Mutational signatures in tumours induced by high and low energy radiation in Trp53 deficient mice

Li, Yun R.; Halliwill, Kyle; Adams, Cassandra; Iyer, Vivek; Riva, Laura; Rashid, Muhammad Usman; Jen, Kuang-Yu; Rosario, Reyno Del; Fredlund, Erik; Hirst, Gillian L.; Alexandrov, Ludmil B.; Adams, David J.; Balmain, Allan

doi:10.1038/s41467-019-14261-4

Cited by 64 publications

(28 citation statements)

References 65 publications

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“…Many chemicals induce DNA damage, thereby increasing the rate of potentially oncogenic DNA replication errors ( 2 ). The same is true for many forms of radiation ( 3 ). Nonmutagenic and nongenotoxic carcinogens act through a variety of secondary mechanisms such as inhibition of the immune system, cell-cycle overdrive to bypass normal DNA replication checkpoints, and induction of inflammation which may lead to both increased cellular proliferation and DNA damage, among others ( 4 ).…”

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confidence: 75%

Direct quantification of in vivo mutagenesis and carcinogenesis using duplex sequencing

Valentine

Young

Fielden

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The ability to accurately measure mutations is critical for basic research and identifying potential drug and chemical carcinogens. Current methods for in vivo quantification of mutagenesis are limited because they rely on transgenic rodent systems that are low-throughput, expensive, prolonged, and do not fully represent other species such as humans. Next-generation sequencing (NGS) is a conceptually attractive alternative for detecting mutations in the DNA of any organism; however, the limit of resolution for standard NGS is poor. Technical error rates (∼1 × 10−3) of NGS obscure the true abundance of somatic mutations, which can exist at per-nucleotide frequencies ≤1 × 10−7. Using duplex sequencing, an extremely accurate error-corrected NGS (ecNGS) technology, we were able to detect mutations induced by three carcinogens in five tissues of two strains of mice within 31 d following exposure. We observed a strong correlation between mutation induction measured by duplex sequencing and the gold-standard transgenic rodent mutation assay. We identified exposure-specific mutation spectra of each compound through trinucleotide patterns of base substitution. We observed variation in mutation susceptibility by genomic region, as well as by DNA strand. We also identified a primordial marker of carcinogenesis in a cancer-predisposed strain of mice, as evidenced by clonal expansions of cells carrying an activated oncogene, less than a month after carcinogen exposure. These findings demonstrate that ecNGS is a powerful method for sensitively detecting and characterizing mutagenesis and the early clonal evolutionary hallmarks of carcinogenesis. Duplex sequencing can be broadly applied to basic mutational research, regulatory safety testing, and emerging clinical applications.

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mentioning

confidence: 75%

Direct quantification of in vivo mutagenesis and carcinogenesis using duplex sequencing

Valentine

Young

Fielden

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…However, this is often the case in any study and we included the clinical information on why subsequent malignancies were more consistent with recurrent disease rather than RT‐induced, which is often not described in the literature. In future work, the use of DNA sequencing and mutational signatures may be employed to reliably distinguish recurrent disease from radiation‐induced cancers 26‐28 . Another potential limitation is the limited follow‐up time.…”

Section: Discussionmentioning

confidence: 99%

Radiation therapy and secondary malignancy in Li‐Fraumeni syndrome: A hereditary cancer registry study

et al. 2020

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Background Li‐Fraumeni Syndrome (LFS) is a rare cancer‐predisposing condition caused by germline mutations in TP53. Conventional wisdom and prior work has implied an increased risk of secondary malignancy in LFS patients treated with radiation therapy (RT); however, this risk is not well‐characterized. Here we describe the risk of subsequent malignancy and cancer‐related death in LFS patients after undergoing RT for a first or second primary cancer. Methods We reviewed a multi‐institutional hereditary cancer registry of patients with germline TP53 mutations who were treated from 2004 to 2017. We assessed the rate of subsequent malignancy and death in the patients who received RT (RT group) as part of their cancer treatment compared to those who did not (non‐RT group). Results Forty patients with LFS were identified and 14 received RT with curative intent as part of their cancer treatment. The median time to follow‐up after RT was 4.5 years. Fifty percent (7/14) of patients in the curative‐intent group developed a subsequent malignancy (median time 3.5 years) compared to 46% of patients in the non‐RT group (median time 5.0 years). Four of seven subsequent malignancies occurred within a prior radiation field and all shared histology with the primary cancer suggesting recurrence rather than new malignancy. Conclusion We found that four of14 patients treated with RT developed in‐field malignancies. All had the same histology as the primary suggesting local recurrences rather than RT‐induced malignancies. We recommend that RT should be considered as part of the treatment algorithm when clinically indicated and after multidisciplinary discussion.

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“…Collectively, these genomic studies provide compelling evidence to support a model in humans and mice without germline mutations where the formation of hematologic malignancies following exposure to ionizing radiation occurs through a non-cell-autonomous mechanism 8,46,47 . However, for individuals harboring germline mutations in DNA damage response genes, such as p53 and Mlh1 , ionizing radiation may cause blood cancers through a more direct cell-autonomous effect by increasing genomic instability in tumor-initiating cells 13,14,45 .…”

Section: Discussionmentioning

confidence: 99%

“…For example, using a mouse model of B-cell lymphoma, Patel et al found that gamma-rays and heavy ion ( 56 Fe) radiation markedly increased the number of insertions and deletions (indels) per tumor only in mice lacking one allele of the mismatch repair gene Mlh1 (Mlh1 +/- ) 13 . Also, using mice carrying different loss of function alleles of the tumor suppressor p53, Li et al observed that the genomic landscape of radiation-induced cancers is influenced by radiation quality, germline p53 deficiency and tissue/cell of origin 14 . Collectively, findings from these genomic studies advance our understanding of mutational processes that underlie the development of radiation-induced cancers.…”

Section: Introductionmentioning

confidence: 99%

Activation of Notch1 drives the development of radiation-induced thymic lymphoma in p53 wild-type mice

Lee

Brock

Hasapis

et al. 2020

Preprint

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Mouse models of radiation-induced thymic lymphoma are widely used to study the development of radiation-induced blood cancers and to gain insights into the biology of human T-lymphoblastic leukemia/lymphoma. Here, we aimed to determine key oncogenic drivers for the development of radiation-induced thymic lymphoma by performing whole-exome sequencing using tumors and paired normal tissues from mice with and without irradiation. Thymic lymphomas from irradiated wild-type (WT), p53+/- and KrasLA1 mice were not observed to harbor significantly higher numbers of non-synonymous somatic mutations compared to thymic lymphomas from unirradiated p53-/- mice. However, we observed distinct patterns of recurrent mutations in genes that control the Notch1 signaling pathway based on the mutational status of p53. Preferential activation of Notch1 signaling in p53 WT lymphomas was also observed at the RNA and protein level. Using reporter mice for activation of the Notch1 signaling we observed that TBI enriched Notch1hi CD44+ thymocytes, which are capable of self-renewal in vivo. Mechanistically, genetic inhibition of Notch1 signaling in thymocytes prevented the formation of radiation-induced thymic lymphoma in p53 WT mice. Taken together, our results demonstrate a critical role of activated Notch1 signaling in driving multi-step carcinogenesis of thymic lymphoma following total-body irradiation in p53 WT mice.

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Mutational signatures in tumours induced by high and low energy radiation in Trp53 deficient mice

Cited by 64 publications

References 65 publications

Direct quantification of in vivo mutagenesis and carcinogenesis using duplex sequencing

Direct quantification of in vivo mutagenesis and carcinogenesis using duplex sequencing

Radiation therapy and secondary malignancy in Li‐Fraumeni syndrome: A hereditary cancer registry study

Activation of Notch1 drives the development of radiation-induced thymic lymphoma in p53 wild-type mice

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