Microsatellite instability-related prognostic risk score (MSI-pRS) defines a subset of lung squamous cell carcinoma (LUSC) patients with genomic instability and poor clinical outcome

Zixin Hu; Zhening Liu; Jiabin Zheng; Yanmei Peng; Xingyu Lu; Jia Li; Kexin Tan; Huijuan Cui

doi:10.3389/fgene.2023.1061002

Microsatellite instability-related prognostic risk score (MSI-pRS) defines a subset of lung squamous cell carcinoma (LUSC) patients with genomic instability and poor clinical outcome

Front Genet. 2023 Feb 17:14:1061002. doi: 10.3389/fgene.2023.1061002. eCollection 2023.

Authors

Zixin Hu^{1

2}, Zhening Liu^{1

2}, Jiabin Zheng², Yanmei Peng³, Xingyu Lu^{1

2}, Jia Li^{1

2}, Kexin Tan^{1

2}, Huijuan Cui²

Affiliations

¹ Beijing University of Chinese Medicine, Beijing, China.
² Department of Oncology, China-Japan Friendship Hospital, Beijing, China.
³ Department of Oncology, Fangshan Hospital, Beijing, China.

Abstract

Background: Lung squamous cell carcinoma (LUSC) shares less typical onco-drivers and target resistance, but a high overall mutation rate and marked genomic complexity. Mismatch repair (MMR) deficiency leads to microsatellite instability (MSI) and genomic instability. MSI is not an ideal option for prognosis of LUSC, whereas its function deserves exploration. Method: MSI status was classified by MMR proteins using unsupervised clustering in the TCGA-LUSC dataset. The MSI score of each sample was determined by gene set variation analysis. Intersections of the differential expression genes and differential methylation probes were classified into functional modules by weighted gene co-expression network analysis. Least absolute shrinkage and selection operator regression and stepwise gene selection were performed for model downscaling. Results: Compared with the MSI-low (MSI-L) phenotype, MSI-high (MSI-H) displayed higher genomic instability. The MSI score was decreased from MSI-H to normal samples (MSI-H > MSI-L > normal). A total of 843 genes activated by hypomethylation and 430 genes silenced by hypermethylation in MSI-H tumors were classified into six functional modules. CCDC68, LYSMD1, RPS7, and CDK20 were used to construct MSI-related prognostic risk score (MSI-pRS). Low MSI-pRS was a protective prognostic factor in all cohorts (HR = 0.46, 0.47, 0.37; p-value = 7.57e-06, 0.009, 0.021). The model contains tumor stage, age, and MSI-pRS that showed good discrimination and calibration. Decision curve analyses indicated that microsatellite instability-related prognostic risk score added extra value to the prognosis. A low MSI-pRS was negatively correlated with genomic instability. LUSC with low MSI-pRS was associated with increased genomic instability and cold immunophenotype. Conclusion: MSI-pRS is a promising prognostic biomarker in LUSC as the substitute of MSI. Moreover, we first declared that LYSMD1 contributed to genomic instability of LUSC. Our findings provided new insights in the biomarker finder of LUSC.

Keywords: TP53; genomic instability; lung squamous cell carcinoma; microsatellite instability; mismatch repair system; prognostic biomarkers.

Grants and funding

This work was supported by the Capital Health Development Scientific Research Project: Combination of Gegen Qinlian tablets with immune checkpoint inhibitors and chemotherapy in advanced lung squamous cell carcinoma: a clinical study (2022-2-4065).