT2 trial, is the first to systematically analyze the concordance between DNA and RNA data and their impact on survival in a multi-cancer context, filling a critical evidence gap in real-world clinical cohorts and providing a strong foundation for the clinical translation of RNA sequencing.
Research Methods and Experiments
The study included 438 patients with advanced cancer from the IMPACT2 trial who received Tempus xT testing, of whom 253 completed both DNA and RNA sequencing. DNA sequencing covered 472 cancer-related genes, detecting single nucleotide variants, copy number variations (CNVs), gene fusions, and splicing variants. RNA sequencing, based on whole-transcriptome analysis, assessed gene expression abnormalities (overexpression or underexpression). A 'concordant event' was defined as an alteration in the same gene detected at both DNA and RNA levels. Fisher’s exact test was used to evaluate associations between DNA and RNA alterations, with Benjamini-Hochberg correction for multiple comparisons. Pathway enrichment analysis was performed using the Reactome database. Overall survival (OS) was analyzed using the Kaplan-Meier method, with log-rank tests across TTB groups (0–2, 3–5, and ≥6 abnormally expressed genes). The relationship between PD-L1 status and TTB was assessed using the Mann-Whitney U test.Key Conclusions and Perspectives
Research Significance and Prospects
This study is the first to systematically evaluate the concordance and clinical implications of DNA and RNA sequencing in a prospective multi-cancer cohort, confirming that RNA sequencing provides biological insights independent of DNA alterations, particularly showing high concordance between copy number variations and expression levels. The strong association between TP53 and VEGFA provides a theoretical basis for developing biomarkers for anti-angiogenic therapy, supporting the prioritization of bevacizumab in patients with TP53 mutations.
Tumor transcriptional burden (TTB) emerges as a novel prognostic marker with independent predictive value for survival, particularly showing significantly shorter survival in patients with high TTB (≥6 genes). This finding suggests that global transcriptional dysregulation may represent a more aggressive tumor phenotype, warranting validation in larger cohorts. Furthermore, the potential link between TTB and PD-L1 status may help identify immunologically "cold" tumors, offering clues for combination therapeutic strategies.
Although RNA-based testing is not yet FDA-approved for treatment selection, this study supports its complementary role in precision oncology, especially in patients lacking targetable DNA alterations. Future research should integrate RNA sequencing into prospective treatment decision frameworks to validate its value in therapy matching and outcome improvement. Combined with AI and machine learning, multi-omics data hold promise for further refining personalized treatment strategies.
Conclusion
Based on data from the IMPACT2 clinical trial, this study systematically analyzed the concordance and clinical significance of integrated DNA and RNA multi-omics data in patients with advanced cancers. The study found that approximately 20% of patients exhibited concordant alterations at both DNA and RNA levels, with copy number variations showing high correlation with expression levels, and a significant association between TP53 alterations and VEGFA overexpression, suggesting potential therapeutic targets. More importantly, tumor transcriptional burden (TTB) was identified as an independent prognostic factor: patients with ≥6 abnormally expressed genes had a median overall survival of only 6.7 months, significantly shorter than those with low TTB. These results emphasize the unique value of RNA sequencing in uncovering the biological complexity of tumors, not only complementing DNA sequencing but also serving as a tool for prognostic stratification. Although a trend toward higher TTB in PD-L1-negative tumors was observed, larger samples are needed for validation. Overall, this study provides strong evidence for the clinical application of RNA sequencing in precision oncology, supporting its integration into multi-omics strategies for optimizing treatment decisions and risk stratification. Prospective trials are needed to evaluate the real-world clinical benefits of RNA-guided therapies.
