RNA-Binding Protein Signature Could Help Stratify Risk in Lung Adenocarcinoma

A new model may be able to better identify which patients will respond to immunotherapy.

Investigators say they have constructed an immune-related RNA-binding protein (RBP) signature that can identify patients with lung adenocarcinoma who are at particularly high risk of poor outcomes.

The findings, published in Frontiers in Molecular Biosciences, appear to be effective independently of other risk factors, such as age, smoking history, and tumor node metastasis (TNM) status.

The authors noted that while multidisciplinary approaches to care have reduced mortality among patients with lung adenocarcinoma, only 15.9% of patients survive 5 years. They said immunotherapy, especially immune checkpoint inhibitors, has shifted treatment patterns, but not all regimens are effective for all patients.

“Some patients can obtain a long-lasting treatment response, but this only accounts for 20% to 40% of all patients,” they wrote.

Those data have created a push to better understand which patients are most likely to benefit from the treatment.

In that quest, the authors turned to RBPs, which regulate posttranscriptional processes, such as RNA splicing, modification, and transport. The investigators said RBPs appear to play an essential role in the occurrence and development of diseases like cancer.

“Identifying RBPs with potential predictive or prognostic functions may further broaden and open up new molecular markers,” they said.

In some cases, investigators have found that dysregulated expression of certain RBPs can affect treatment response.

“RBPs are considered essential regulators in the immune system and may be involved in immune modulation in the tumor microenvironment,” the authors wrote. “However, RBPs associated with immune-related genes (IRGs) are rarely reported.”

Zhang and colleagues wanted to see whether they could establish a coexpression network between RBPs and IRGs in order to develop an immune-related RBP signature that could serve as an effective prognostic marker.

They performed a correlation analysis on 497 lung adenocarcinoma cases to establish a coexpression network of RBPs and IRGs. Then they screened the RBPs to identify an immune-related RBP signature. Finally, they independently validated their findings using additional case cohorts. The result was a 4-gene signature involving DDX56, CTSL, ZC3H12D, and PSMC5.

The authors found patients with high-risk signatures had a significantly worse prognosis, tended to be older, and had an advanced TNM stage. However, the analysis also showed that the signature was predictive of outcomes even aside from age, gender, smoking history, TNM stage, or epidermal growth factor receptor mutation status.

High-risk scores correlated with tumor-infiltrating lymphocytes and higher PD-L1 protein expression, neoantigens, and tumor mutational burden. The investigators said this could indicate that the signature might be useful in predicting response to immunotherapy.

“In summary, the [immune-related RBP] gene signature provides an attractive platform for risk stratification of prognosis and efficacy in patients with [lung adenocarcinoma], which has important implications for the clinical management of patients with this fatal malignancy,” they concluded.

Although the model was successful at risk-stratifying patients, the authors said there were limits to its efficacy in predicting survival. They said it might be useful to combine the signature with clinical features to better enhance survival prediction. They also said further validation of the model is necessary to prove the concept.

Still, they said their study provides “important clues” about the role of RBP and its potential to help better risk stratify patients with lung adenocarcinoma.

Reference

Xu L, Li W, Yang T, et al. Immune-related RNA-binding protein-based signature with predictive and prognostic implications in patients with lung adenocarcinoma. Front Mol Biosci. Published online May 13, 2022. doi:10.3389/fmolb.2022.807622