Cancer-Associated Mutations but No Cancer: Insights into the Early Steps of Carcinogenesis and Implications for Early Cancer Detection

Abstract

Cancer is a disease of aging fueled by the accumulation of somatic mutations. While mutations in tumors are well characterized, little is known about the early mutational processes that initiate tumorigenesis. Recent advances in next-generation sequencing (NGS) have enabled the detection of mutations in normal tissue, revealing an unanticipated high level of age-related somatic mutations affecting most individuals and tissues. Surprisingly, many of these mutations are similar to mutations commonly found in tumors, suggesting an ongoing process of positive selection and clonal expansion akin to what occurs in cancer, but within normal tissue. Here we discuss some of the most important biological and clinical implications of these novel findings, with a special focus on their impact for cancer detection and prediction.

Keywords: aging; cancer-associated mutations; early cancer detection; somatic mutations; tumor evolution.

Figure 1. Key Figure. Somatic Evolution as a Process of Normal Human Aging and Cancer

DNA mutations inevitably accumulate throughout life due to DNA replication and environmental and lifestyle factors. Mutations might be neutral (grey lines), deleterious (X), or might confer a proliferative advantage and the cell clonally expands (green, blue, yellow). These initial clonal expansions provide pools of mutated cells in which subsequent mutations could enable transformation properties. The large majority of clones, however, do not evolve into malignancy, which is likely due to the action of tumor suppressor mechanisms. In a subset of individuals, at older ages, tumor suppressor mechanisms are bypassed by the accumulation of additional mutations that abrogate these mechanisms and/or by their declining action with age (e.g., decreased immunity). Additional rounds of mutation, selection, and clonal expansions enable cancer cells to acquire the malignant properties characteristic of this disease. A biopsy taken at mid-age (blue broken line rectangle) might carry cancer-associated mutations from cells that have clonally expanded but are not malignant (often termed biological background mutations). In a biopsy taken when cancer has developed (orange broken line rectangle), the tumor derived clone might be identifiable due to its larger size compared with the background clones. Abbreviation: ROS, reactive oxygen species.

Figure 2.. Features of Cancer Mutations in Normal Tissue (A), Identified Challenges (B), and Potential Solutions (C).

The high prevalence of cancer-associated mutations in normal tissue challenges the specificity of cancer diagnostic tests based on liquid biopsies. This challenge highlights the urgent need to characterize mutations in normal tissue in order to enable the distinction of age-related clonal expansions from truly carcinogenic ones.