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


Authors: Selenica, P.; Marra, A.; Choudhury, N. J.; Gazzo, A.; Falcon, C. J.; Patel, J.; Pei, X.; Zhu, Y.; Ng, C. K. Y.; Curry, M.; Heller, G.; Zhang, Y. K.; Berger, M. F.; Ladanyi, M.; Rudin, C. M.; Chandarlapaty, S.; Lovly, C. M.; Reis-Filho, J. S.; Yu, H. A.
Article Title: APOBEC mutagenesis, kataegis, chromothripsis in EGFR-mutant osimertinib-resistant lung adenocarcinomas
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. © 2022 European Society for Medical Oncology
Keywords: controlled study; human tissue; oncoprotein; gene mutation; human cell; major clinical study; genetics; mutation; proto-oncogene proteins; comparative study; gold standard; metabolism; protein kinase inhibitor; lung neoplasms; epidermal growth factor receptor; cohort analysis; drug resistance; pathology; drug resistance, neoplasm; protein tyrosine kinase; protein kinase inhibitors; lung tumor; lung adenocarcinoma; gene rearrangement; protein-tyrosine kinases; receptor protein-tyrosine kinases; aniline compounds; cancer tissue; egfr; egfr gene; protein ret; mutagenesis; egfr protein, human; anaplastic lymphoma kinase; molecularly targeted therapy; adenocarcinoma of lung; acquired resistance; aniline derivative; ret gene; erbb receptors; alk gene; chromothripsis; humans; human; article; whole exome sequencing; osimertinib; mutational signatures; apobec; apolipoprotein b mrna editing enzyme catalytic polypeptide like; apobec gene; rtk gene
Journal Title: Annals of Oncology
Volume: 33
Issue: 12
ISSN: 0923-7534
Publisher: Oxford University Press  
Date Published: 2022-12-01
Start Page: 1284
End Page: 1295
Language: English
DOI: 10.1016/j.annonc.2022.09.151
PUBMED: 36089134
PROVIDER: scopus
PMCID: PMC10360454
DOI/URL:
Notes: The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding author is MSK author Helena A. Yu -- Export Date: 3 January 2023 -- Source: Scopus
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
  1. Glenn Heller
    400 Heller
  2. Helena Alexandra Yu
    288 Yu
  3. Marc Ladanyi
    1332 Ladanyi
  4. Michael Forman Berger
    768 Berger
  5. Xin Pei
    136 Pei
  6. Charles Rudin
    495 Rudin
  7. Pier Selenica
    193 Selenica
  8. Juber Ahamad Abdul Bari Patel
    33 Patel
  9. Michael A Curry
    32 Curry
  10. Andrea Maria Gazzo
    56 Gazzo
  11. Christina Jade Falcon
    45 Falcon
  12. Yingjie Zhu
    31 Zhu
  13. Antonio Marra
    46 Marra