535P - Alteration in NKX2-1 CN reshapes the oncogenic, immunologic, and prognostic landscapes in NSCLC

Background

Copy number alterations (CNAs) are common consequences of genome instability in lung cancer. Focal amplifications in NKX2-1 copy number (CN) have been frequently observed in non-small cell lung cancer (NSCLC). However, beyond CN gain, little is known about the complete landscape of NKX2-1 CNAs, their clinical significance, and their therapeutic implications in NSCLC.

Methods

Correlations of NKX2-1 expression with EGFR driver mutations and PD-L1 co-expression were studied using immunohistochemistry and PCR from tumors of recruited Filipino patients (n=45). Clinical features of NSCLC with NKX2-1 CNAs were resolved at the tumor and clonal levels using the molecular profiles of LUAD and LUSC participants from TCGA (n=1,130), and deconvoluted single-cell RNA-seq data from Bivona project (n=1,654), respectively.

Results

NKX2-1 expression and CN variations correlated significantly (r= 0.264; p<0.001). However, NKX2-1 CNAs exert a stronger influence on the combined EGFR and PD-L1 status of NSCLC tumors (p<0.05) than expression (p>0.05). NKX2-1 CN gain was prognostic of favorable survival (p=0.018), whereas, NKX2-1 CN loss prognosed worse survival (p=0.041). Mutational architecture in Y-chromosome differentiates the two prognostic groups. There were 19,941 synonymous mutations and 1,408 genome-wide CN perturbations associated with NKX2-1 CNAs. Tumors with NKX2-1 CN gain had higher B cell (p<0.001) and total T cell estimates (p=0.003). NKX2-1 CN loss was associated with colder tumors due to higher M2 macrophage infiltrates (p=0.011) and higher expression of immune checkpoint proteins, CD274 (p=0.025), VTCN1 (p<0.001), and LGALS9 (p=0.002). Lymphocyte marker signature in CN gain was prognostic of longer disease-free survival (p=0.005).

Conclusions

NKX2-1 CNAs are associated with tumors that exhibit clinically diverse characteristics, and with unique oncogenic, immunologic, and prognostic signatures.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Department of Science and Technology - Philippine Council for Health Research and Development.

Funding

Department of Science and Technology - Philippine Council on Health Research and Development.

Disclosure

All authors have declared no conflicts of interest.