Precancer: Mutant clones in normal epithelium outcompete and eliminate esophageal micro-tumors

Colom, Bartomeu; Herms, Albert; Dentro, Stefan C.; C, King; Sood, Roshan; Alcolea, Maria P.; Fernández‐Antorán, David; Sh, Ong; Jc, Fowler; Mahbubani, Krishnaa; Saeb‐Parsy, Kourosh; Gerstung, Moritz; Hall, Benjamin A.; Jones, Philip H.

doi:10.1101/2021.06.25.449880

“…Later studies discovered CH without driver mutations is highly prevalent ( Zink et al, 2017 ), raising the question whether CH is a pre-cancerous state. These observations raise the question whether these clonal expansions represent pre-cancer states, or if the enhanced clonality of a tissue is a characteristic of normal aging ( Brash, 2015 ; Colom et al, 2021 ).…”

Section: Cancer Driver Induction By Environmental Genotoxinsmentioning

confidence: 99%

The Mutagenic Impact of Environmental Exposures in Human Cells and Cancer: Imprints Through Time

Huber

¹

,

Hoeck

²

,

Boxtel

³

2021

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During life, the DNA of our cells is continuously exposed to external damaging processes. Despite the activity of various repair mechanisms, DNA damage eventually results in the accumulation of mutations in the genomes of our cells. Oncogenic mutations are at the root of carcinogenesis, and carcinogenic agents are often highly mutagenic. Over the past decade, whole genome sequencing data of healthy and tumor tissues have revealed how cells in our body gradually accumulate mutations because of exposure to various mutagenic processes. Dissection of mutation profiles based on the type and context specificities of the altered bases has revealed a variety of signatures that reflect past exposure to environmental mutagens, ranging from chemotherapeutic drugs to genotoxic gut bacteria. In this review, we discuss the latest knowledge on somatic mutation accumulation in human cells, and how environmental mutagenic factors further shape the mutation landscapes of tissues. In addition, not all carcinogenic agents induce mutations, which may point to alternative tumor-promoting mechanisms, such as altered clonal selection dynamics. In short, we provide an overview of how environmental factors induce mutations in the DNA of our healthy cells and how this contributes to carcinogenesis. A better understanding of how environmental mutagens shape the genomes of our cells can help to identify potential preventable causes of cancer.

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“…It was found that tissues, such as skin, lung and oesophagus, that had a direct exposure to environmental carcinogenic factors (UV radiation, smoking and nutritional habits), or had a very high proliferation rate exhibited the highest mutation burden [18]. There is also some evidence that in certain situations mutant clones in normal epithelium can play an anti-tumorigenic role [19].…”

Section: Introductionmentioning

confidence: 99%

The architecture of clonal expansions in morphologically normal tissue from cancerous and non-cancerous prostates

Buhigas

¹

,

Warren

²

,

Leung

³

et al. 2022

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Background Up to 80% of cases of prostate cancer present with multifocal independent tumour lesions leading to the concept of a field effect present in the normal prostate predisposing to cancer development. In the present study we applied Whole Genome DNA Sequencing (WGS) to a group of morphologically normal tissue (n = 51), including benign prostatic hyperplasia (BPH) and non-BPH samples, from men with and men without prostate cancer. We assess whether the observed genetic changes in morphologically normal tissue are linked to the development of cancer in the prostate. Results Single nucleotide variants (P = 7.0 × 10–03, Wilcoxon rank sum test) and small insertions and deletions (indels, P = 8.7 × 10–06) were significantly higher in morphologically normal samples, including BPH, from men with prostate cancer compared to those without. The presence of subclonal expansions under selective pressure, supported by a high level of mutations, were significantly associated with samples from men with prostate cancer (P = 0.035, Fisher exact test). The clonal cell fraction of normal clones was always higher than the proportion of the prostate estimated as epithelial (P = 5.94 × 10–05, paired Wilcoxon signed rank test) which, along with analysis of primary fibroblasts prepared from BPH specimens, suggests a stromal origin. Constructed phylogenies revealed lineages associated with benign tissue that were completely distinct from adjacent tumour clones, but a common lineage between BPH and non-BPH morphologically normal tissues was often observed. Compared to tumours, normal samples have significantly less single nucleotide variants (P = 3.72 × 10–09, paired Wilcoxon signed rank test), have very few rearrangements and a complete lack of copy number alterations. Conclusions Cells within regions of morphologically normal tissue (both BPH and non-BPH) can expand under selective pressure by mechanisms that are distinct from those occurring in adjacent cancer, but that are allied to the presence of cancer. Expansions, which are probably stromal in origin, are characterised by lack of recurrent driver mutations, by almost complete absence of structural variants/copy number alterations, and mutational processes similar to malignant tissue. Our findings have implications for treatment (focal therapy) and early detection approaches.

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“…While cancer is a disease with genetic mutations at its root, additional cell and tissue dynamics may play a large role whether a cell with driver mutations may expand and progress into cancer. Intra-tissue clonal dynamics (Colom et al, 2021;Kakiuchi and Ogawa, 2021) or the immune system (De Visser et al, 2006) may prevent the outgrowths of cells with cancer driver mutations. And, often neglected, both the immune system and clonal dynamics could be altered by exposure to (genotoxic) environmental factors.…”

Section: Discussionmentioning

confidence: 99%

“…Later studies discovered CH without driver mutations is highly prevalent , raising the question whether CH is a pre-cancerous state. These observations raise the question whether these clonal expansions represent pre-cancer states, or if the enhanced clonality of a tissue is a characteristic of normal aging (Brash, 2015;Colom et al, 2021).…”

Section: Driver Mutations In Non-malignant Tissuementioning

confidence: 99%

Mapping mutations in human cells

Huber¹

0

View full text Add to dashboard Cite

During life, the DNA of our cells is continuously exposed to external damaging processes. Despite the activity of various repair mechanisms, DNA damage eventually results in the accumulation of mutations in the genomes of our cells. Oncogenic mutations are at the root of carcinogenesis, and carcinogenic agents are often highly mutagenic. Over the past decade, whole genome sequencing data of healthy and tumor tissues have revealed how cells in our body gradually accumulate mutations because of exposure to various mutagenic processes. Dissection of mutation profiles based on the type and context specificities of the altered bases has revealed a variety of signatures that reflect past exposure to environmental mutagens, ranging from chemotherapeutic drugs to genotoxic gut bacteria. In this review, we discuss the latest knowledge on somatic mutation accumulation in human cells, and how environmental mutagenic factors further shape the mutation landscapes of tissues. In addition, not all carcinogenic agents induce mutations, which may point to alternative tumor-promoting mechanisms, such as altered clonal selection dynamics. In short, we provide an overview of how environmental factors induce mutations in the DNA of our healthy cells and how this contributes to carcinogenesis. A better understanding of how environmental mutagens shape the genomes of our cells can help to identify potential preventable causes of cancer.12

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Precancer: Mutant clones in normal epithelium outcompete and eliminate esophageal micro-tumors

Cited by 5 publications

References 39 publications

The Mutagenic Impact of Environmental Exposures in Human Cells and Cancer: Imprints Through Time

The Mutagenic Impact of Environmental Exposures in Human Cells and Cancer: Imprints Through Time

The architecture of clonal expansions in morphologically normal tissue from cancerous and non-cancerous prostates

Mapping mutations in human cells

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