APOBEC mutagenesis, kataegis, chromothripsis in EGFR-mutant osimertinib-resistant lung adenocarcinomas

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1284-1295
Number of pages12
JournalAnnals of Oncology
Issue number12
StatePublished - Dec 2022


  • EGFR
  • acquired resistance
  • mutational signatures
  • osimertinib

ASJC Scopus subject areas

  • Hematology
  • Oncology


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