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  • Review Article
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Clonal expansion in non-cancer tissues

Nature Reviews Cancer volume 21, pages 239–256 (2021)Cite this article

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Abstract

Cancer is a clonal disorder derived from a single ancestor cell and its progenies that are positively selected by acquisition of ‘driver mutations’. However, the evolution of positively selected clones does not necessarily imply the presence of cancer. On the contrary, it has become clear that expansion of these clones in phenotypically normal or non-cancer tissues is commonly seen in association with ageing and/or in response to environmental insults and chronic inflammation. Recent studies have reported expansion of clones harbouring mutations in cancer driver genes in the blood, skin, oesophagus, bronchus, liver, endometrium and bladder, where the expansion could be so extensive that tissues undergo remodelling of an almost entire tissue. The presence of common cancer driver mutations in normal tissues suggests a strong link to cancer development, providing an opportunity to understand early carcinogenic processes. Nevertheless, some driver mutations are unique to normal tissues or have a mutation frequency that is much higher in normal tissue than in cancer, indicating that the respective clones may not necessarily be destined for evolution to cancer but even negatively selected for carcinogenesis depending on the mutated gene. Moreover, tissues that are remodelled by genetically altered clones might define functionalities of aged tissues or modified inflammatory processes. In this Review, we provide an overview of major findings on clonal expansion in phenotypically normal or non-cancer tissues and discuss their biological significance not only in cancer development but also in ageing and inflammatory diseases.

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Fig. 1: Clonal evolution in normal tissues.
Fig. 2: Clonal expansion in normal tissues in various organs.
Fig. 3: Biological significance of positively selected clones in normal tissues.

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Authors and Affiliations

  1. Department of Pathology and Tumour Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Nobuyuki Kakiuchi & Seishi Ogawa

  2. Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Nobuyuki Kakiuchi

  3. Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto, Japan

    Seishi Ogawa

  4. Department of Medicine, Centre for Haematology and Regenerative Medicine, Karolinska Institute, Stockholm, Sweden

    Seishi Ogawa

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  1. Nobuyuki Kakiuchi
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  2. Seishi Ogawa
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Correspondence to Seishi Ogawa.

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Glossary

Driver mutations

Those mutations that confer selective advantage for their target cells to allow clonal outgrowth, whereas those mutations acquired prior to a driver mutation are also inherited by driver-mutated and clonally expanded cells despite conferring no selective roles and are called passenger mutations.

Positively selected clones

Clones that outcompete surrounding cells by acquisition of driver mutations that confer selective advantages to the cells.

Lyonized cells

Those cells undergoing inactivation of one of the two X chromosome copies in females.

Skewed chromosome X inactivation

In the presence of a clone, inactivation of one of the two chromosomes in early development of female organisms (lyonization) may be skewed from the 1:1 ratio that is expected for a random process, which can be used to infer the presence of clonal evolution in the sample of interest.

Genetic drift

A change in the frequency of an existing gene variant in a population due to random sampling of cells or organisms.

Allele dropout

The preferential amplification of one of a pair of heterozygous alleles frequently observed in amplification from a single cell or a small number of cells, in which the other allele is totally under-represented or fails to be detected.

Ratio of non-synonymous to synonymous mutations

(dN/dS). The ratio of the number of non-synonymous substitutions per non-synonymous site to the number of synonymous substitutions per synonymous site, frequently used as an indicator of selective pressure acting on a protein coding gene.

Variant allele frequency

The frequency of the mutated allele, correlating with the clonal cell fraction within a sample, that is calculated by dividing the number of mutant reads by the total number of reads that encompass the mutated position in sequencing analysis.

Loss of heterozygosity

An allelic state in which one of the two parental alleles is lost with or without copy number loss, providing a common mechanism of biallelic inactivation of tumour suppressor genes or duplication of a gain-of-function mutation accompanied by loss of wild-type alleles.

Parity

The number of times a female has given birth.

Chromothripsis

A mutational process by which clustered chromosomal rearrangements occur in a single event affecting one or a few chromosomes.

Negative selection

The selective removal of defective/disadvantageous alleles or cells having such alleles from a population of species or cells.

Field carcinogenesis

A biological process in which large areas of tissues or organs are affected by carcinogenic alterations.

Epi-mutations

Heritable changes without any accompanying actual base pair changes in primary DNA sequences, which are typically represented by DNA methylation, histone modifications and other mechanisms.

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Kakiuchi, N., Ogawa, S. Clonal expansion in non-cancer tissues. Nat Rev Cancer 21, 239–256 (2021). https://doi.org/10.1038/s41568-021-00335-3

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