The potential clinical benefit of routine comprehensive genomic profiling in non-small cell lung cancer for the detection of prognostic co-mutations – A multicenter next generation sequencing study

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• In 70.3% of the samples without an actionable genomic alteration, a mutation in the clinically relevant co-mutations TP53, STK11 and KEAP1 is detected. • Broad panel molecular diagnostic testing identifies additional clinically relevant mutations unaccounted for with limited Sanger sequencing. • Alterations in TP53 are mostly present in the DNA-binding domain of the TP53 -gene. • Most alterations in STK11 are detected in exon 1, which is hypothesized to be correlated to an oncogenic isoform. Non-driver mutations such as TP53, STK11 and KEAP1 are clinically relevant in determining immunotherapy efficacy in patients with non-small cell lung cancer (NSCLC). The aim of this study is to determine the prevalence and clinical relevance of variations in TP53, STK11 and KEAP1 in patients in the analysis of NSCLC, using targeted next-generation sequencing. This real-life prospective multicenter cohort study from July 2022 until October 2023 utilized samples of patients in the analysis of NSCLC. The samples were subjected to a targeted DNA NGS panel and, if indicated, RNA sequencing. The outcome of the molecular diagnostics was retrieved, including driver alterations and more in-depth analysis of TP53, STK11 and KEAP1 . In 134 of the 437 samples an actionable genomic alteration (AGA) was detected. Of the remaining samples, 213 carried a mutation in either TP53, STK11 and/or KEAP1 , while 90 harbored either variants of unknown significance (VUS) (16) or no variant (74). In-depth analysis showed 77 alterations of STK11 , with 56 pathogenic and 21 VUS. Most STK11 variants were identified in exon 1, which is hypothesized to be correlated to an oncogenic isoform. Moreover, variants in KEAP1 were mostly VUS, with 48 VUS and 24 mutations. Lastly, 264 TP53 alterations, of which 249 pathogenic and 15 VUS, occurred, with an even spread in the DNA-binding domain. This study demonstrated the broad spectrum of variants in STK11, KEAP1 and TP53 in routine panel-based DNA NGS, with 70.3% of the samples without AGA showing a potential clinically relevant mutation in TP53, STK11 and/or KEAP1 .

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