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

Kuijk, Ewart; Kranenburg, Onno; Cuppen, Edwin; Hoeck, Arne van

doi:10.21203/rs.3.rs-1435993/v1

Cited by 4 publications

(4 citation statements)

References 42 publications

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“…1e), these features were generally more prevalent in patients with metastatic tumors and thus very likely contributed to the observed SV increase in metastatic tumors. Finally, prior exposure to radiotherapy treatment was strongly associated with small deletions in breast and prostate cancers (in agreement with radiotherapy-treated secondary malignancies 55 , gliomas 37 , and healthy tissue 56 ). This suggests that, among common anti-cancer therapies, radiotherapy in particular significantly contributes to the SV landscape in treatment-surviving cancer cells.…”

Section: Genomic and Clinical Features Associated With Structural Var...supporting

confidence: 69%

Pan-cancer whole genome comparison of primary and metastatic solid tumors

Cuppen

Martínez-Jiménez

Movasati

et al. 2022

Preprint

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Metastatic cancer remains almost inevitably a lethal disease. A better understanding of disease progression and response to therapies therefore remains of utmost importance. Here, we characterize the genomic differences between early-stage untreated primary tumors and late-stage treated metastatic tumors using a harmonized pan-cancer (re-)analysis of 7,152 whole-genome-sequenced tumors. In general, our analysis shows that metastatic tumors have a low intra-tumor heterogeneity, high genomic instability and increased frequency of structural variants with comparatively a modest increase in the number of small genetic variants. However, these differences are cancer type specific and are heavily impacted by the exposure to cancer therapies. Five cancer types, namely breast, prostate, thyroid, kidney clear carcinoma and pancreatic neuroendocrine, are a clear exception to the rule, displaying an extensive transformation of their genomic landscape in advanced stages. These changes were supported by increased genomic instability and involved substantial differences in tumor mutation burden, clock-based molecular signatures and the landscape of driver alterations as well as a pervasive increase in structural variant burden. The majority of cancer types had either moderate genomic differences (e.g., cervical and colorectal cancers) or highly consistent genomic portraits (e.g., ovarian cancer and skin melanoma) when comparing early- and late-stage disease. Exposure to treatment further scars the tumor genome and introduces an evolutionary bottleneck that selects for known therapy-resistant drivers in approximately half of treated patients. Our data showcases the potential of whole-genome analysis to understand tumor evolution and provides a valuable resource to further investigate the biological basis of cancer and resistance to cancer therapies.

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Section: Genomic and Clinical Features Associated With Structural Var...supporting

confidence: 69%

Pan-cancer whole genome comparison of primary and metastatic solid tumors

Cuppen

Martínez-Jiménez

Movasati

et al. 2022

Preprint

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show abstract

“…Finally, prior exposure to radiotherapy treatment was strongly associated with small deletions in breast and prostate cancers (in agreement with radiotherapy-treated secondary malignancies [109], gliomas [172], and healthy tissue [271]). This suggests that, among common anti-cancer therapies, radiotherapy in particular significantly contributes to the SV landscape in treatment-surviving cancer cells.…”

Section: Genomic and Clinical Features Associated With Structural Var...supporting

confidence: 67%

Understanding and diagnosing cancer through its mutational history

Luan¹

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Studying cancer genomesThe human genome contains the instructions to build, maintain and reproduce a human organism, and is encoded in deoxyribonucleic acid (DNA). DNA is a polymer of nucleotides (adenine (A), cytosine (C), thymine (T) and guanine (G)) that coils together to form a double helix. The average human genome consists of roughly 6 billion nucleotides that are organized over 23 pairs of chromosomes. About 1-2% of the genome codes for the ~20,000 genes, most of which are eventually transcribed into mRNA and subsequently translated into proteins. The remainder of the genome (at least in part) plays an important role in regulating the expression of genes [1].In normal cells, growth and division (together called cell proliferation) is tightly controlled by hundreds of genes. However, mutations in these genes (or its regulatory elements) can lead to the outgrowth of cells that are able to proliferate uncontrollably and avoid cell death; in other words, cancer. Cancerous cells may eventually escape their original environment and colonize other tissues (i.e. metastasize), which can be driven by mutations but also other factors such as environmental pressures [2]. The mutations that contribute to cancer are primarily those acquired over the lifetime of an individual (somatic mutations), though inherited germline mutations can also increase cancer risk [3].DNA sequencing is commonly used to study mutations in cancer. The first generation of sequencing technology (Sanger sequencing) was used to determine the full sequence of the human genome, but was limited to sequencing one DNA fragment of up to 1,000 bases at a time. The next-generation sequencing (NGS) technologies that emerged shortly after allowed for massively parallel sequencing (thousands to millions) of multiple short DNA fragments (tens to hundreds of bases). These next generation 'short-read' sequencing techniques typically involve breaking the DNA of a sample into random short fragments that are amplified and then sequenced to produce 'reads'. Mapping assembly is then performed, whereby reads are compared ('mapped') to a reference genome and pieced together to form a continuous genomic sequence of the sample which allows for the detection of genetic differences (mutations) [4]. NGS technology enabled fast and cost effective whole genome sequencing (WGS), which has recently led to large scale pan-cancer studies involving thousands of cancer patients [5,6].Typically, to study the full spectrum of mutations in cancer patients, a tumor and normal sample (commonly blood or nearby healthy tissue) are both sequenced and mapped to a human reference genome. Important to note is that the human reference genome is an aggregate of the full genome sequences across multiple donors and thus does not represent the genome of one individual [7]. Changes in nucleotide sequences between the sample and reference genome are considered 'variants'. Variants found in the normal sample are considered germline mutations, and these are subtracted from those found in the tumor t...

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“…Though 5-Fluorouracil is known to leave a distinct SBS signature (SBS17a), no evidence of it was seen in this cohort, in line with its mechanism of mutagenicity on dividing – and not quiescent – cells 12 . Conversely, adducts generated by melphalan-and platinum-based agents are not dependent on cell turnover 9, 12 and induce mutagenesis in tumor and normal tissues 19, 20 . In fact, the mutational burden between de novo AML and tMN without melphalan or platinum exposure were strikingly similar (Wilcoxon test, p = 0.587; Fig 1e ), adding evidence that chemotherapies typically associated with tMN may facilitate malignancy in absence of any appreciable increase in SBS mutagenesis 12 .…”

Section: The Mutational Landscape Of Therapy-related Malignanciesmentioning

confidence: 99%

“…It has been suggested that anti-cancer therapies exert positive selective pressure on CH bearing pre-leukemic driver mutations and that expansion is not contingent on the increased mutational burden relative to de novo AML 17, 18 with speculation that other cellular machinery may be altered by exposure. Despite this, distinct DNA-damaging cytotoxic agents can measurably alter the mutational profile in each exposed cell, including in normal tissue 6, 19, 20 . The application of mutational signatures to whole genome sequencing (WGS) data has allowed for direct quantitation of chemotherapy-mediated DNA damage and revealed that a subset of tMN with prior platinum exposure do indeed have an increased, chemotherapy-specific, mutational burden as compared to non-platinum-exposed tMN 12 .…”

mentioning

confidence: 99%

Chemotherapy Signatures Map Evolution of Therapy-Related Myeloid Neoplasms

Diamond

Ziccheddu

Maclachlan

et al. 2022

Preprint

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Patients treated with cytotoxic therapies, including autologous stem cell transplantation, are at risk for developing therapy-related myeloid neoplasms1, 2. Pre-leukemic clones (i.e., clonal hematopoiesis) are detectable years before the development of these aggressive malignancies3-5, though the genomic events leading to transformation and expansion are not well-defined. Here, leveraging distinctive chemotherapy-associated mutational signatures6-12 from whole-genome sequencing data and targeted sequencing of pre-chemotherapy samples, we reconstruct the evolutionary life-history of 39 therapy-related myeloid malignancies. A dichotomy is revealed, in which neoplasms with evidence of chemotherapy-induced mutagenesis from platinum and melphalan are relatively hypermutated and enriched for complex structural variants (i.e., chromothripsis), while neoplasms with alternative exposures bear a similar profile to de novo acute myeloid leukemia. Using chemotherapy-associated mutational signatures as a temporal barcode in each patient’s life, we estimate that several complex events and genomic drivers are acquired after chemotherapy exposure. In the case of treatment with high-dose melphalan and autologous stem cell transplantation, we demonstrate that the procedure allows clonal hematopoiesis to escape chemotherapy exposure entirely, and to be reinfused to expand to malignancy. This information reveals a novel mode of malignant progression for therapy-related malignancies that is not reliant on direct mutagenesis or even exposure to chemotherapy, itself, and prompts further investigation into leukemia-permissive effects of cytotoxic drugs.

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

Cited by 4 publications

References 42 publications

Pan-cancer whole genome comparison of primary and metastatic solid tumors

Pan-cancer whole genome comparison of primary and metastatic solid tumors

Understanding and diagnosing cancer through its mutational history

Chemotherapy Signatures Map Evolution of Therapy-Related Myeloid Neoplasms

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