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Review
. 2023 Jul 5;16(7):369-378.
doi: 10.1158/1940-6207.CAPR-22-0469.

Clonal Evolution in Healthy and Premalignant Tissues: Implications for Early Cancer Interception Strategies

Jayant K Rane  1   2   3 , Alexander M Frankell  3   4 , Clare E Weeden  3 , Charles Swanton  3   4   5
Affiliations
Review

Clonal Evolution in Healthy and Premalignant Tissues: Implications for Early Cancer Interception Strategies

Jayant K Rane et al. Cancer Prev Res (Phila). .

Abstract

Histologically normal human tissues accumulate significant mutational burden with age. The extent and spectra of mutagenesis are comparable both in rapidly proliferating and post-mitotic tissues and in stem cells compared with their differentiated progeny. Some of these mutations provide increased fitness, giving rise to clones which, at times, can replace the entire surface area of tissues. Compared with cancer, somatic mutations in histologically normal tissues are primarily single-nucleotide variations. Interestingly though, the presence of these mutations and positive clonal selection in isolation remains a poor indicator of potential future cancer transformation in solid tissues. Common clonally expanded mutations in histologically normal tissues also do not always represent the most frequent early mutations in cancers of corresponding tissues, indicating differences in selection pressures. Preliminary evidence implies that stroma and immune system co-evolve with age, which may impact selection dynamics. In this review, we will explore the mutational landscape of histologically normal and premalignant human somatic tissues in detail and discuss cell-intrinsic and environmental factors that can determine the fate of positively selected mutations within them. Precisely pinpointing these determinants of cancer transformation would aid development of early cancer interventional and prevention strategies.

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Conflict of interest statement

Conflict of interest:

C.S. acknowledges grant support from AstraZeneca, Boehringer-Ingelheim, BMS, Pfizer, Roche-Ventana, Invitae (previously Archer Dx (collaboration in minimal residual disease sequencing technologies)) and Ono Pharmaceutical. C.S. is an AstraZeneca Advisory Board member and Chief Investigator for the AZ MeRmaiD 1 and 2 clinical trials and is also Co-Chief Investigator of the NHS Galleri trial funded by GRAIL and a paid member of GRAIL’s SAB. He receives consultant fees from Achilles Therapeutics (also a SAB member), Bicycle Therapeutics (also a SAB member), Genentech, Medicxi, Roche Innovation Centre–Shanghai, Metabomed (until July 2022), and the Sarah Cannon Research Institute. C.S. had stock options in Apogen Biotechnologies and GRAIL until June 2021, and currently has stock options in Epic Bioscience, Bicycle Therapeutics, and has stock options and is co-founder of Achilles Therapeutics. C.S. is an inventor on a European patent application relating to an assay technology to detect tumour recurrence (PCT/GB2017/053289), the patent has been licensed to commercial entities and under his terms of employment, C.S. is due a revenue share of any revenue generated from such licence(s). C.S. holds patents relating to targeting neoantigens (PCT/EP2016/059401), identifying patient responses to immune checkpoint blockade (PCT/EP2016/071471), determining HLA LOH (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221), identifying patients who respond to cancer treatment (PCT/GB2018/051912), a US patent relating to detecting tumour mutations (PCT/US2017/28013), methods for lung cancer detection (US20190106751A1) and both a European and US patent related to identifying indel mutation targets (PCT/GB2018/051892) and is a co-inventor on a patent application to determine methods and systems for tumour monitoring (PCT/EP2022/077987). C.S. is a named inventor on a provisional patent related to a ctDNA detection algorithm. A.M.F. is a named inventor on a patent application to determine methods and systems for tumour monitoring (PCT/EP2022/077987). J.K.R. and C.E.W declares no competing interests.

Figures

Figure 1
Figure 1
Sources of mutations in histologically normal tissues. The mutations were assessed in epithelial cells of solid organs and a variety of haematopoietic cells while assessing blood or bone marrow. The samples were derived from individuals with no known cancer diagnosis for the assessed tissue on histological examination (Created with BioRender.com).
Figure 2
Figure 2
Changes in histologically normal tissues with age a. Large clones in rapidly dividing tissues without distinct anatomical units (e.g., oesophagus and skin) b. Restricted clonal size to anatomical unit in minority of tissue units (e.g., colon) or majority of tissue units (e.g., endometrium) (Created with BioRender.com).
Figure 3
Figure 3
Changes in the mutational spectra in the histologically normal oesophagus and Barrett’s oesophagus compared with oesophageal dysplasia and adenocarcinoma.
Figure 4
Figure 4
Cancer diagnosis (a) and 1-year survival as per stage (b) in common cancer diagnosed across England between 2012-14 (public health England data).
Figure 5
Figure 5
Potential determinants of carcinogenic transformation of histologically normal tissue carrying clonally expanded mutations in cancer driver genes and its application to design the early intervention strategies for cancer prevention and detection (Created with BioRender.com).
See this image and copyright information in PMC

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