Exploring diverse programmed cell-death patterns to develop a novel gene signature for predicting the prognosis of lung adenocarcinoma patients.

Abstract

Programmed cell death (PCD) plays a critical role in tumor progression and malignancy, and exploring its relationship with lung adenocarcinoma (LUAD)'s survival outcomes is important for personalized diagnosis and treatment. This study aimed to identify survival-related genes and construct an effective prognostic indicator for LUAD based on 12 forms of PCD. A total of 1,933 candidate genes related to PCD were collected from published studies and public data center. A prognostic gene signature, called the cell death index (CDI), was established based on RNA-Seq and immunohistochemistry (IHC). IHC staining on tissue microarray was applied for the validation of protein level. Moreover, GSE42127, GSE72094 were used as validation datasets. The CDI based on expression level of nine genes (CCNB2, HMGA1, CACNA2D2, BUB1B, BTG2, KIF14, PTGDS, SERPINB5, BRCA1) was highly predictive for overall survival (OS) of LUAD in our cohort [36-month area under the curve (AUC): 0.750, 60-month AUC: 0.809]. The CDI was further validated in independent cohorts (GSE72094, 36-month AUC: 0.717, 60-month AUC: 0.737; GSE42127, 12-month AUC: 0.829, 60-month AUC: 0.663). And the CDI was found to be an independent prognostic factor after adjusting for other clinical characteristics. Furthermore, the high-CDI group was associated with upregulated tumor immune infiltration compared to the low-CDI group. This study identified a 9-gene signature (CDI) based on PCD-related genes that accurately predicted the prognosis of LUAD patients. The CDI could serve as a valuable prognostic indicator and guide personalized therapeutic strategies for LUAD.