Somatic KMT2D loss-of-function mutations in lung squamous cell carcinoma: a single-center cohort study

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. 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. We analyzed that the presence of loss-of-function (LoF) mutations (nonsense, frameshift, and splice-site variants) in histone-lysine N-methyltransferase 2D ( ) 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 LoF in 90.9% (10/11) LUSC and 33.3% (2/6) LUAD. Notably, the mutation allele fraction (MAF) of was very similar to that of 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 LoF mutations had amplification and/or amplification. Our results prompted that somatic LoF mutations of occur frequently in LUSC, but are less frequent in LUAD and therefore may potentially contribute to the pathogenesis of LUSC. Concurrent mutations, amplification, and amplification are very common in LUSC cases with LoF mutations. It needs more deeper investigation on the interplay of the genes and pathways and uses larger cohorts in the future.