ABSTRACT
BACKGROUND: Studies of targeted therapy resistance in lung cancer have primarily focused on single-gene alterations. Based on prior work implicating apolipoprotein b mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) mutagenesis in histological transformation of epidermal growth factor receptor (EGFR)-mutant lung cancers, we hypothesized that mutational signature analysis may help elucidate acquired resistance to targeted therapies. PATIENTS AND METHODS: APOBEC mutational signatures derived from an Food and Drug Administration-cleared multigene panel [Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT)] using the Signature Multivariate Analysis (SigMA) algorithm were validated against the gold standard of mutational signatures derived from whole-exome sequencing. Mutational signatures were decomposed in 3276 unique lung adenocarcinomas (LUADs), including 93 paired osimertinib-naïve and -resistant EGFR-mutant tumors. Associations between APOBEC and mechanisms of resistance to osimertinib were investigated. Whole-genome sequencing was carried out on available EGFR-mutant lung cancer samples (10 paired, 17 unpaired) to investigate large-scale genomic alterations potentially contributing to osimertinib resistance. RESULTS: APOBEC mutational signatures were more frequent in receptor tyrosine kinase (RTK)-driven lung cancers (EGFR, ALK, RET, and ROS1; 25%) compared to LUADs at large (20%, P < 0.001); across all subtypes, APOBEC mutational signatures were enriched in subclonal mutations (P < 0.001). In EGFR-mutant lung cancers, osimertinib-resistant samples more frequently displayed an APOBEC-dominant mutational signature compared to osimertinib-naïve samples (28% versus 14%, P = 0.03). Specifically, mutations detected in osimertinib-resistant tumors but not in pre-treatment samples significantly more frequently displayed an APOBEC-dominant mutational signature (44% versus 23%, P < 0.001). EGFR-mutant samples with APOBEC-dominant signatures had enrichment of large-scale genomic rearrangements (P = 0.01) and kataegis (P = 0.03) in areas of APOBEC mutagenesis. CONCLUSIONS: APOBEC mutational signatures are frequent in RTK-driven LUADs and increase under the selective pressure of osimertinib in EGFR-mutant lung cancer. APOBEC mutational signature enrichment in subclonal mutations, private mutations acquired after osimertinib treatment, and areas of large-scale genomic rearrangements highlights a potentially fundamental role for APOBEC mutagenesis in the development of resistance to targeted therapies, which may be potentially exploited to overcome such resistance.
Subject(s)
Adenocarcinoma of Lung , Chromothripsis , Lung Neoplasms , Humans , Protein-Tyrosine Kinases/genetics , Drug Resistance, Neoplasm/genetics , Proto-Oncogene Proteins/genetics , ErbB Receptors/genetics , ErbB Receptors/metabolism , Aniline Compounds/pharmacology , Aniline Compounds/therapeutic use , Adenocarcinoma of Lung/drug therapy , Adenocarcinoma of Lung/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mutation , Receptor Protein-Tyrosine Kinases/genetics , Mutagenesis , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic useSubject(s)
Humans , Male , Female , Adult , Middle Aged , Carrier State/microbiology , Health Personnel , Staphylococcus aureus/isolation & purification , Methicillin Resistance , Microbial Sensitivity Tests , Nasal Mucosa/microbiology , Patients , Renal Insufficiency, Chronic , Teicoplanin , VancomycinSubject(s)
Humans , Male , Female , Adult , Middle Aged , Staphylococcus aureus/isolation & purification , Health Personnel , Carrier State/microbiology , Methicillin Resistance , Renal Insufficiency, Chronic , Nasal Mucosa/microbiology , Patients , Teicoplanin , Vancomycin , Microbial Sensitivity TestsABSTRACT
Siendo las diarreas una de las causas prioritarias de mortalidad infantil, se reseñan los datos epidemiológicos a nivel mundial. Se exponen los resultados de una investigación microbiológica efectuada sobre 150 niños de ambos sexos, de 0 a 5 años con diarrea, recabándose los datos socioeconómicos, higiénico-sanitarios y el estado nutricional. Se registró un 32,6 por ciento de patología bacteriana, 37 por ciento parasitaria y el 23 por ciento virológica. Se establece una relación con el grado de desnutrición y con los demás factores asociados y se destaca el avance de las posibilidades diagnósticas actuales
Subject(s)
Humans , Male , Female , Infant, Newborn , Infant , Child, Preschool , Clinical Laboratory Techniques/statistics & numerical data , Diarrhea, Infantile/epidemiology , Feces/microbiology , Diarrhea, Infantile/microbiology , Diarrhea, Infantile/parasitology , Feces/parasitologySubject(s)
Humans , Clinical Laboratory Techniques , Culture Media , Diarrhea, Infantile/diagnosis , Feces/microbiology , Aeromonas/isolation & purification , Algorithms , Campylobacter/isolation & purification , Clinical Laboratory Techniques/instrumentation , Clinical Laboratory Techniques/standards , Culture Media/classification , Diarrhea, Infantile/therapy , Escherichia coli/isolation & purification , Feces/parasitology , Salmonella/isolation & purification , Shigella/isolation & purification , Vibrio cholerae/isolation & purification , Yersinia/isolation & purificationABSTRACT
Siendo las diarreas una de las causas prioritarias de mortalidad infantil, se reseñan los datos epidemiológicos a nivel mundial. Se exponen los resultados de una investigación microbiológica efectuada sobre 150 niños de ambos sexos, de 0 a 5 años con diarrea, recabándose los datos socioeconómicos, higiénico-sanitarios y el estado nutricional. Se registró un 32,6 por ciento de patología bacteriana, 37 por ciento parasitaria y el 23 por ciento virológica. Se establece una relación con el grado de desnutrición y con los demás factores asociados y se destaca el avance de las posibilidades diagnósticas actuales (AU)
