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Mutations in long-lived epithelial stem cells and their clonal progeny in pre-malignant lesions and in oral squamous cell carcinoma.

Authors
  • Melis, Marta1, 2
  • Zhang, Tuo3, 4
  • Scognamiglio, Theresa5
  • Gudas, Lorraine J1, 2, 6
  • 1 Department of Pharmacology, Weill Cornell Medicine, New York, NY, USA.
  • 2 Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
  • 3 Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA. , (Israel)
  • 4 Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA.
  • 5 Pathology and Laboratory Medicine, Cornell University Joan and Sanford I Weill Medical College, New York, NY, USA.
  • 6 Weill Cornell Graduate School of Biomedical Sciences, New York, NY, USA.
Type
Published Article
Journal
Carcinogenesis
Publisher
Oxford University Press
Publication Date
Nov 13, 2020
Volume
41
Issue
11
Pages
1553–1564
Identifiers
DOI: 10.1093/carcin/bgaa019
PMID: 32115621
Source
Medline
Language
English
License
Unknown

Abstract

Oral squamous cell carcinomas (OSCCs) are the most common cancers of the oral cavity, but the molecular mechanisms driving OSCC carcinogenesis remain unclear. Our group previously established a murine OSCC model based on a 10-week carcinogen [4-nitroquinoline 1-oxide (4-NQO)] treatment. Here we used K14CreERTAM;Rosa26LacZ mice to perform lineage tracing to delineate the mutational profiles in clonal cell populations resulting from single, long-lived epithelial stem cells, here called LacZ+ stem cell clones (LSCCs). Using laser-capture microdissection, we examined mutational changes in LSCCs immediately after the 10-week 4-NQO treatment and >17 weeks after 4-NQO treatment. We found a 1.8-fold ±0.4 (P = 0.009) increase in single-nucleotide variants and insertions/deletions (indels) in tumor compared with pre-neoplastic LSCCs. The percentages of indels and of loss of heterozygosity events were 1.3-fold±0.3 (P = 0.02) and 2.2-fold±0.7 (P = 0.08) higher in pre-neoplastic compared with tumor LSCCs. Mutations in cell adhesion- and development-associated genes occurred in 83% of the tumor LSCCs. Frequently mutated genes in tumor LSCCs were involved in planar cell polarity (Celsr1, Fat4) or development (Notch1). Chromosomal amplifications in 50% of the tumor LSCCs occurred in epidermal growth factor receptor, phosphoinositide 3-kinase and cell adhesion pathways. All pre-neoplastic and tumor LSCCs were characterized by key smoking-associated changes also observed in human OSCC, C>A and G>T. DeconstructSigs analysis identified smoking and head and neck cancer as the most frequent mutational signatures in pre-neoplastic and tumor LSCCs. Thus, this model recapitulates a smoking-associated mutational profile also observed in humans and illustrates the role of LSCCs in early carcinogenesis and OSCCs. © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]

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