title: Mutant TP53 disrupts age-related accumulation patterns of somatic mutations in multiple cancer types.
abstract: Most cancers are driven by somatic mutations in proto-oncogenes and tumor suppressor genes. Genetic changes in a tumor may accumulate in the tissue self-renewal phase prior to neoplasm. The risk of sporadic mutations increases with age. In this regard, a positive association between patient age and the accumulated mutation burden in tumors exists for many cancer types. However, the reported lines of evidence for such a connection are still limited. TP53 is the most frequently mutated cancer gene. The encoded p53 protein plays crucial roles in DNA repair. Hereby, we speculate that mutant TP53 can disrupt the age-related accumulation patterns of somatic mutations in tumors. We performed linear model analysis on the clinically-annotated genomic data published by TCGA. We found that there was a significant interaction between TP53 genotype (mutant versus wild-type) and patient age at the initial clinical date on somatic mutation burden for five cancers. That is, the regression coefficients of mutation burden on patient age were significant (p < 0.05) for TP53 wild-type tumors but not the mutant counterparts. This disparity was further verified by comparing the group-specific regression coefficients. This finding confirmed our hypothesis and provided unique insights into p53-related tumorigenesis such as the potential temporal order of driver mutations.
authors.affiliation: Department of Computer Science, Xavier University of Louisiana, New Orleans, LA, USA.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Tulane Cancer Center, Tulane University, New Orleans, LA, USA.
authors.forename: Erik K
authors.initials: EK
authors.lastname: Flemington
authors.affiliation: Department of Computer Science, Xavier University of Louisiana, New Orleans, LA, USA. Electronic address: kzhang@xula.edu.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
mesh_terms: D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
chemical_list: D016159:Tumor Suppressor Protein p53
keywords: TP53; age-related patterns; linear models; multiple cancer types; somatic mutations