APOBEC mutagenesis and selection for NFE2L2 contribute to the origin of lung squamous-cell carcinoma. (September 2022)

• Record Type: Journal Article
• Authors: Cannataro, Vincent L.; Kudalkar, Shalley; Dasari, Krishna; Gaffney, Stephen G.; Lazowski, Heather M.; Jackson, Laura K.; Yildiz, Isil; Das, Rahul K.; Gould Rothberg, Bonnie E.; Anderson, Karen S.; Townsend, Jeffrey P.
• Is Part Of: Lung cancer. Volume 171(2022)
• Page Start: 34
• Page End: 41
• Publication Date: 2022-09
• Subjects: Cancer evolution -- Molecular signatures -- NFE2L2 -- APOBEC -- Molecular epidemiology; Lungs -- Cancer -- Periodicals; Lung Neoplasms -- Abstracts; Lung Neoplasms -- Periodicals; Poumons -- Cancer -- Périodiques; Lungs -- Cancer; Periodicals; Electronic journals; Electronic journals; 616.99424
• DOI: 10.1016/j.lungcan.2022.07.004
• Languages: English
• ISSNs: 0169-5002

Abstract

Highlights: Both endogenous and exogenous mutational processes contribute to LUSC mutagenesis. Variants contributing to the cancer phenotype are associated with aging, tobacco smoking, and APOBEC mutagenesis. Variants of high effect in TP53 are attributable to signatures associated with tobacco smoking. Variants of high effect in PIK3CA and NFE2L2 are attributable to signatures associated with APOBEC activity. APOBEC3B effectively deaminates an NFE2L2 oligonucleotide sequence in vitro. Abstract: Lung squamous-cell carcinoma originates as a consequence of oncogenic molecular variants arising from diverse mutagenic processes such as tobacco, defective homologous recombination, aging, and cytidine deamination by APOBEC proteins. Only some of the many variants generated by these processes actually contribute to tumorigenesis. Therefore, molecular investigation of mutagenic processes such as cytidine deamination by APOBEC should also determine whether the mutations produced by these processes contribute substantially to the growth and survival of cancer. Here, we determine the processes that gave rise to mutations of 681 lung squamous-cell carcinomas, and quantify the probability that each mutation was the product of each process. We then calculate the contribution of each mutation to increases in cellular proliferation and survival. We performed in vitro experiments to determine cytidine deamination activity of APOBEC3B against oligonucleotides corresponding with genomic sequences that give rise to variants of high cancer effect size. The largest APOBEC-related cancer effects are attributable to mutations in PIK3CA and NFE2L2. We demonstrate that APOBEC effectively deaminates NFE2L2 at the locations that confer high cancer effect. Overall, we demonstrate that APOBEC activity can lead to mutations in NFE2L2 that have large contributions to cancer cell growth and survival, and that NFE2L2 is an attractive potential target for therapeutic intervention.