Combination of genomic instability score and TP53 status for prognosis prediction in lung adenocarcinoma

Abstract

The genomic instability (GI) /homologous recombination deficiency (HRD) score, calculated as the sum of the events of loss of heterozygosity (LOH), large-scale state transition (LST) and telomere allele imbalance (TAI), is used to guide the choice of treatment in several cancers, but its relationship with genomic features, clinicopathological characteristics and prognosis in lung cancer is poorly understood, which could lead to population bias in prospective studies. We retrospectively analyzed 1011 lung cancer patients whose tumor samples were successfully profiled by high-throughput sequencing panel including GI/HRD score. Alterations of many cancer suppressor genes were associated with higher GI/HRD scores, biallelic inactivation of TP53 was correlated with a high GI/HRD score. A combination of two gene alterations exhibited a higher GI/HRD scores than single gene alterations. The GI/HRD score was associated with advanced stages in lung adenocarcinoma but not in lung squamous cell carcinoma. Furthermore, patients with higher GI/HRD scores had significantly shorter overall survival and progression-free survival than patients with lower GI/HRD scores. Finally, patients with a combination of a higher GI/HRD scores and TP53 alteration exhibited an extremely poor prognosis compared with patients with a lower GI/HRD scores and wild-type TP53 (overall survival, training cohort, hazard ratio (HR) = 8.56, P < 0.001; validation cohort, HR = 6.47, P < 0.001; progression-free survival, HR = 4.76, P < 0.001). Our study revealed the prognostic value of the GI/HRD score in lung adenocarcinoma, but not for all lung cancer. Moreover, the combination of the GI/HRD score and TP53 status could be a promising strategy to predict the prognosis of patients with lung adenocarcinoma.

Fig. 1. The association of GI/HRD scores and genomic alterations in NSCLC.

a Distribution of HRD-related events (LOH, LST and TAI) on chromosomes. b Heatmap of genomic alterations (rate≥5%) and HRD scores. Red asterisks indicate positive correlations between gene alterations and HRD scores, and black asterisks indicate negative correlations. *Adjusted P < 0.05; **adjusted P < 0.01; *** adjusted P < 0.001. n = 1011. Student’s t test.

Fig. 2. The combination of altered genes is related to the GI/HRD score in NSCLC.

a Co-occurrence (red square) and mutually exclusive (blue square) gene alterations of NSCLC. *Adjusted P < 0.05; **adjusted P < 0.01. n = 1011. Fisher’s test. b GI/HRD score in patients with the indicated co-occurring gene alterations compared to single gene alterations. A indicates alteration, and W indicates wild-type. c GI/HRD score in patients with different TMB (tumor mutational burden) and ploidy levels. *P < 0.05; **P < 0.01. n = 1011. Student’s t test. Error bars represent standard error of the mean (SEM).

Fig. 3. ROC curves of the prediction of characteristics of advanced cancer with GI/HRD score and other markers in LUAD with complete clinicopathological features.

The area under the ROC curve and P value of the indicated markers are shown. ***Adjusted P < 0.001.

Fig. 4. Combination of GI/HRD score and TP53 status to predict overall and progression-free survival in LUAD.

a Overall survival analysis of LUAD patients with high GI/HRD score versus those with low GI/HRD score in the training cohort (n = 225) and validation cohort (n = 225). The cutoff value was determined by the highest 20% (All LUAD patients in Supplementary Fig. 3D, n = 800). GI/HRD score ≥24 was defined as GI/HRD score^high for further analysis. b Model of the genomic instability prognostic risk score (GI-pRS) according to multivariable analysis in Table 1. c, d Overall survival analysis was performed in the training cohort and validation cohort stratified by GI-pRS.