NKX2-1 拷贝数改变与非小细胞肺癌的致癌、免疫和预后重塑相关

NK2 homeobox 1 (NKX2-1) copy number alterations (CNAs) are frequently observed in lung cancer.

However, little is known about the complete landscape of focal alterations in NKX2-1 copy number (CN), their clinical significance and their therapeutic implications in non-small cell lung cancer (NSCLC). The correlations between NKX2-1 expression and EGFR driver mutations and programmed death ligand 1 (PD-L1) co-expression were studied using immunohistochemistry and PCR from the 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 patients with lung adenocarcinoma and lung squamous cell carcinoma from The Cancer Genome Atlas (n=1,130), and deconvoluted single-cell RNA-seq data from the Bivona project (n=1,654), respectively. Despite a significant and positive correlation between expression and CN (r=0. 264; P<0. 001), NKX2-1 CNAs exerted a stronger influence on the combined EGFR and PD-L1 status of NSCLC tumors than expression.

NKX2-1 CN gain was prognostic of favorable survival (P=0. 018) and a better response to targeted therapy. NKX2-1 CN loss predicted a worse survival (P=0. 041). Mutational architecture in the Y-chromosome differentiated 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 expressed lymphocyte markers more heterogeneously than those with CN loss.

Higher expression of tumor-infiltrating lymphocyte gene signatures in CN gain was prognostic of longer disease-free survival (P=0. 005). 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 immunologically 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).

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