Cells with cancer-associated mutations overtake our tissues as we age

Abstract

Background: To shed light on the earliest events in oncogenesis, there is growing interest in understanding the mutational landscapes of normal tissues across ages. In the last decade, next-generation sequencing of human tissues has revealed a surprising abundance of cells with what would be considered oncogenic mutations. Aims: We performed a meta-analysis on previously published sequencing data on normal tissues to categorize mutations based on their presence in cancer and showcase the quantity of cells with cancer-associated mutations in cancer-free individuals. Methods and results: We analyzed sequencing data from these studies of normal tissues to determine the prevalence of cells with mutations in three different categories across multiple age groups: (1) mutations in genes designated as drivers, (2) mutations that are in the Cancer Gene Census (CGC), and (3) mutations in the CGC that are considered pathogenic. As we age, the percentage of cells in all three levels increase significantly, reaching over 50% of cells having oncogenic mutations for multiple tissues in the older age groups. The clear enrichment for these mutations, particularly at older ages, likely indicates a strong selection for the resulting phenotypes. Combined with an estimation of the number of cells in tissues, we calculate that most older, cancer-free individuals possess at least 100 billion cells that harbor at least one oncogenic mutation, presumably emanating from a fitness advantage conferred by these mutations that promote clonal expansion. Conclusions: These studies of normal tissues have highlighted the specific drivers of clonal expansion and how frequently they appear in us. Their high prevalence throughout cancer-free individuals necessitates a reconsideration of the oncogenicity of these mutations, which could shape methods of detection, prevention, and treatment of cancer, as well as of the potential impact of these mutations on tissue function and our health.