The evolution of hematopoietic cells under cancer therapy

Pich, Oriol; Cortés-Bullich, Albert; Muiños, Ferran; Pratcorona, Marta; González-Pérez, Abel; López‐Bigas, Núria

doi:10.1038/s41467-021-24858-3

Cited by 43 publications

(71 citation statements)

References 81 publications

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“…Hence, only mutations in surviving cancer cells that have undergone clonal expansion during, or after, chemotherapy treatment can be identified and quantified using this approach. Recently, clonal expansion in non-cancerous tissue has been exploited to study chemotherapy-related mutations in hematopoietic cells 10 . For solid tissue, clonal mutations can be identified with bulk sequencing of microscale sampled tissue [11][12][13] .…”

Section: Introductionmentioning

confidence: 99%

Common anti-cancer therapies induce somatic mutations in stem cells of healthy tissue

Kuijk

Kranenburg

Cuppen

et al. 2022

Preprint

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Comprehensive analyses of genome-wide mutation profiles has revealed that specific anti-cancer drugs, such as 5-fluorouracil (5-FU), are highly mutagenic to cancer cells and cultured cells. The systemic administration of these chemotherapies presents a potential genotoxic hazard to healthy tissues, however, the true mutational impact on normal cells of patients is not known. Here, we examined genome-wide somatic mutation patterns in healthy adult stem cells (ASCs) of the colon or the liver from 14 colorectal cancer patients that received first-line systemic chemotherapy and/or local radiotherapy. The platinum-based chemo-drug Oxaliplatin induced 500-1000 mutations in each colon ASC of all treated patients. The effects of 5-FU treatment were more variable between cells and patients, ranging from a complete absence of 5-FU mutagenesis to the accumulation of up to 500 mutations in individual colon ASCs. In contrast with the colon, normal ASCs from the liver escaped platinum and 5-FU mutagenesis after systemic treatment. Local radiation therapy resulted in the accumulation of 50-100 deletions between 5bp to 10kbp and structural rearrangements in colon ASCs. Thus, while 5-FU and platinum drugs are highly effective at killing cancer cells, their systemic use does also lead to a concomitant increase of the mutational burden in long-lived normal stem cells responsible for tissue renewal and thus pose a potential source for developing second cancers.

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Section: Introductionmentioning

confidence: 99%

Common anti-cancer therapies induce somatic mutations in stem cells of healthy tissue

Kuijk

Kranenburg

Cuppen

et al. 2022

Preprint

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“…Recent studies implicate that the replicative state of a cell is an important determinant for incorporating chemotherapy-induced DNA damage ( Pich et al, 2021 ). According to this model, the turnover of damaged nucleotides is so quickly, that only cells in a replicative state during chemotherapy exposure will incorporate damaged nucleotides during DNA-replication.…”

Section: Topographies Of Environmentally Induced Mutationsmentioning

confidence: 99%

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

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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“…This is the first report of SBS25 in relapsed cHL, demonstrating that similar to other cancers, cHL can acquire hundreds of mutations after exposure to distinct chemotherapy agents. 10,26,[34][35][36] The presence of a large SBS25 clonal mutational burden can be seen as a unique barcoding, reflecting the expansion of one single tumor cell that survived front-line treatment and subsequently took the clonal dominance. [35][36][37] Leveraging this concept and estimating the SBS25 contribution before and after the three large chromosomal gains in this case, we observed chemotherapy-related mutations both before and after the large chromosomal gains.…”

Section: Mutational Signaturesmentioning

confidence: 99%

“…10,26,[34][35][36] The presence of a large SBS25 clonal mutational burden can be seen as a unique barcoding, reflecting the expansion of one single tumor cell that survived front-line treatment and subsequently took the clonal dominance. [35][36][37] Leveraging this concept and estimating the SBS25 contribution before and after the three large chromosomal gains in this case, we observed chemotherapy-related mutations both before and after the large chromosomal gains. The presence of chemotherapy related mutations preceding large chromosomal gains indicates that these CNA events were acquired after exposure to chemotherapy.…”

Section: Mutational Signaturesmentioning

confidence: 99%

Molecular evolution of classic Hodgkin lymphoma revealed through whole genome sequencing of Hodgkin and Reed Sternberg cells

Maura

Ziccheddu

Xiang

et al. 2021

Preprint

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The rarity of malignant Hodgkin and Reed Sternberg (HRS) cells within a classic Hodgkin lymphoma (cHL) biopsy limits the ability to study the genomics of cHL. To circumvent this, our group has previously optimized fluorescence-activated cell sorting to purify HRS cells. Here we leveraged this method to report the first whole genome sequencing landscape of HRS cells and reconstruct the chronology and likely etiology of pathogenic events prior to the clinical diagnosis of cHL. We identified alterations in driver genes not previously described in cHL, a high activity of the APOBEC mutational signature, and the presence complex structural variants including chromothripsis. We found that the high ploidy observed in cHL is often acquired through multiple, independent large chromosomal gain events including whole genome duplication. The first of these likely occurs several years prior to the diagnosis of cHL, and the last gains typically occur very close to the time of diagnosis. Evolutionary timing analyses revealed that driver mutations in B2M, BCL7A, GNA13, and PTPN1, and the onset of AID driven mutagenesis usually preceded large chromosomal gains. The study provides the first temporal reconstruction of cHL pathogenesis and suggests a relatively long time course between the first pathogenic event and the clinical diagnosis.

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The evolution of hematopoietic cells under cancer therapy

Cited by 43 publications

References 81 publications

Common anti-cancer therapies induce somatic mutations in stem cells of healthy tissue

Common anti-cancer therapies induce somatic mutations in stem cells of healthy tissue

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

Molecular evolution of classic Hodgkin lymphoma revealed through whole genome sequencing of Hodgkin and Reed Sternberg cells

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