166P - Integrative multi-omics refine molecular diagnostics in non-small cell lung cancer

Background

Molecular testing of somatic drivers in tumours expands personalised therapy with improved outcomes. Yet, actionable mutations are found in only 20% of non-small cell lung cancer (NSCLC). Our study aimed to improve molecular diagnostics by connecting somatic mutational signatures with proteogenomic profiles.

Methods

Targeted next-generation sequencing (NGS) test (APEX), whole genome sequencing (WGS), RNA sequencing (RNAseq) and targeted proteomics (Olink) were conducted on Southeast Asian NSCLC tumour/matched adjacent normal pairs. Integrative analyses were conducted to correlate somatic mutational signatures (single-base substitution (SBS), small insertions and deletions (ID) and copy number variation (CN)) with transcriptomic and proteomic profiles. Immune landscape was spatially resolved with multiplex immunohistochemistry (mIHC) staining.

Results

NGS-based molecular testing confirmed actionable mutations (EGFR, ALK, RET, MET) in only half of the cohort, with EGFR mutants found in 7 cases. Integrative multi-omics unravelled distinctive transcriptomic and proteomic features in Asian NSCLC that stratified tumours into function subtypes, reflecting key cancer hallmarks. Tumours exhibiting tobacco-associated mutagenesis (SBS4 signature) display heightened oxidative and hypoxic stress signals, accompanied by a subtype-specific immunosuppressive microenvironment, stressing potential benefits from a combined anti-angiogenic therapy with chemotherapy in SBS4-positive lung squamous cell carcinoma (LUSC). Oncogene-driven lung adenocarcinoma (LUAD) tumours with underlying APOBEC3A mutagenesis (SBS2/13 signature) also displayed perturbed NOTCH signalling akin to persistent, drug-resistant tumours, indicative of a shorter response duration to single agent target therapies among the SBS2/13-positive cases.

Conclusions

Our findings underscore the diagnostic potential of multi-omics in NSCLC, urging the implementation of somatic mutational signatures to advance molecular testing and treatment of NSCLC.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Ministry of Education, Singapore.

Disclosure

All authors have declared no conflicts of interest.