Concordance analysis of DNA and RNA profiling: The MD Anderson IMPACT2 study in precision oncology
Stephanie T Schmidt1,2, Mehmet A Baysal3, Siqing Fu3
1Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Abstract:
DNA profiling is an established method for cancer treatment selection, while RNA profiling remains investigational. We explored associations between DNA and RNA alterations and between the number of genes with altered expression and overall survival (OS) using patient data from IMPACT2 (NCT02152254), a randomized study evaluating molecular profiling for guiding cancer therapy across tumor types. Molecular profiling, including DNA next-generation sequencing, was performed on all 829 patients in the IMPACT2 study. RNA profiling was performed by Tempus for 253 of 829 patients. We evaluated the concordance between DNA and RNA profiling, analyzed OS in 217 treated patients with RNA profiling, and assessed PD-L1 status and number of genes with altered expression. Fifty patients exhibited 58 concordant events, i.e., genomic and expression alteration(s) in the same gene, including 38 copy number events, and 41 patients had statistically significant concordance. We identified 123 gene pairs with significant associations between genomic and expression alterations (p < 0.05), including TP53 alterations with VEGFA overexpression. The median OS for patients with 0-2, 3-5, and ≥6 genes with altered expression was 9.8, 11.9, and 6.7 months, respectively (p = 0.03). These results underscore RNA profiling's potential actionability, and altered expression in ≥6 genes was associated with shorter OS. Significant concordance of TP53 alterations with VEGFA overexpression may partially explain tumor response to bevacizumab in TP53-mutant patients.
Insights
RNA profiling shows potential for cancer treatment selection by revealing gene expression alterations. More than six altered genes correlate with shorter overall survival, highlighting RNA
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- DNA profiling is standard for cancer treatment selection, but RNA profiling is still under investigation.
- The IMPACT2 study (NCT02152254) evaluated molecular profiling for guiding cancer therapy across various tumor types.
Purpose of the Study:
- To explore associations between DNA and RNA alterations in cancer patients.
- To investigate the link between the number of genes with altered expression and overall survival (OS).
- To assess the concordance between DNA and RNA profiling results.
Main Methods:
- Molecular profiling, including DNA next-generation sequencing, was performed on 829 IMPACT2 study patients.
- RNA profiling was conducted for 253 patients.
- Concordance between DNA and RNA profiling was evaluated, and OS was analyzed in 217 treated patients.
Main Results:
- Fifty patients showed 58 concordant DNA and RNA events, with 41 demonstrating statistically significant concordance.
- 123 gene pairs exhibited significant associations between genomic and expression alterations (p < 0.05), including TP53 alterations with VEGFA overexpression.
- Patients with ≥6 genes showing altered expression had a shorter median OS (6.7 months) compared to those with 0-2 (9.8 months) or 3-5 (11.9 months) altered genes (p = 0.03).
Conclusions:
- RNA profiling demonstrates potential actionability in cancer treatment selection.
- An increased number of genes with altered expression (≥6) is associated with poorer overall survival.
- The observed concordance between TP53 alterations and VEGFA overexpression may inform bevacizumab response in TP53-mutant cancers.
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