Genome-wide profiling of non-smoking-related lung cancer cells reveals common RB1 rearrangements associated with histopathologic transformation in EGFR-mutant tumors

E. Pros, M. Saigi, D. Alameda, G. Gomez-Mariano, B. Martinez-Delgado, J. J. Alburquerque-Bejar, J. Carretero, R. Tonda, A. Esteve-Codina, I. Catala, R. Palmero, M. Jove, C. Lazaro, A. Patiño-Garcia, I. Gil-Bazo, S. Verdura, A. Teulé, J. Torres-Lanzas, D. Sidransky, N. ReguartR. Pio, O. Juan-Vidal, E. Nadal, E. Felip, L. M. Montuenga, M. Sanchez-Cespedes

Research output: Contribution to journalArticlepeer-review

Abstract

Background: The etiology and the molecular basis of lung adenocarcinomas (LuADs) in nonsmokers are currently unknown. Furthermore, the scarcity of available primary cultures continues to hamper our biological understanding of non-smoking-related lung adenocarcinomas (NSK-LuADs). Patients and methods: We established patient-derived cancer cell (PDC) cultures from metastatic NSK-LuADs, including two pairs of matched EGFR-mutant PDCs before and after resistance to tyrosine kinase inhibitors (TKIs), and then performed whole-exome and RNA sequencing to delineate their genomic architecture. For validation, we analyzed independent cohorts of primary LuADs. Results: In addition to known non-smoker-associated alterations (e.g. RET, ALK, EGFR, and ERBB2), we discovered novel fusions and recurrently mutated genes, including ATF7IP, a regulator of gene expression, that was inactivated in 5% of primary LuAD cases. We also found germline mutations at dominant familiar-cancer genes, highlighting the importance of genetic predisposition in the origin of a subset of NSK-LuADs. Furthermore, there was an over-representation of inactivating alterations at RB1, mostly through complex intragenic rearrangements, in treatment-naive EGFR-mutant LuADs. Three EGFR-mutant and one EGFR-wild-type tumors acquired resistance to EGFR-TKIs and chemotherapy, respectively, and histology on re-biopsies revealed the development of small-cell lung cancer/squamous cell carcinoma (SCLC/LuSCC) transformation. These features were consistent with RB1 inactivation and acquired EGFR-T790M mutation or FGFR3–TACC3 fusion in EGFR-mutant tumors. Conclusions: We found recurrent alterations in LuADs that deserve further exploration. Our work also demonstrates that a subset of NSK-LuADs arises within cancer-predisposition syndromes. The preferential occurrence of RB1 inactivation, via complex rearrangements, found in EGFR-mutant tumors appears to favor SCLC/LuSCC transformation under growth-inhibition pressures. Thus RB1 inactivation may predict the risk of LuAD transformation to a more aggressive type of lung cancer, and may need to be considered as a part of the clinical management of NSK-LuADs patients.

Original languageEnglish (US)
Pages (from-to)274-282
Number of pages9
JournalAnnals of Oncology
Volume31
Issue number2
DOIs
StatePublished - Feb 2020

Keywords

  • EGFR
  • RB1
  • lung adenocarcinoma
  • nonsmokers
  • tyrosine kinase inhibitors
  • whole-exome sequencing

ASJC Scopus subject areas

  • Hematology
  • Oncology

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