Abstract
BackgroundIt 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 bodyThe 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.ConclusionsIn 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.
Highlights
It has long been known that mutations are at the core of many diseases, most notably cancer
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
Several studies have found an approximate range of human germline mutation rates: 1.0–1.2 × 10−8 per nucleotide per generation and up to 10% of these mutations are deleterious to some degree [3, 4]
Summary
Studying the transition of tissues from normal to diseased may enable early diagnosis as well as mechanisms for targeted pharmacology Even though this branch of science is in its infancy, the scientific dogma is changing with the awareness that heavily mutated tissues are not necessarily hallmarks of disease but are the new normal [58]. More studies and projects are addressing this dearth of information, studying genetic events and clonal properties from a wide variety of tissue samples and participants [21] One such initiative is the National Cancer Institute’s Pre-Cancer Genome Atlas [60], a large-scale collaboration to create a comprehensive database of histological and genomic/proteomic data from premalignant lesions which will produce new opportunities for early detection and risk stratification.
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