Lung-Enriched Mutations in the p53 Tumor Suppressor: A Paradigm for Tissue-Specific Gain of Oncogenic Function

Molecular Cancer Research : MCR
Julie A Barta, Steven B McMahon

Abstract

Lung cancer, the leading cause of cancer-related mortality in the United States, occurs primarily due to prolonged exposure to an array of carcinogenic compounds in cigarette smoke. These carcinogens create bulky DNA adducts, inducing alterations including missense mutations in the tumor suppressor gene TP53TP53 is the most commonly mutated gene in many human cancers, and a specific set of these variants are enriched in lung cancer (at amino acid residues V157, R158, and A159). This perspective postulates that lung-enriched mutations can be explained, in part, by biological selection for oncogenic gain-of-function (GOF) mutant p53 alleles at V157, R158, and A159. This hypothesis explaining tissue-specific TP53 mutations is further supported by mouse model studies of the canonical TP53 hotspots showing that tumor spectra and GOF activities are altered with mutation type. Therefore, although smoking-related lung cancer unequivocally arises due to the mutagenic environment induced by tobacco carcinogens, this perspective provides a rationale for the preferential selection of lung-enriched V157, R158, and A159 mutant p53.

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Citations

Nov 30, 2019·Oxidative Medicine and Cellular Longevity·Francesco CiccareseStefano Indraccolo
Jun 4, 2021·Experimental Biology and Medicine·Nathalie FuentesPatricia Silveyra
Jun 6, 2021·Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology·Loretta ErhunmwunseeStacy W Gray

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