TY - JOUR
T1 - Somatic variation in normal tissues
T2 - friend or foe of cancer early detection?
AU - Acha-Sagredo, A
AU - Ganguli, P
AU - Ciccarelli, F D
N1 - Funding Information:
This work was supported by Cancer Research UK [grant numbers C43634/A25487, EDDPJT-Nov21∖100010 to FDC]; the Cancer Research UK City of London Centre [grant number C7893/A26233 to FDC]; innovation programme under the Marie Skłodowska-Curie [grant number CONTRA-766030]; and the Francis Crick Institute , which receives its core funding from Cancer Research UK [grant number FC001002], the UK Medical Research Council [grant number FC001002], and the Wellcome Trust [grant number FC001002]. For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission.
Publisher Copyright:
© 2022 The Author(s)
PY - 2022/12
Y1 - 2022/12
N2 - Background: 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. Design: We analyzed 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. Results: 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 clonal expansion are tissue-specific and inactivate tumor suppressor genes involved in chromatin modification and cell growth signaling. 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 favoring clonal expansion also drive tumorigenesis. Conclusion: Somatic variation and the factors governing homeostasis of normal tissues should be taken into account when devising strategies for cancer prevention and early detection.
AB - Background: 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. Design: We analyzed 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. Results: 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 clonal expansion are tissue-specific and inactivate tumor suppressor genes involved in chromatin modification and cell growth signaling. 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 favoring clonal expansion also drive tumorigenesis. Conclusion: Somatic variation and the factors governing homeostasis of normal tissues should be taken into account when devising strategies for cancer prevention and early detection.
UR - http://www.scopus.com/inward/record.url?scp=85143142098&partnerID=8YFLogxK
U2 - 10.1016/j.annonc.2022.09.156
DO - 10.1016/j.annonc.2022.09.156
M3 - Review article
C2 - 36162751
SN - 0923-7534
VL - 33
SP - 1239
EP - 1249
JO - Annals of Oncology
JF - Annals of Oncology
IS - 12
ER -