Related Experiment Video
Updated: Dec 8, 2025
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
KRAS G12D mutation predicts lower TMB and drives immune suppression in lung adenocarcinoma
Ge Gao1, Weiting Liao2, Qizhi Ma1
1Department of Thoracic Oncology, Cancer Center, West China Hospital, Chengdu, Sichuan Province, 610041, China.
Objectives:
The efficacy of anti- programmed cell death 1 (PD-1)/PD-1 ligand (PD-L1) immune checkpoint inhibitors remains controversial in patients with KRAS mutation. In addition, whether and how KRAS gene and its mutant subtypes might influence immunity has not been clarified yet. Here we examine some important biomarkers for the efficacy of immunotherapy in specific KRAS subtypes.
Materials And Methods:
We conducted a bioinformatics analysis on somatic mutations data, transcriptome sequencing data and proteomic data from The Cancer Genome Atlas (TCGA) database. CIBERSORT was used to provide an estimation of the abundances of immune cells using gene expression data.
Results:
From a cohort of 567 patients with lung adenocarcinoma (LUAD) based on TCGA, the overall mutation rate of KRAS was 26.29 %, including KRAS/TP53 co-mutation rate of 9.7 %. We observed increased Tumor mutation burden (TMB) in KRAS mutant group compared with wild type, while no difference in PD-L1 expression and immune cell infiltration. More importantly, TP53 and KRAS/TP53 co-mutation group not only significantly increased tumor mutation burden, but also had higher PD-L1 protein level and immune cell infiltration. We further focused on influence of KRAS mutant subtype on immune biomarker. The most prevalent mutant subtype of KRAS in lung adenocarcinoma was G12C(9.88 %,56/567), followed by G12 V(5.82 %,33/567), G12D(3.00 %,17/567), G12A(3.00 %,17/567), respectively. Among them, G12D mutation appeared to be a special mutant subtype with an obviously lower TMB. This low mutation load was more significant when co-mutation with TP53. Besides, our results also revealed significantly decreased expressions of PD-L1 protein level and immune cell infiltration (activated CD4 memory T cell, helper T cell, M1 macrophage and NK cell) in KRAS G12D/TP53 mutant group.
Conclusion:
KRAS G12D/TP53 co-mutation drives immune suppression and might be a negative predictive biomarker for anti-PD-1/PD-L1 immune checkpoint inhibitors in patients with lung adenocarcinoma.
Insights
KRAS G12D/TP53 co-mutation in lung adenocarcinoma suppresses immunity, potentially predicting poor response to PD-1/PD-L1 inhibitors. This finding is crucial for understanding immunotherapy efficacy in KRAS-mutated cancers.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- The efficacy of immune checkpoint inhibitors (ICIs) like anti-programmed cell death 1 (PD-1)/PD-1 ligand (PD-L1) is debated in KRAS-mutated cancers.
- The specific impact of KRAS gene mutations and their subtypes on anti-tumor immunity remains unclear.
Purpose of the Study:
- To investigate the influence of KRAS mutations and their subtypes on immune biomarkers.
- To identify potential predictive biomarkers for immunotherapy response in lung adenocarcinoma.
Main Methods:
- Bioinformatics analysis of The Cancer Genome Atlas (TCGA) database, including somatic mutations, transcriptome, and proteomic data.
- Estimation of immune cell abundances using CIBERSORT based on gene expression data.
Main Results:
- KRAS mutations were found in 26.29% of lung adenocarcinoma (LUAD) patients, with KRAS/TP53 co-mutation in 9.7%.
- KRAS mutant tumors showed increased Tumor Mutation Burden (TMB), but PD-L1 expression and immune cell infiltration were not significantly different compared to wild-type.
- KRAS G12D/TP53 co-mutation was associated with significantly lower TMB, decreased PD-L1 protein levels, and reduced infiltration of key immune cells (CD4 memory T cells, helper T cells, M1 macrophages, NK cells).
Conclusions:
- KRAS G12D/TP53 co-mutation drives immune suppression in LUAD.
- This specific co-mutation may serve as a negative predictive biomarker for anti-PD-1/PD-L1 therapy in lung adenocarcinoma.
More Related Videos
Related Concept Videos
02:38The Ras Gene
Ras is a...
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
02:23Abnormal Proliferation
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...