scholarly journals Network-based approaches elucidate differences within APOBEC and clock-like signatures in breast cancer

2019 ◽  
Author(s):  
Yoo-Ah Kim ◽  
Damian Wojtowicz ◽  
Rebecca Sarto Basso ◽  
Itay Sason ◽  
Welles Robinson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Somatic Mutations ◽  
Cancer Genome ◽  
Mutational Signatures ◽  
Dna Damage And Repair ◽  
Cancer Genomes ◽  
Cancer Mutations ◽  
Functional Pathways ◽  
Dna Maintenance

AbstractStudies of cancer mutations typically focus on identifying cancer driving mutations. However, in addition to the mutations that confer a growth advantage, cancer genomes accumulate a large number of passenger somatic mutations resulting from normal DNA damage and repair processes as well as mutations triggered by carcinogenic exposures or cancer related aberrations of DNA maintenance machinery. These mutagenic processes often produce characteristic mutational patterns called mutational signatures. Understanding the etiology of the mutational signatures shaping a cancer genome is an important step towards understanding tumorigenesis. Considering mutational signatures as phenotypes, we asked two complementary questions (i) what are functional pathways whose geneexpressionprofiles are associated with mutational signatures, and (ii) what aremutated pathways(if any) that might underlie specific mutational signatures? We have been able to identify pathways associated with mutational signatures on both expression and mutation levels. In particular, our analysis provides novel insights into mutagenic processes in breast cancer by capturing important differences in the etiology of different APOBEC related signatures and the two clock-like signatures. These results are important for understanding mutagenic processes in cancer and for developing personalized drug therapies.

scholarly journals Detecting presence of mutational signatures in cancer with confidence

2017 ◽  
Author(s):  
Xiaoqing Huang ◽  
Damian Wojtowicz ◽  
Teresa M. Przytycka
Keyword(s):  
Breast Cancer ◽  
Somatic Mutations ◽  
Decomposition Methods ◽  
R Package ◽  
The Novel ◽  
Cancer Etiology ◽  
Mutational Signatures ◽  
Dna Damage And Repair ◽  
Cancer Genomes ◽  
Additional Support

AbstractCancers arise as the result of somatically acquired changes in the DNA of cancer cells. However, in addition to the mutations that confer a growth advantage, cancer genomes accumulate a large number of somatic mutations resulting from normal DNA damage and repair processes as well as mutations triggered by carcinogenic exposures or cancer related aberrations of DNA mainte-nance machinery. These mutagenic processes often produce characteristic mutational patterns called mutational signatures. Decomposition of cancer’s mutation catalog into mutations consistent with such signatures can provide valuable information about cancer etiology. However, the results from different decomposition methods are not always consistent. Hence, one needs to not only be able to decompose a patient’s mutational profile into signatures but also to establish the accuracy of such decomposition. We proposed two complementary ways of measuring confidence and stability of decomposition results and applied them to analyze mutational signatures in breast cancer genomes. We identified very stable and highly unstable signatures, as well as signatures that have been missed altogether. We also provided additional support for the novel signatures. Our results emphasize the importance of assessing the confidence and stability of inferred signature contributions. All tools developed in this paper have been implemented in an R package, called SignatureEstimation, which is available from https://www.ncbi.nlm.nih.gov/CBBresearch/Przytycka/index.cgi#signatureestimation.

scholarly journals RepairSig: Deconvolution of DNA damage and repair contributions to the mutational landscape of cancer

2020 ◽  
Author(s):  
Damian Wojtowicz ◽  
Jan Hoinka ◽  
Bayarbaatar Amgalan ◽  
Yoo-Ah Kim ◽  
Teresa M. Przytycka
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Mutational Signatures ◽  
Dna Damage And Repair ◽  
Therapeutic Implications ◽  
Mutational Landscape ◽  
Repair Processes ◽  
Cancer Genomes ◽  
Current Paradigm ◽  
Mutational Processes

AbstractMany mutagenic processes leave characteristic imprints on cancer genomes known as mutational signatures. These signatures have been of recent interest regarding their applicability in studying processes shaping the mutational landscape of cancer. In particular, pinpointing the presence of altered DNA repair pathways can have important therapeutic implications. However, mutational signatures of DNA repair deficiencies are often hard to infer. This challenge emerges as a result of deficient DNA repair processes acting by modifying the outcome of other mutagens. Thus, they exhibit non-additive effects that are not depicted by the current paradigm for modeling mutational processes as independent signatures. To close this gap, we present RepairSig, a method that accounts for interactions between DNA damage and repair and is able to uncover unbiased signatures of deficient DNA repair processes. In particular, RepairSig was able to replace three MMR deficiency signatures previously proposed to be active in breast cancer, with just one signature strikingly similar to the experimentally derived signature. As the first method to model interactions between mutagenic processes, RepairSig is an important step towards biologically more realistic modeling of mutational processes in cancer. The source code for RepairSig is publicly available at https://github.com/ncbi/RepairSig.

scholarly journals The Repertoire of Mutational Signatures in Human Cancer

2018 ◽  
Author(s):  
Ludmil B Alexandrov ◽  
Jaegil Kim ◽  
Nicholas J Haradhvala ◽  
Mi Ni Huang ◽  
Alvin WT Ng ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Human Cancer ◽  
Base Substitution ◽  
Mutational Signatures ◽  
Insertion And Deletion ◽  
Damage Repair ◽  
Cancer Genomes ◽  
Dataset Size ◽  
Dna Maintenance ◽  
Mutational Processes

ABSTRACTSomatic mutations in cancer genomes are caused by multiple mutational processes each of which generates a characteristic mutational signature. Using 84,729,690 somatic mutations from 4,645 whole cancer genome and 19,184 exome sequences encompassing most cancer types we characterised 49 single base substitution, 11 doublet base substitution, four clustered base substitution, and 17 small insertion and deletion mutational signatures. The substantial dataset size compared to previous analyses enabled discovery of new signatures, separation of overlapping signatures and decomposition of signatures into components that may represent associated, but distinct, DNA damage, repair and/or replication mechanisms. Estimation of the contribution of each signature to the mutational catalogues of individual cancer genomes revealed associations with exogenous and endogenous exposures and defective DNA maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes contributing to the development of human cancer including a comprehensive reference set of mutational signatures in human cancer.

scholarly journals DNA deaminases induce break-associated mutation showers with implication of APOBEC3B and 3A in breast cancer kataegis

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Benjamin JM Taylor ◽  
Serena Nik-Zainal ◽  
Yee Ling Wu ◽  
Lucy A Stebbings ◽  
Keiran Raine ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Abasic Site ◽  
Dna Breaks ◽  
Mutational Signatures ◽  
Genome Wide ◽  
Cancer Genomes ◽  
Strand Breakage ◽  
Cytidine Deamination ◽  
Apobec Family ◽  
Insight Into

Breast cancer genomes have revealed a novel form of mutation showers (kataegis) in which multiple same-strand substitutions at C:G pairs spaced one to several hundred nucleotides apart are clustered over kilobase-sized regions, often associated with sites of DNA rearrangement. We show kataegis can result from AID/APOBEC-catalysed cytidine deamination in the vicinity of DNA breaks, likely through action on single-stranded DNA exposed during resection. Cancer-like kataegis can be recapitulated by expression of AID/APOBEC family deaminases in yeast where it largely depends on uracil excision, which generates an abasic site for strand breakage. Localized kataegis can also be nucleated by an I-SceI-induced break. Genome-wide patterns of APOBEC3-catalyzed deamination in yeast reveal APOBEC3B and 3A as the deaminases whose mutational signatures are most similar to those of breast cancer kataegic mutations. Together with expression and functional assays, the results implicate APOBEC3B/A in breast cancer hypermutation and give insight into the mechanism of kataegis.

scholarly journals Mutational signatures are jointly shaped by DNA damage and repair

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Nadezda V. Volkova ◽  
Bettina Meier ◽  
Víctor González-Huici ◽  
Simone Bertolini ◽  
Santiago Gonzalez ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Excision Repair ◽  
Point Mutations ◽  
Mutational Signatures ◽  
Dna Damage And Repair ◽  
C Elegans ◽  
Dna Repair Deficiency ◽  
Dna Alterations ◽  
Repair Pathways

AbstractCells possess an armamentarium of DNA repair pathways to counter DNA damage and prevent mutation. Here we use C. elegans whole genome sequencing to systematically quantify the contributions of these factors to mutational signatures. We analyse 2,717 genomes from wild-type and 53 DNA repair defective backgrounds, exposed to 11 genotoxins, including UV-B and ionizing radiation, alkylating compounds, aristolochic acid, aflatoxin B1, and cisplatin. Combined genotoxic exposure and DNA repair deficiency alters mutation rates or signatures in 41% of experiments, revealing how different DNA alterations induced by the same genotoxin are mended by separate repair pathways. Error-prone translesion synthesis causes the majority of genotoxin-induced base substitutions, but averts larger deletions. Nucleotide excision repair prevents up to 99% of point mutations, almost uniformly across the mutation spectrum. Our data show that mutational signatures are joint products of DNA damage and repair and suggest that multiple factors underlie signatures observed in cancer genomes.

scholarly journals Characteristics of mutational signatures of unknown etiology

NAR Cancer ◽  
2020 ◽  
Vol 2 (3) ◽  
Author(s):  
Xiaoju Hu ◽  
Zhuxuan Xu ◽  
Subhajyoti De
Keyword(s):  
Dna Damage ◽  
Point Mutations ◽  
Gc Content ◽  
Unknown Origin ◽  
Unknown Etiology ◽  
Mutational Signatures ◽  
Dna Damage And Repair ◽  
Disease Etiology ◽  
Repair Processes ◽  
A Genome

Abstract Although not all somatic mutations are cancer drivers, their mutational signatures, i.e. the patterns of genomic alterations at a genome-wide scale, provide insights into past exposure to mutagens, DNA damage and repair processes. Computational deconvolution of somatic mutation patterns and expert curation pan-cancer studies have identified a number of mutational signatures associated with point mutations, dinucleotide substitutions, insertions and deletions, and rearrangements, and have established etiologies for a subset of these signatures. However, the mechanisms underlying nearly one-third of all mutational signatures are not yet understood. The signatures with established etiology and those with hitherto unknown origin appear to have some differences in strand bias, GC content and nucleotide context diversity. It is possible that some of the hitherto ‘unknown’ signatures predominantly occur outside gene regions. While nucleotide contexts might be adequate to establish etiologies of some mutational signatures, in other cases additional features, such as broader (epi)genomic contexts, including chromatin, replication timing, processivity and local mutational patterns, may help fully understand the underlying DNA damage and repair processes. Nonetheless, remarkable progress in characterization of mutational signatures has provided fundamental insights into the biology of cancer, informed disease etiology and opened up new opportunities for cancer prevention, risk management, and therapeutic decision making.

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