التفاصيل البيبلوغرافية
| العنوان: |
APOBEC mutagenesis, kataegis, chromothripsis in EGFR-mutant osimertinib-resistant lung adenocarcinomas |
| المؤلفون: |
P, Selenica, A, Marra, N J, Choudhury, A, Gazzo, C J, Falcon, J, Patel, X, Pei, Y, Zhu, C K Y, Ng, M, Curry, G, Heller, Y-K, Zhang, M F, Berger, M, Ladanyi, C M, Rudin, S, Chandarlapaty, C M, Lovly, J S, Reis-Filho, H A, Yu |
| بيانات النشر: |
Oxford University Press, 2022. |
| سنة النشر: |
2022 |
| مصطلحات موضوعية: |
Chromothripsis, Aniline Compounds, Lung Neoplasms, Receptor Protein-Tyrosine Kinases, Adenocarcinoma of Lung, Hematology, Protein-Tyrosine Kinases, ErbB Receptors, Oncology, Drug Resistance, Neoplasm, Mutagenesis, Proto-Oncogene Proteins, Mutation, Humans, 610 Medicine & health, Protein Kinase Inhibitors |
| الوصف: |
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.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.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%, P0.001); across all subtypes, APOBEC mutational signatures were enriched in subclonal mutations (P0.001). 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%, P0.001). 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.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. |
| DOI: |
10.48350/172874 |
| URL الوصول: |
https://explore.openaire.eu/search/publication?articleId=doi_dedup___::489362d8fe1f3452c071fd88fa3f3ebb |
| Rights: |
EMBARGO |
| رقم الانضمام: |
edsair.doi.dedup.....489362d8fe1f3452c071fd88fa3f3ebb |
| قاعدة البيانات: |
OpenAIRE |