A novel prognostic signature for lung adenocarcinoma based on cuproptosis-related lncRNAs: A Review

Abstract

Lung adenocarcinoma (LUAD) is a highly heterogeneous disease with complex pathogenesis, high mortality, and poor prognosis. Cuproptosis is a new type of programmed cell death triggered by copper accumulation that may play an important role in cancer. LncRNAs are becoming valuable prognostic factors in cancer patients. The effect of cuproptosis-related lncRNAs (CRlncRNAs) on LUAD has not been clarified. Based on the Cancer Genome Atlas database, CRlncRNAs were screened by co-expression analysis of cuproptosis- related genes and lncRNAs. Using CRlncRNAs, Cox and LASSO regression analyses constructed a risk prognostic model. The predictive efficacy of the model was assessed and validated using survival analysis, receiver operating characteristic curve, univariate and multifactor Cox regression analysis, and principal component analysis. A nomogram was constructed and calibration curves were applied to enhance the predictive efficacy of the model. Tumor Mutational Burden analysis and chemotherapeutic drug sensitivity prediction were performed to assess the clinical feasibility of the risk model. The novel prognostic signature consisted of 5 potentially high-risk CRlncRNAs, MAP3K20-AS1, CRIM1-DT, AC006213.3, AC008035.1, and NR2F2-AS1, and 5 potentially protective CRlncRNAs, AC090948.1, AL356481.1, AC011477.2, AL031600.2, and AC026355.2, which had accurate and robust predictive power for LUAD patients. Collectively, the novel prognostic signature constructed based on CRlncRNAs can effectively assess and predict the prognosis of patients and provide a new perspective for the diagnosis and treatment of LUAD.

Figure 1.

Study flowchart shows the process of constructing and assessing the 10-CRlncRNAs prognostic signature for lung adenocarcinoma. CRlncRNAs = Cuproptosis-Related lncRNAs.

Figure 2.

(A) Forest plot of univariate Cox regression analysis; (B) The dynamic process of applying Lasso regression analysis to filter variables; (C) Selection process of the optimal cross-validation parameter λ in the LASSO model; (D) Correlation Heatmap of CRlncRNAs with CRGs, red color indicates a positive correlation and blue color indicates negative correlation. CRGs = cuproptosis-related genes, CRlncRNAs = cuproptosis-related lncRNAs, LASSO = least absolute shrinkage and selection operator.

Figure 3.

(A–C) Kaplan–Meier survival curves; (D–F) Risk Scoring Curves; (G–I) Survival state scatterplot, the green dots represent survival and the red dots represent death; (J–L) Heatmap of 10 CRlncRNAs expressions in the high-risk and low-risk groups for the construction of prognostic signature. CRlncRNAs = cuproptosis-related lncRNAs.

Figure 4.

(A) Clinical Multi-index ROC curves for The AUC of risk score, age, gender, and stage of LUAD patients; (B) Time-dependent ROC curves for The AUC of overall survival at 1, 3, and 5 years of LUAD patients; (C) Univariate Cox regression analysis; (D) Multinomial Cox regression analysis; (E) Construction of a nomogram combined clinical indicators and risk score for predicting survival probabilities at 1, 3, and 5 years of LUAD patients; (F) Calibration charts for validating the predictive accuracy of the 1-year, 3-year, and 5-year survival probabilities of the nomogram. (G–L) Subgroups of clinical indicators Kaplan–Meier survival analysis of LUAD patients. (G) Age<=65; (H) Age > 65; (I) Female; (J) Male; (K) Stage I–II; (L) Stage III–IV. AUC = area under the curve, LUAD = lung adenocarcinoma, ROC = receiver operating characteristic curve.

Figure 5.

PCA between low and high-risk groups. (A) the all genes set, (B) Cuproptosis Genes set, (C) CRlncRNAs set, (D) 10 CRlncRNAs set. CRlncRNAs = cuproptosis-related lncRNAs, PCA = principal component analysis.

Figure 6.

(A–B) Tumor mutation burden analysis of the difference between the high-risk group and low-risk group in LUAD patients; (C) Kaplan–Meier survival analysis of high TMB group (H-TMB) and low TMB group(L-TMB); (D) Kaplan–Meier survival analysis between the groups of H-TMB + high risk, H-TMB + low risk, L-TMB + high risk, and L-TMB + low risk, Comparison of MST between groups: H-TMB + low risk group > L-TMB + low risk group > H-TMB + high risk group > L-TMB + high risk group. LUAD = lung adenocarcinoma, MST = median survival time, TMB = tumor mutational burden.

Figure 7.

Correlation scatterplot of IC50 of chemotherapeutic drugs and risk score. (A–K) IC50 of chemotherapy drugs was negatively correlated with risk score; (L–S) IC50 of chemotherapy drugs was positively correlated with a risk score. (A) (5Z)-7-Oxozeaenol, (B) A-770041, (C) AP-24534, (D) BEZ235, (E) CGP-60474, (F) Cytarabine, (G) Dasatinib, (H) Pazopanib, (I) Saracatinib, (J) THZ-2-49, (K) WH-4-023, (H) Pazopanib, (I) Saracatinib, (J) THZ-2-49, (K) WH-4-023, (L) CP724714, (M) FH535, (N) Gefitinib, (O) MP470, (P) NSC-207895, (Q) PD-0325901, (R) rTRAIL, (S) TAK-715. IC50 = 50% inhibitory concentration.

Figure 8.

Boxplot showing the mean differences in estimated IC50 of chemotherapy drugs between the high and low-risk groups. (A) (5Z)-7-Oxozeaenol, (B) A-770041, (C) AP-24534, (D) BEZ235, (E) CGP-60474, (F) Cytarabine, (J) Dasatinib, (H) Pazopanib, (I) Saracatinib, (J) THZ-2-49, (K) WH-4-023, (H) Pazopanib, (I) Saracatinib, (J) THZ-2-49, (K) WH-4-023, (L) CP724714, (M) FH535, (N) Gefitinib, (O) MP470, (P) NSC-207895, (Q) PD-0325901, (R) rTRAIL, (S) TAK-715. IC50 = 50% inhibitory concentration.