[Variant Allele Frequency Stratification and EGFR Co-mutation Characteristics in AKT1 E17K-mutant Non-small Cell Lung Cancer].
- 1Department of Pathology, Beijing Chest Hospital, Capital Medical University/ Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China.
Abstract
Background
AKT serine/threonine kinase 1 (AKT1) E17K, the most common activating mutation of AKT1, is an established druggable driver in breast cancer; however, it is exceedingly rare in non-small cell lung cancer (NSCLC), with its clinical significance remaining unclear. Variant allele frequency (VAF) may partially reflect the clonal proportion of a mutation, offering clues to the clonal characteristics of such rare mutations. This study investigated the relationship between AKT1 E17K VAF and co-mutation with classic driver genes such as epidermal growth factor receptor (EGFR) in NSCLC, aiming to explore the potential role of this mutation in tumor clonal evolution.Methods
Next-generation sequencing (NGS) data of lung cancer patients at Beijing Chest Hospital, Capital Medical University from June 2019 to April 2026 were retrospectively analyzed. After deduplication of 13,003 tests, 11,368 unique patients (including small cell lung cancer) were identified, among whom 35 harbored AKT1 E17K mutations (overall detection rate 0.31%), all being NSCLC; 5 external consultation cases were excluded, leaving 30 cases for analysis. Continuous VAF analysis was designated as the primary analysis, with an exploratory cutoff of 10%.Results
Of the 30 patients, 20 (66.7%) were adenocarcinoma. Median follow-up was 12 months (range: 1-55 months). The EGFR co-mutation rate was lower in the high-VAF group (≥10%, n=17) than in the low-VAF group (<10%, n=13; 11.8% vs 46.2%), reaching nominal significance before correction [P=0.049, odds ratio (OR)=0.156] but not after Bonferroni adjustment (adjusted P=0.246). The median VAF was lower in the EGFR co-mutated group than in the EGFR wild-type group (1.37% vs 13.73%, P=0.071). Continuous analysis showed a negative trend between VAF and EGFR co-mutation (ρ=-0.340, P=0.066). After adjusting for histological type using Firth-corrected Logistic regression, the direction of the association remained unchanged but was no longer nominally significant (OR=0.21, 95%CI: 0.03-1.33, P=0.097).Conclusions
AKT1 E17K VAF showed a negative trend with EGFR co-mutation; however, the association did not remain significant after correction for multiple comparisons or adjustment for histological type, and may be partly influenced by histological composition. These findings should be regarded as hypothesis-generating and require validation in larger multi-center cohorts.
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BibTeX
@article{zhao2026variant,
title = {{[Variant Allele Frequency Stratification and EGFR Co-mutation Characteristics in AKT1 E17K-mutant Non-small Cell Lung Cancer].}},
author = {Dan Zhao and Deyang Xie and Nana Zhang and Lili Zhang and Kun Li and Nanying Che},
journal = {Zhongguo fei ai za zhi = Chinese journal of lung cancer},
year = {2026},
month = aug,
doi = {10.3779/j.issn.1009-3419.2026.106.24},
url = {https://europepmc.org/article/MED/42896970},
note = {CC BY},
}
RIS
TY - JOUR
TI - [Variant Allele Frequency Stratification and EGFR Co-mutation Characteristics in AKT1 E17K-mutant Non-small Cell Lung Cancer].
AU - Dan Zhao
AU - Deyang Xie
AU - Nana Zhang
AU - Lili Zhang
AU - Kun Li
AU - Nanying Che
PY - 2026
DA - 2026/08/01
JO - Zhongguo fei ai za zhi = Chinese journal of lung cancer
DO - 10.3779/j.issn.1009-3419.2026.106.24
UR - https://europepmc.org/article/MED/42896970
AB - Background AKT serine/threonine kinase 1 (AKT1) E17K, the most common activating mutation of AKT1, is an established druggable driver in breast cancer; however, it is exceedingly rare in non-small cell lung cancer (NSCLC), with its clinical significance remaining unclear. Variant allele frequency (VAF) may partially reflect the clonal proportion of a mutation, offering clues to the clonal characteristics of such rare mutations. This study investigated the relationship between AKT1 E17K VAF and co-mutation with classic driver genes such as epidermal growth factor receptor (EGFR) in NSCLC, aiming to explore the potential role of this mutation in tumor clonal evolution.Methods Next-generation sequencing (NGS) data of lung cancer patients at Beijing Chest Hospital, Capital Medical University from June 2019 to April 2026 were retrospectively analyzed. After deduplication of 13,003 tests, 11,368 unique patients (including small cell lung cancer) were identified, among whom 35 harbored AKT1 E17K mutations (overall detection rate 0.31%), all being NSCLC; 5 external consultation cases were excluded, leaving 30 cases for analysis. Continuous VAF analysis was designated as the primary analysis, with an exploratory cutoff of 10%.Results Of the 30 patients, 20 (66.7%) were adenocarcinoma. Median follow-up was 12 months (range: 1-55 months). The EGFR co-mutation rate was lower in the high-VAF group (≥10%, n=17) than in the low-VAF group (<10%, n=13; 11.8% vs 46.2%), reaching nominal significance before correction [P=0.049, odds ratio (OR)=0.156] but not after Bonferroni adjustment (adjusted P=0.246). The median VAF was lower in the EGFR co-mutated group than in the EGFR wild-type group (1.37% vs 13.73%, P=0.071). Continuous analysis showed a negative trend between VAF and EGFR co-mutation (ρ=-0.340, P=0.066). After adjusting for histological type using Firth-corrected Logistic regression, the direction of the association remained unchanged but was no longer nominally significant (OR=0.21, 95%CI: 0.03-1.33, P=0.097).Conclusions AKT1 E17K VAF showed a negative trend with EGFR co-mutation; however, the association did not remain significant after correction for multiple comparisons or adjustment for histological type, and may be partly influenced by histological composition. These findings should be regarded as hypothesis-generating and require validation in larger multi-center cohorts.
SN - 1009-3419
SN - 1999-6187
ER -