Mutations in normal tissues—some diagnostic and clinical implications

Abstract

Abstract Background It has long been known that mutations are at the core of many diseases, most notably cancer. Mutational analysis of tissues and fluids is useful for cancer and other disease diagnosis and management. Main body The prevailing cancer development hypothesis posits that cancer originates from mutations in cancer-driving genes that accumulate in tissues over time. These mutations then confer special characteristics to cancer cells, known as the hallmarks of cancer. Mutations in specific driver genes can lead to the formation of cancerous subclones and mutation risk increases with age. New research has revealed an unexpectedly large number of mutations in normal tissues; these findings could have significant implications to the understanding of the pathobiology of cancer and for disease diagnosis and therapy. Here, we discuss how the prevalence of mutations in normal tissues provides novel and relevant insights about clonal development in cancer and other diseases. Specifically, this review will focus on discussing mutations in normal tissues in the context of developing specific, circulating tumor DNA (ctDNA) tests for cancer, and evaluating clonal hematopoiesis as a predictor of blood cancers and cardiovascular pathology, as well as their implications to the phenomena of neural mosaicism in the context of Alzheimer’s disease. Conclusions In view of these new findings, the fundamental differences between the accumulation of genetic alterations in healthy, aging tissues compared to cancer and cardiovascular or neural diseases will need to be better delineated in the future.