ORAOV1, CCND1, and MIR548K Are the Driver Oncogenes of the 11q13 Amplicon in Squamous Cell Carcinoma

Author:

Mahieu Céline I.1ORCID,Mancini Andrew G.2ORCID,Vikram Ellee P.1ORCID,Planells-Palop Vicente1ORCID,Joseph Nancy M.3ORCID,Tward Aaron D.1ORCID

Affiliation:

1. 1Department of Otolaryngology, Head and Neck Surgery, University of California San Francisco, San Francisco, Calfornia.

2. 2MaxCyte, Inc., Gaithersburg, Maryland.

3. 3Department of Pathology, University of California San Francisco, San Francisco, California.

Abstract

Abstract 11q13 amplification is a frequent event in human cancer and in particular in squamous cell carcinomas (SCC). Despite almost invariably spanning 10 genes, it is unclear which genetic components of the amplicon are the key driver events in SCC. A combination of computational, in vitro, ex vivo, and in vivo models leveraging efficient primary human keratinocyte genome editing by Cas9-RNP electroporation, identified ORAOV1, CCND1, and MIR548K as the critical drivers of the amplicon in head and neck SCC. CCND1 amplification drives the cell cycle in a CDK4/6/RB1-independent fashion and may confer a novel dependency on RRM2. MIR548K contributes to epithelial–mesenchymal transition. Finally, we identify ORAOV1 as an oncogene that acts likely via its ability to modulate reactive oxygen species. Thus, the 11q13 amplicon drives SCC through at least three independent genetic elements and suggests therapeutic targets for this morbid and lethal disease. Implications: This work demonstrates novel mechanisms and ways to target these mechanisms underlying the most common amplification in squamous cell carcinoma, one of the most prevalent and deadly forms of human cancer.

Funder

National Institute of Dental and Craniofacial Research

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology,Molecular Biology

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