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Published on: September 20, 2016
Somatic KMT2D loss-of-function mutations in lung squamous cell carcinoma: a single-center cohort study
Zekui Fang1, Xiping Wu1, Li Xiao2
1Department of Pulmonary and Critical Care Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Background:
The significant progress has been made in targeted therapy for lung adenocarcinoma (LUAD) in the past decade. Only few targeted therapeutics have yet been approved for the treatment of lung squamous cell carcinoma (LUSC). Several higher frequency of gene alterations are identified as potentially actionable in LUSC. Our work aimed to explore the complex interplay of multiple genetic alterations and pathways contributing to the pathogenesis of LUSC, with a very low frequency of a single driver molecular alterations to develop more effective therapeutic strategies in the future.
Methods:
We retrospectively analyzed the targeted next-generation sequencing (NGS) data (approximately 600 genes) of 335 patients initially diagnosed with non-small cell lung cancer (NSCLC) at our institution between January 2019 and March 2023 and explored the somatic genome alteration difference between LUSC and LUAD.
Results:
We analyzed that the presence of loss-of-function (LoF) mutations (nonsense, frameshift, and splice-site variants) in histone-lysine N-methyltransferase 2D (KMT2D) was much more prevalent in LUSC (11/53, 20.8%) than in LUAD (6/282, 2.1%). Moreover, our data indicated TP53 co-mutated with KMT2D LoF in 90.9% (10/11) LUSC and 33.3% (2/6) LUAD. Notably, the mutation allele fraction (MAF) of KMT2D was very similar to that of TP53 in the co-mutated cases. Genomic profiling of driver gene mutations of NSCLC showed that 81.8% (9/11) of the patients with LUSC with KMT2D LoF mutations had PIK3CA amplification and/or FGFR1 amplification.
Conclusions:
Our results prompted that somatic LoF mutations of KMT2D occur frequently in LUSC, but are less frequent in LUAD and therefore may potentially contribute to the pathogenesis of LUSC. Concurrent TP53 mutations, FGFR1 amplification, and PIK3CA amplification are very common in LUSC cases with KMT2D LoF mutations. It needs more deeper investigation on the interplay of the genes and pathways and uses larger cohorts in the future.
Insights
Loss-of-function mutations in KMT2D are common in lung squamous cell carcinoma (LUSC) but rare in lung adenocarcinoma (LUAD). These mutations often co-occur with TP53, FGFR1, and PIK3CA alterations in LUSC, suggesting new therapeutic targets.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Lung adenocarcinoma (LUAD) has seen significant progress in targeted therapy.
- Lung squamous cell carcinoma (LUSC) has limited targeted therapeutics, despite actionable gene alterations.
- Understanding LUSC pathogenesis requires exploring complex genetic interactions.
Purpose of the Study:
- To investigate the role of genetic alterations in LUSC pathogenesis.
- To explore the interplay of multiple genetic alterations and pathways in LUSC.
- To identify potential therapeutic strategies for LUSC based on genetic profiles.
Main Methods:
- Retrospective analysis of targeted next-generation sequencing (NGS) data from 335 non-small cell lung cancer (NSCLC) patients.
- Comparison of somatic genome alterations between LUSC and LUAD cohorts.
- Analysis of specific gene mutations including KMT2D, TP53, PIK3CA, and FGFR1.
Main Results:
- Loss-of-function (LoF) mutations in KMT2D were significantly more prevalent in LUSC (20.8%) than LUAD (2.1%).
- KMT2D LoF mutations frequently co-occurred with TP53 mutations in LUSC (90.9%).
- LUSC cases with KMT2D LoF mutations often showed PIK3CA and/or FGFR1 amplification (81.8%).
Conclusions:
- Somatic LoF mutations in KMT2D may contribute to LUSC pathogenesis.
- Concurrent TP53 mutations and PIK3CA/FGFR1 amplifications are common in LUSC with KMT2D LoF.
- Further investigation with larger cohorts is needed to understand gene and pathway interplay in LUSC.
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