Integrating DNA and RNA profiling is a promising approach to advance cancer characterisation and guide clinical decision-making
In the era of precision medicine, molecular analysis of tumour lesions has significantly modified clinical strategies by combining morphological diagnosis and genomic assessment. Comprehensive sequencing platforms – which decode the complexity of molecular hallmarks in cancer cells – are fundamental to detecting tumour alterations simultaneously by exploring the DNA and RNA of tumour cells. This strategy becomes crucial in diseases harbouring several tumour suppressor protein inactivating alterations (‘loss phenotype’). The comprehensive analysis of the entire spectrum of inactivating mutations (single nucleotide variations [SNVs], insertion/deletion mutations [INDELs], large rearrangements or intronic alterations) can consistently identify patients who are eligible for personalised therapeutic schemes. As a consequence, concomitant analysis of DNA and RNA may substantially improve the positivity rate of clinically significant molecular alterations, thereby optimising the clinical management of patients with cancer.
Methylthioadenosine phosphorylase (MTAP) acts as a key player in the molecular pathway that stabilises methionine levels. MTAP ‘loss of function’ alterations are detectable in 15% of patients with solid tumours, impacting cancer progression. Molecular testing of these alterations requires integrative analytical strategies evaluating DNA and RNA alterations that contribute to a ‘null phenotype’ of the protein to improve treatment options for patients whose tumours are not driven by oncogene addiction.
As shown at the ESMO Asia Congress 2025, MTAP detection rate was significantly correlated with poor prognosis and lower clinical response to immune checkpoint inhibitors (ICIs) (Abstract 765MO). Results showed a median progression-free survival of 3.4 months versus 5.8 months (hazard ratio [HR] 1.74, 95% CI 1.10–2.75) for ICI-treated patients with solid tumours harbouring MTAP loss versus wildtype MTAP, respectively, in the nationwide Japanese genomic screening programmes, SCRUM-Japan SCREEN and MONSTAR-SCREEN-1 and -2, which combined genomic data and xCell deconvolution analysis plus gene set enrichment analysis (GSEA) for two series of patients (cohort A, n=764; cohort B, n=714) (Cancer Sci. 2021;112:4425–4432; Cancer Discov. 2024;14:2243–2261). These findings rely on the implementation of comprehensive technical strategies (FoundationOne® CDx and Caris MI Tumor Seek Hybrid™), which can detect both genomic and transcriptomic data in one shot. In the study, immune cell engagement in tumour lesions was also investigated, and data clearly revealed lower infiltration of CD4+ and CD8+ T-cells, and M2 macrophages in tumours with a high prevalence of MTAP loss.
This study highlights that next-generation sequencing (NGS) platforms are cutting-edge testing strategies for the concomitant assessment of CDKN2A/CDKN2B inactivating mutations in MTAP-addicted tumours. It also demonstrates how genomic fingerprinting via comprehensive genomic profiling can optimise clinical algorithms for patients monitored in dedicated molecular programmes. Moreover, transcriptome profiles also identified downregulation in DNA repair, transcriptional and epigenetic regulatory pathways that correlated significantly with the accumulation of methylthioadenosine. This paves the way for further investigations on PRMT5 and MAT2A inhibitors, which may potentially reshape the clinical landscape for patients with MTAP-deficient tumours and DNA repair and epigenetic downregulations.
Personalisation of clinical algorithms is a rapidly evolving area in oncology where genomic assessment and expression profiles are two sides of the same coin – so, they need to be investigated simultaneously to guide each case toward its best clinical option.
By combining genomic and transcriptomic data, we can build multiparametric layers that more precisely decode the molecular hallmarks of cancer – this is the era of ‘3D biology’, which is already transforming cancer care. Within this framework, true integration of biological sources, analytical strategies and molecular data becomes essential for guiding clinical decision-making particularly when precision drugs are lacking. Further investigation is needed to consolidate data interpretation strategies that can support clinical evidence in an increasingly complex molecular environment.
