Acha-Sagredo, A.; Ganguli, P.; Ciccarelli, F.D. Somatic Variation in Normal Tissues: Friend or Foe of Cancer Early Detection? Annals of Oncology 2022, 33, 1239–1249, doi:10.1016/j.annonc.2022.09.156.
Acha-Sagredo, A.; Ganguli, P.; Ciccarelli, F.D. Somatic Variation in Normal Tissues: Friend or Foe of Cancer Early Detection? Annals of Oncology 2022, 33, 1239–1249, doi:10.1016/j.annonc.2022.09.156.
Acha-Sagredo, A.; Ganguli, P.; Ciccarelli, F.D. Somatic Variation in Normal Tissues: Friend or Foe of Cancer Early Detection? Annals of Oncology 2022, 33, 1239–1249, doi:10.1016/j.annonc.2022.09.156.
Acha-Sagredo, A.; Ganguli, P.; Ciccarelli, F.D. Somatic Variation in Normal Tissues: Friend or Foe of Cancer Early Detection? Annals of Oncology 2022, 33, 1239–1249, doi:10.1016/j.annonc.2022.09.156.
Abstract
Seemingly normal tissues progressively become populated by mutant clones over time. Most of these clones bear mutations in well-known cancer genes but only rarely do they transform into cancer. This poses questions on what triggers cancer initiation and what implications somatic variation has for cancer early detection. We analysed recent mutational screens of healthy and cancer-free diseased tissues to compare somatic drivers and the causes of somatic variation across tissues. We then reviewed the mechanisms of clonal expansion and their relationships with age and diseases other than cancer. We finally discussed the relevance of somatic variation for cancer initiation and how it can help or hinder cancer detection and prevention. The extent of somatic variation is highly variable across tissues and depends on intrinsic features, such as tissue architecture and turnover, as well as the exposure to endogenous and exogenous insults. Most somatic mutations driving clone expansion are tissue-specific and inactivate tumour suppressor genes involved in chromatin modification and cell growth signalling. Some of these genes are more frequently mutated in normal tissues than cancer, indicating a context-dependent cancer promoting or protective role. Mutant clones can persist over a long time or disappear rapidly, suggesting that their fitness depends on the dynamic equilibrium with the environment. The disruption of this equilibrium is likely responsible for their transformation into malignant clones and knowing what triggers this process is key for cancer prevention and early detection. Somatic variation should be considered in liquid biopsy, where it may contribute cancer-independent mutations, and in the identification of cancer drivers, since not all mutated genes favouring clonal expansion also drive tumourigenesis. Somatic variation and the factors governing homeostasis of normal tissues should be taken into account when devising strategies for cancer prevention and early detection.
Keywords
Somatic evolution; driver gene; clone selection; healthy tissues; cancer initiation; cancer early detection
Subject
Biology and Life Sciences, Biology and Biotechnology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
