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

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 TP53 TP53 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.

Figure 1.. Patterns in TP53 mutations vary by tumor type.

Number of somatic missense mutations are plotted for the most frequently mutated amino acid residues in the TP53 gene, by solid tumor type. Data are from The Cancer Genome Atlas (TCGA). (19) Total numbers of samples with TP53 missense mutations are: Lung adenocarcinoma and squamous cell carcinoma, 505; Breast adenocarcinoma, 179; Head and neck squamous cell carcinoma (HNSCC), 253; Gastric adenocarcinoma, 131; Ovarian serous cystadenocarcinoma, 179; Esophageal adenocarcinoma, 110; Hepatocellular carcinoma (HCC), 71; Colorectal adenocarcinoma, 83; Pancreatic adenocarcinoma, 72.

Figure 2.. Co-occurring mutations with TP53 in lung adenocarcinoma and lung squamous cell samples from AACR Project GENIE v3.0.0.

Prevalence of common co-occurring mutations in A. lung adenocarcinoma, and B. squamous cell lung cancers is shown for tumors harboring any mutation in TP53 vs. the cohort of lung-enriched mutations.