Mutations in normal tissues—some diagnostic and clinical implications

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.

Whole genome sequencing of low input circulating cell‐free DNA obtained from normal human subjects

“…This frequency has been reported frequently in the literature and resembles the COSMIC database clock-like mutation signature, SBS5. Fiala and Diamandis (2020) reviewed mutations present in normal tissues and venous liquid biopsies in the context of developing specific ctDNA test for cancer, evaluating clonal hematopoiesis, cardiovascular pathology, and neural mosaicism in Alzheimer's disease (Fiala & Diamandis, 2020). In this review paper, work by Lodato et al (2018), delineated three mutational signatures from single cell neurons isolated from the prefrontal cortex and hippocampus brain regions from healthy subjects and those diagnosed with early onset, hereditary neurodegenerative disorders, Cockayne syndrome, and Xeroderma pigmentosum (Lodato et al, 2018).…”

Aging and Cancer: The Waning of Community Bonds

“…However, none of these protective strategies attains perfect efficiency, thereby leading to the accumulation of DNA alterations that are typically observed during aging in several cell types, including stem cell compartments [ 40 , 46 , 47 , 48 , 49 ]. Building on the somatic mutation theory of cancer development, it is then postulated that the age-associated progressive rise in mutational burden increases the possibility of the appearance of overtly neoplastic cells endowed with the right combination of altered genes [ 50 , 51 , 52 ]. A more updated/refined version of this hypothesis centers on the emergence of rare cells harboring a “mutator phenotype”, which would set the stage for additional genetic alterations and neoplastic progression [ 53 ].…”

Mass spectrometric profiling of DNA adducts in the human stomach associated with damage from environmental factors

“…In addition, promoter methylation in gastric and urothelial mucosa has been widely investigated [ 8 , 9 ]. Reports of mutations found in “normal” tissues by using deep sequencing have given us new insight into our understanding of the origin of human cancer [ 10 , 11 ]. The initial events responsible for these carcinogenic and irreversible mutations involve DNA adduct formation, which is the focus of this paper.…”