Characterizing Mutational Signatures in Human Cancer Cell Lines Reveals Episodic APOBEC Mutagenesis

Petljak, Mia; Alexandrov, Ludmil B.; Brammeld, Jonathan; Price, Stacey; Wedge, David C.; Großmann, Sebastian; Dawson, Kevin J.; Ju, Young Seok; Iorio, Francesco; Tubío, José M. C.; Koh, Ching Chiek; Georgakopoulos-Soares, Ilias; Rodríguez-Martín, Bernardo; Otlu, Burçak; O’Meara, Sarah; Butler, Adam; Menzies, Andrew; Bhosle, Shriram G.; Raine, Keiran; Jones, David R.; Teague, Jon W.; Beal, Kathryn; Latimer, Calli; O’Neill, Laura P.; Zamora, Jorge; Anderson, Elizabeth; Patel, Nikita; Maddison, Mark; Ng, Bee Ling; Graham, Jennifer; Garnett, Mathew J.; McDermott, Ultan; Nik-Zainal, Serena; Campbell, Peter J.; Stratton, Michael R.

doi:10.1016/j.cell.2019.02.012

Cited by 356 publications

(400 citation statements)

References 75 publications

(189 reference statements)

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“…Since the destabilizing SNP was associated with lung cancer 1 , these data suggested that A3H Hap I somatic mutations may be detrimental to cancer progression perhaps due to extensive mutagenesis leading to cell dysfunction or immune recognition. This is consistent with A3H Hap I mutations being identified early in cancer and the episodic nature of APOBEC3-induced mutations in cancer 1,13,32 .…”

Section: K121e Destabilizes A3h Hap Isupporting

confidence: 86%

“…Although there have been multiple reports of A3B, A3A, or A3H Hap I individually being involved in a cancer, it is not known if more than one APOB EC3 is expressed in a cancer cell at the same time and what would be the effects 13,[16][17][18]31 . What has recently been identified is that APOBEC3 mutations occur epis odically in cancers 32 . This is thought to be because constant expression and mutagenesis would result in cell death or recognition by the immune system, rather than creating a "just right" level of mutagenesis for cancer evolution.…”

Section: Introductionmentioning

confidence: 99%

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Induced mutagenesis by the DNA cytosine deaminase APOBEC3H Haplotype I protects against lung cancer

Hix

Wong²,

Flath³

et al. 2020

Preprint

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200 words) The DNA cytosine deaminases APOBEC3A, APOBEC3B, and APOBEC3H Haplotype I can induce mutations in cells that lead to cancer evolution. The database of cancer biomarkers in DNA repair genes (DNArCdb) identified a single nucleotide polymorphism (rs139298) of APOBEC3H Haplotype I that is involved in lung cancer 1 . Here, we show that this single nucleotide polymorphism causes the destabilization of APOBEC3H Haplotype I. Computational analysis suggests that the resulting K121E change affects the structure of APOBEC3H leading to active site disruption and destabilization of the RNA-mediated dimer interface. A K117E mutation in a K121E background stabilized the APOBEC3H Haplotype I, enabled biochemical study, and showed that the K121E affected catalytic activity, single-stranded DNA binding, and oligomerization on single-stranded DNA. That the destabilization of a DNA mutator would be associated with lung cancer suggests that 2 too much mutation could result in immune recognition or death of tumor cells, suggesting that multiple APOBEC3s would not be expressed in the same tumor cells. In support of this hypothesis, stably expressed APOBEC3H Haplotype I caused a high amount of double-stranded DNA breaks in a lung cancer cell line that endogenously expressed APOBEC3B. Altogether, the data support the model that high APOBEC3 mutations in tumors are protective.

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Section: K121e Destabilizes A3h Hap Isupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Induced mutagenesis by the DNA cytosine deaminase APOBEC3H Haplotype I protects against lung cancer

Hix

Wong²,

Flath³

et al. 2020

Preprint

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“…Uracil is thought to be removed by Uracil DNA Glycosylase UNG; subsequent synthesis by error-prone TLS REV1 leads to C>G mutations (Morganella et al, 2016;Roberts and Gordenin, 2014) . Indeed, a lack of C>G mutations has been observed in a cancer cell line with UNG silencing (Kim et al, 2015;Petljak et al, 2019) .…”

Section: Mutagenic Consequences Of Dna Repair and Damage Sensing Defimentioning

confidence: 99%

Mutational signatures are jointly shaped by DNA damage and repair

Volkova

Meier

González-Huici

et al. 2019

Preprint

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AbstractMutations arise when DNA lesions escape DNA repair. To delineate the contributions of DNA damage and DNA repair deficiency to mutagenesis we sequenced 2,717 genomes of wild-type and 53 DNA repair defective C. elegans strains propagated through several generations or exposed to 11 genotoxins at multiple doses. Combining genotoxin exposure and DNA repair deficiency alters mutation rates or leads to unexpected mutation spectra in nearly 40% of all experimental conditions involving 9/11 of genotoxins tested and 32/53 genotypes. For 8/11 genotoxins, signatures change in response to more than one DNA repair deficiency, indicating that multiple genes and pathways are involved in repairing DNA lesions induced by one genotoxin. For many genotoxins, the majority of observed single nucleotide variants results from error-prone translesion synthesis, rather than primary mutagenicity of altered nucleotides. Nucleotide excision repair mends the vast majority of genotoxic lesions, preventing up to 99% of mutations. Analogous mutagenic DNA damage-repair interactions can also be found in cancers, but, except for rare cases, effects are weak owing to the unknown histories of genotoxic exposures and DNA repair status. Overall, our data underscore that mutation spectra are joint products of DNA damage and DNA repair and imply that mutational signatures computationally derived from cancer genomes are more variable than currently anticipated.

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“…The mutations signatures were compared with those of the Welcome Trust Sanger Institute, whose catalog of signature now reaches a total of 40 35 . The aging signature and mismatch repair signature are enriched in both groups.…”

Section: Fig 3: Mutational Processes Identified In the Case Group Anmentioning

confidence: 99%

Somatic Genetic Aberrations in Benign Breast Disease and the Risk of Subsequent Breast Cancer

Zeng¹,

et al. 2019

Preprint

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One Sentence Summary: Genetic aberrations in benign breast lesions distinguish breast cancer cases from controls and predict cancer risk.Abstract: It is largely unknown how the risk of development of breast cancer is transduced by somatic genetic alterations. To address this lacuna of knowledge and acknowledging that benign breast disease (BBD) is an established risk factor for breast cancer, we established a case-control study: The Benign Breast & Cancer Risk (BBCAR) Study. Cases are women with BBD who developed subsequent invasive breast cancer (IBC) at least 3 years after the biopsy and controls are women with BBD who did not develop IBC (median follow-up 16.6 years). We selected 135 cases and individually matched controls (1:2) to cases based on age and type of benign disease: non-proliferative or proliferation without atypia. Whole exome sequencing was performed on DNA from the benign lesions and from subsets with available germline DNA or tumor DNA. Although the number of cases and controls with copy number variation data is limited, several amplifications and deletions are exclusive to the cases. In addition to two known mutational signatures, a novel signature was identified that is significantly (p=0.007) associated with triple negative breast cancer. The somatic mutation rate in benign lesions is similar to that of invasive breast cancer and does not differ between cases and controls. Two mutated genes are significantly associated with time to the diagnosis of breast cancer, and mutations shared between the benign biopsy tissue and the breast malignancy for the ten cases for which we had matched pairs were identified. BBD tissue is a rich source of clues to breast oncogenesis.

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Characterizing Mutational Signatures in Human Cancer Cell Lines Reveals Episodic APOBEC Mutagenesis

Cited by 356 publications

References 75 publications

Induced mutagenesis by the DNA cytosine deaminase APOBEC3H Haplotype I protects against lung cancer

Induced mutagenesis by the DNA cytosine deaminase APOBEC3H Haplotype I protects against lung cancer

Mutational signatures are jointly shaped by DNA damage and repair

Somatic Genetic Aberrations in Benign Breast Disease and the Risk of Subsequent Breast Cancer

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