FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2919337517> ?p ?o ?g. }

• W2919337517 endingPage "1294.e20" @default.
• W2919337517 startingPage "1282" @default.
• W2919337517 abstract "•Annotation of mutational signatures across 1,001 cancer cell lines and 577 PDXs•Activities of mutational processes determined over time in cancer cell lines•APOBEC-associated mutagenesis is often ongoing and can be episodic•Detection of mutational signatures by single-cell sequencing Multiple signatures of somatic mutations have been identified in cancer genomes. Exome sequences of 1,001 human cancer cell lines and 577 xenografts revealed most common mutational signatures, indicating past activity of the underlying processes, usually in appropriate cancer types. To investigate ongoing patterns of mutational-signature generation, cell lines were cultured for extended periods and subsequently DNA sequenced. Signatures of discontinued exposures, including tobacco smoke and ultraviolet light, were not generated in vitro. Signatures of normal and defective DNA repair and replication continued to be generated at roughly stable mutation rates. Signatures of APOBEC cytidine deaminase DNA-editing exhibited substantial fluctuations in mutation rate over time with episodic bursts of mutations. The initiating factors for the bursts are unclear, although retrotransposon mobilization may contribute. The examined cell lines constitute a resource of live experimental models of mutational processes, which potentially retain patterns of activity and regulation operative in primary human cancers. Multiple signatures of somatic mutations have been identified in cancer genomes. Exome sequences of 1,001 human cancer cell lines and 577 xenografts revealed most common mutational signatures, indicating past activity of the underlying processes, usually in appropriate cancer types. To investigate ongoing patterns of mutational-signature generation, cell lines were cultured for extended periods and subsequently DNA sequenced. Signatures of discontinued exposures, including tobacco smoke and ultraviolet light, were not generated in vitro. Signatures of normal and defective DNA repair and replication continued to be generated at roughly stable mutation rates. Signatures of APOBEC cytidine deaminase DNA-editing exhibited substantial fluctuations in mutation rate over time with episodic bursts of mutations. The initiating factors for the bursts are unclear, although retrotransposon mobilization may contribute. The examined cell lines constitute a resource of live experimental models of mutational processes, which potentially retain patterns of activity and regulation operative in primary human cancers. Each mutational process operative in a cell leaves a mutational signature imprinted on its genome (Stratton et al., 2009Stratton M.R. Campbell P.J. Futreal P.A. The cancer genome.Nature. 2009; 458: 719-724Crossref PubMed Scopus (2385) Google Scholar). Using mathematical approaches applied to thousands of catalogs of somatic mutations from the range of human cancer types (Alexandrov et al., 2013bAlexandrov L.B. Nik-Zainal S. Wedge D.C. Campbell P.J. Stratton M.R. Deciphering signatures of mutational processes operative in human cancer.Cell Rep. 2013; 3: 246-259Abstract Full Text Full Text PDF PubMed Scopus (735) Google Scholar), more than 40 base substitution and ten genome rearrangement mutational signatures have thus far been identified (Alexandrov et al., 2018Alexandrov L.B. Kim J. Haradhvala N.J. Huang M.N. Ng A.W.T. Boot A. Covington K.R. Gordenin D.A. Bergstrom E. Lopez-Bigas N. et al.The Repertoire of Mutational Signatures in Human Cancer.bioRxiv. 2018; https://doi.org/10.1101/322859Crossref Google Scholar, Alexandrov et al., 2013aAlexandrov L.B. Nik-Zainal S. Wedge D.C. Aparicio S.A. Behjati S. Biankin A.V. Bignell G.R. Bolli N. Borg A. Børresen-Dale A.L. et al.Australian Pancreatic Cancer Genome InitiativeICGC Breast Cancer ConsortiumICGC MMML-Seq ConsortiumICGC PedBrainSignatures of mutational processes in human cancer.Nature. 2013; 500: 415-421Crossref PubMed Scopus (6221) Google Scholar, Li et al., 2017Li Y. Roberts N.D. Weischenfeldt J. Wala J.A. Shapira O. Schumacher S. Khurana E. Korbel J.O. Imielinski M. Beroukhim R. et al.Patterns of structural variation in human cancer.bioRxiv. 2017; https://doi.org/10.1101/181339Crossref Scopus (0) Google Scholar, Nik-Zainal et al., 2016Nik-Zainal S. Davies H. Staaf J. Ramakrishna M. Glodzik D. Zou X. Martincorena I. Alexandrov L.B. Martin S. Wedge D.C. et al.Landscape of somatic mutations in 560 breast cancer whole-genome sequences.Nature. 2016; 534: 47-54Crossref PubMed Scopus (1257) Google Scholar). There is currently insight into the mutational processes underlying about half of these signatures (Helleday et al., 2014Helleday T. Eshtad S. Nik-Zainal S. Mechanisms underlying mutational signatures in human cancers.Nat. Rev. Genet. 2014; 15: 585-598Crossref PubMed Scopus (523) Google Scholar, Petljak and Alexandrov, 2016Petljak M. Alexandrov L.B. Understanding mutagenesis through delineation of mutational signatures in human cancer.Carcinogenesis. 2016; 37: 531-540Crossref PubMed Scopus (64) Google Scholar). However, many questions remain pertaining to the biology of their underlying mechanisms, which require experimental models to be addressed. The somatic mutational catalog of a cancer genome is the aggregate of mutations that has been generated by multiple mutational processes active at any point during the cell lineage from the fertilized egg to the cancer cell (Stratton et al., 2009Stratton M.R. Campbell P.J. Futreal P.A. The cancer genome.Nature. 2009; 458: 719-724Crossref PubMed Scopus (2385) Google Scholar). Some mutational processes may operate continuously and for the full duration of the cell lineage, as proposed for the processes underlying signatures 1 and 5, which are ubiquitous among cancer types and are found in normal cells (Alexandrov et al., 2015Alexandrov L.B. Jones P.H. Wedge D.C. Sale J.E. Campbell P.J. Nik-Zainal S. Stratton M.R. Clock-like mutational processes in human somatic cells.Nat. Genet. 2015; 47: 1402-1407Crossref PubMed Scopus (546) Google Scholar, Blokzijl et al., 2016Blokzijl F. de Ligt J. Jager M. Sasselli V. Roerink S. Sasaki N. Huch M. Boymans S. Kuijk E. Prins P. et al.Tissue-specific mutation accumulation in human adult stem cells during life.Nature. 2016; 538: 260-264Crossref PubMed Scopus (537) Google Scholar). Others may operate over only part of the lineage and may no longer be active when the cancer is sampled, for example, exposures to tobacco smoke and ultraviolet light. Comparisons of mutations generated during different phases of the evolution of individual human cancers in vivo suggest that some mutational processes show varying degrees of activity over time (Gerstung et al., 2017Gerstung M. Clemency J. Leshchiner I. Dentro S.C. Gonzalez S. Mitchell T.J. Rubanova Y. Anur P. Rosebrock D. Yu K. et al.The evolutionary history of 2,658 cancers.bioRxiv. 2017; https://doi.org/10.1101/161562Crossref Scopus (0) Google Scholar, McGranahan et al., 2015McGranahan N. Favero F. de Bruin E.C. Birkbak N.J. Szallasi Z. Swanton C. Clonal status of actionable driver events and the timing of mutational processes in cancer evolution.Sci. Transl. Med. 2015; 7: 283ra54Crossref PubMed Scopus (448) Google Scholar, Nik-Zainal et al., 2012aNik-Zainal S. Alexandrov L.B. Wedge D.C. Van Loo P. Greenman C.D. Raine K. Jones D. Hinton J. Marshall J. Stebbings L.A. et al.Breast Cancer Working Group of the International Cancer Genome ConsortiumMutational processes molding the genomes of 21 breast cancers.Cell. 2012; 149: 979-993Abstract Full Text Full Text PDF PubMed Scopus (1282) Google Scholar). To provide a resource for experimental investigation of the biological mechanisms underlying the repertoire of mutational signatures, we first annotated mutational signatures on sets of publicly available models, including 1,001 immortal human cell lines (COSMIC Cell Line Project) and 577 patient-derived xenografts (PDXs; NCI Patient-Derived Models Repository) derived from a broad spectrum of cancer types. The panel includes most widely used models in cancer research and therapeutics testing and is being extensively characterized genomically, transcriptomally, epigenomically, and for biological responses to therapeutics (Garnett et al., 2012Garnett M.J. Edelman E.J. Heidorn S.J. Greenman C.D. Dastur A. Lau K.W. Greninger P. Thompson I.R. Luo X. Soares J. et al.Systematic identification of genomic markers of drug sensitivity in cancer cells.Nature. 2012; 483: 570-575Crossref PubMed Scopus (1696) Google Scholar, Iorio et al., 2016Iorio F. Knijnenburg T.A. Vis D.J. Bignell G.R. Menden M.P. Schubert M. Aben N. Gonçalves E. Barthorpe S. Lightfoot H. et al.A Landscape of Pharmacogenomic Interactions in Cancer.Cell. 2016; 166: 740-754Abstract Full Text Full Text PDF PubMed Scopus (946) Google Scholar). We subsequently used a subset of the cancer cell lines to experimentally assess whether mutational processes underlying mutational signatures continue to be active during in vitro culture and to characterize their temporal patterns of activity. Cell lines continuing to acquire mutational signatures represent informative models for future investigation of their underlying mechanisms. The presence and relative contributions of single base substitution signatures (SBSs) were determined in each of 1,001 cancer cell lines (Figure 1; Table S3) and 577 PDX models (Table S3), derived from more than 40 cancer types using previously generated whole-exome DNA sequences (STAR Methods; signature patterns in Figure S1 and Table S1). The analysis revealed a novel signature of unknown origin in Hodgkin’s lymphoma cell lines characterized by T>A base substitutions (termed SBS25; Figures 1 and S1). During manuscript revision, attribution of a more limited set of mutational signatures to the same set of cancer cell lines was reported (Jarvis et al., 2018Jarvis M.C. Ebrahimi D. Temiz N.A. Harris R.S. Mutation Signatures Including APOBEC in Cancer Cell Lines.JNCI Cancer Spectr. 2018; 2https://doi.org/10.1093/pky002Crossref PubMed Google Scholar).Figure S1Core Set of the Annotated Mutational Signatures, Related to Figures 1, 3, 5, and 6Show full caption(A) The core set of the mutational signatures, including the Platinum set of the PCAWG signatures and SBS25 discovered in Hodgkin’s lymphoma cell lines. Signatures are displayed according to the alphabetical 96-substitution classification on horizontal axes, defined by the six color-coded substitution types and sequence context immediately 5′ and 3′ to the mutated base axes (as per panel B). Vertical axes differ between individual signatures for visualization of their patterns (numerical patterns in Table S1) and indicate the percentage of mutations attributed to specific mutation types, adjusted to genome-wide trinucleotide frequencies. We thank PCAWG Mutational Signatures Working Group for the figure.(B) Transcriptional strand bias for SBS25. The mutational signature is displayed according to the 192-subsitution classification, incorporating the six substitution types in color-coded panels, the sequence context immediately 5′ and 3′ to the mutated base and whether the mutated base (in pyrimidine context) is on the transcribed (blue bars) or untranscribed (red bars) strand.View Large Image Figure ViewerDownload Hi-res image Download (PPT) (A) The core set of the mutational signatures, including the Platinum set of the PCAWG signatures and SBS25 discovered in Hodgkin’s lymphoma cell lines. Signatures are displayed according to the alphabetical 96-substitution classification on horizontal axes, defined by the six color-coded substitution types and sequence context immediately 5′ and 3′ to the mutated base axes (as per panel B). Vertical axes differ between individual signatures for visualization of their patterns (numerical patterns in Table S1) and indicate the percentage of mutations attributed to specific mutation types, adjusted to genome-wide trinucleotide frequencies. We thank PCAWG Mutational Signatures Working Group for the figure. (B) Transcriptional strand bias for SBS25. The mutational signature is displayed according to the 192-subsitution classification, incorporating the six substitution types in color-coded panels, the sequence context immediately 5′ and 3′ to the mutated base and whether the mutated base (in pyrimidine context) is on the transcribed (blue bars) or untranscribed (red bars) strand. The majority of the base substitution signatures observed in primary cancers (Alexandrov et al., 2018Alexandrov L.B. Kim J. Haradhvala N.J. Huang M.N. Ng A.W.T. Boot A. Covington K.R. Gordenin D.A. Bergstrom E. Lopez-Bigas N. et al.The Repertoire of Mutational Signatures in Human Cancer.bioRxiv. 2018; https://doi.org/10.1101/322859Crossref Google Scholar) were found in the examined cell line and PDX models (Figure 1; Table S3). These included signatures of exogenous environmental exposures such as SBS4, caused by tobacco-smoke exposure, in lung cancers; SBS7a-b and SBS38, caused by ultraviolet light, in melanoma models; SBS11, likely caused by temozolomide treatment, in melanoma and glioma cell lines; SBS22, caused by aristolochic acid (Poon et al., 2013Poon S.L. Pang S.T. McPherson J.R. Yu W. Huang K.K. Guan P. Weng W.H. Siew E.Y. Liu Y. Heng H.L. et al.Genome-wide mutational signatures of aristolochic acid and its application as a screening tool.Sci. Transl. Med. 2013; 5: 197ra101Crossref PubMed Scopus (207) Google Scholar), in a bladder cancer cell line; and SBS35, associated with platinum compound chemotherapy (Boot et al., 2018Boot A. Huang M.N. Ng A.W.T. Ho S.C. Lim J.Q. Kawakami Y. Chayama K. Teh B.T. Nakagawa H. Rozen S.G. In-depth characterization of the cisplatin mutational signature in human cell lines and in esophageal and liver tumors.Genome Res. 2018; 28: 654-665Crossref PubMed Scopus (80) Google Scholar), in ovarian and sarcoma models. Signatures associated with mutational processes of endogenous origins were also found, including SBS2 and SBS13, associated with APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) cytidine deaminase DNA-editing activity (Nik-Zainal et al., 2012aNik-Zainal S. Alexandrov L.B. Wedge D.C. Van Loo P. Greenman C.D. Raine K. Jones D. Hinton J. Marshall J. Stebbings L.A. et al.Breast Cancer Working Group of the International Cancer Genome ConsortiumMutational processes molding the genomes of 21 breast cancers.Cell. 2012; 149: 979-993Abstract Full Text Full Text PDF PubMed Scopus (1282) Google Scholar), in cell lines and PDXs from breast, bladder, head and neck, cervix, lung, esophageal, and non-melanoma skin carcinomas; signatures associated with microsatellite instability (MSI) due to defective DNA mismatch repair (MMR) (SBS6, SBS15, SBS21, and SBS26) and due to a concurrent loss of MMR and proofreading functions of polymerases epsilon (POLE; SBS14) or polymerase delta (POLD; SBS20) (Haradhvala et al., 2018Haradhvala N.J. Kim J. Maruvka Y.E. Polak P. Rosebrock D. Livitz D. Hess J.M. Leshchiner I. Kamburov A. Mouw K.W. et al.Distinct mutational signatures characterize concurrent loss of polymerase proofreading and mismatch repair.Nat. Commun. 2018; 9: 1746Crossref PubMed Scopus (86) Google Scholar), in colorectal, gastric, and endometrial models; SBS10a-b, due to mutations in POLE, in colorectal, endometrial, and stomach models; SBS36, associated with defective base excision repair and MUTYH mutations (Pilati et al., 2017Pilati C. Shinde J. Alexandrov L.B. Assié G. André T. Hélias-Rodzewicz Z. Ducoudray R. Le Corre D. Zucman-Rossi J. Emile J.F. et al.Mutational signature analysis identifies MUTYH deficiency in colorectal cancers and adrenocortical carcinomas.J. Pathol. 2017; 242: 10-15Crossref PubMed Scopus (85) Google Scholar, Viel et al., 2017Viel A. Bruselles A. Meccia E. Fornasarig M. Quaia M. Canzonieri V. Policicchio E. Urso E.D. Agostini M. Genuardi M. et al.A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer.EBioMedicine. 2017; 20: 39-49Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar), in pancreatic cell lines; and SBS3, associated with defective homologous recombination-based double-strand break (HR-DSB) DNA repair often due to BRCA1 or BRCA2 inactivation (Nik-Zainal et al., 2012aNik-Zainal S. Alexandrov L.B. Wedge D.C. Van Loo P. Greenman C.D. Raine K. Jones D. Hinton J. Marshall J. Stebbings L.A. et al.Breast Cancer Working Group of the International Cancer Genome ConsortiumMutational processes molding the genomes of 21 breast cancers.Cell. 2012; 149: 979-993Abstract Full Text Full Text PDF PubMed Scopus (1282) Google Scholar), in breast, ovarian, sarcoma, and esophageal models. Finally, signatures of uncertain and speculative origins (Alexandrov et al., 2018Alexandrov L.B. Kim J. Haradhvala N.J. Huang M.N. Ng A.W.T. Boot A. Covington K.R. Gordenin D.A. Bergstrom E. Lopez-Bigas N. et al.The Repertoire of Mutational Signatures in Human Cancer.bioRxiv. 2018; https://doi.org/10.1101/322859Crossref Google Scholar) were also observed, including SBS17a-b in gastric and esophageal models; SBS18, potentially due to reactive-oxygen-species-induced DNA damage, in neuroblastoma cell lines; SBS9, which might result from aberrant processing of AID-induced cytidine deamination by polymerase η, in lymphoma cell lines; and SBS28, SBS34, SBS39, and SBS40, which were found mainly in the cancer types in which they had been previously reported. SBS1 (associated with deamination of 5-methyl cytosine) and SBS5 (of unknown origin) are ubiquitous among cancer types (Alexandrov et al., 2015Alexandrov L.B. Jones P.H. Wedge D.C. Sale J.E. Campbell P.J. Nik-Zainal S. Stratton M.R. Clock-like mutational processes in human somatic cells.Nat. Genet. 2015; 47: 1402-1407Crossref PubMed Scopus (546) Google Scholar) and were present in most cancer cell lines and PDXs. However, some SBS1 and SBS5 mutations are likely attributable to residual germline variants, which remain because of the non-availability of normal DNAs from the same individuals for most cancer cell lines (STAR Methods) and which are also constituted of these two signatures (Rahbari et al., 2016Rahbari R. Wuster A. Lindsay S.J. Hardwick R.J. Alexandrov L.B. Turki S.A. Dominiczak A. Morris A. Porteous D. Smith B. et al.UK10K ConsortiumTiming, rates and spectra of human germline mutation.Nat. Genet. 2016; 48: 126-133Crossref PubMed Scopus (324) Google Scholar). A small subset of signatures was absent from the examined datasets (SBS7c, SBS12, SBS16, SBS24) or found less often than expected (e.g., SBS3) (Alexandrov et al., 2018Alexandrov L.B. Kim J. Haradhvala N.J. Huang M.N. Ng A.W.T. Boot A. Covington K.R. Gordenin D.A. Bergstrom E. Lopez-Bigas N. et al.The Repertoire of Mutational Signatures in Human Cancer.bioRxiv. 2018; https://doi.org/10.1101/322859Crossref Google Scholar). These may be due to the small numbers of somatic mutations in exome sequences, the small numbers of mutations some signatures contribute to individual cancers, the obscuring presence of residual germline variants, the relatively featureless profiles of some signatures that may be more difficult to detect, and/or the genuine absence of the signatures (Alexandrov et al., 2013bAlexandrov L.B. Nik-Zainal S. Wedge D.C. Campbell P.J. Stratton M.R. Deciphering signatures of mutational processes operative in human cancer.Cell Rep. 2013; 3: 246-259Abstract Full Text Full Text PDF PubMed Scopus (735) Google Scholar). Some signatures were detected in a small proportion of models from cancer classes in which they have not been previously reported (Alexandrov et al., 2018Alexandrov L.B. Kim J. Haradhvala N.J. Huang M.N. Ng A.W.T. Boot A. Covington K.R. Gordenin D.A. Bergstrom E. Lopez-Bigas N. et al.The Repertoire of Mutational Signatures in Human Cancer.bioRxiv. 2018; https://doi.org/10.1101/322859Crossref Google Scholar). Such instances likely reflect past misclassification, past cross-contamination, or minor misattribution of mutational signatures. To investigate the patterns of activity of mutational processes underlying a wide range of signatures, we selected 28 cell lines derived from cancers of the breast, colorectum, uterus, lung, stomach, cervix, ovary, head and neck, skin (melanoma and squamous), white blood cells (B cell lymphoma and leukemia), and neuroblastoma (Figure 3A). One or more of these had high contributions from mutational signatures of tobacco smoke (SBS4); ultraviolet light (SBS7a-d); aberrant APOBEC cytidine deaminase activity (SBS2 and SBS13); defective DNA MMR with MSI (SBS6, SBS15, SBS21, SBS26); concurrent loss of MMR and proofreading functions in POLD (SBS20) and POLE (SBS14); aberrant POLE activity (SBS10a-b); deficiency of HR-DSB repair (SBS3); and signatures of uncertain origin including SBS17a-b (frequently found in esophageal and gastric cancers), SBS18 (found commonly in neuroblastoma), and SBS28 (common in colorectal and endometrial cancers with mutations in POLE). SBS1 and SBS5 were detected in most cell lines. One or more single-cell-derived subclones were established from the stock cultures of each of the 28 cancer cell lines (STAR Methods; Figure 2). These subclones of the stock culture were termed “parent” clones. Parent clones were then propagated in culture for up to 161 days (Table S2). Following this period of cultivation, a further round of subcloning was carried out on the cell population from each parent clone, and one or more single-cell subclones were derived (Figure 2). These single-cell subclones of the parent clone were termed “daughter” clones. Daughter clones were expanded in culture to generate a population of cells from which sufficient DNA for further analysis could be obtained. DNAs extracted from parent and daughter clones were whole-exome and/or whole-genome sequenced, and mutations were called (STAR Methods; Figure S7). Subtraction of mutations present in parent clones from those in related daughter clones yielded the mutation sets acquired predominantly during the periods of in vitro propagation between the two subcloning events (STAR Methods). Subtraction of mutations present in the stock cell lines from mutations in their corresponding parent clones (or in some instances, subtraction of mutations shared by two parent lines) revealed mutations acquired mostly between the establishment of the most recent common ancestor cell of the stock cell line and isolation of the single parent cells (STAR Methods). The signature profile of 100 whole-genome- and 41 whole-exome-sequenced daughter clones alongside their corresponding 58 parent clones was then generated (Figure 3; Table S3; STAR Methods). Certain mutational signatures present in stock cell lines were not generated during in vitro culture of their descendant clones (Figure 3; Table S3). These included SBS4 and SBS7 due to tobacco smoke and ultraviolet light, respectively, to which the examined lung cancer (NCI-H650) and melanoma (Mewo) cell lines were not exposed during in vitro culture. In addition, SBS17a-b did not continue to be acquired in vitro in the stomach (AGS) cell line overwhelmed with these signatures. All other signatures present in stock cell lines continued to be generated during culture of descendant clones from at least some cell lines. Multiple mutational signatures have previously been associated with defective mismatch repair (SBS6, SBS14, SBS15, SBS20, SBS21, SBS26) (Alexandrov et al., 2018Alexandrov L.B. Kim J. Haradhvala N.J. Huang M.N. Ng A.W.T. Boot A. Covington K.R. Gordenin D.A. Bergstrom E. Lopez-Bigas N. et al.The Repertoire of Mutational Signatures in Human Cancer.bioRxiv. 2018; https://doi.org/10.1101/322859Crossref Google Scholar). In some cell lines, the particular signature(s) present in the stock converted to different defective MMR signature(s) during in vitro culture (e.g., acute lymphocytic leukemia MOLT-4) or remained roughly stable (e.g., colorectal cancer CW-2) (Figure 3; Table S3). In others, certain signatures appeared to be present in the stock cell line but were absent from all or some clones and vice versa. However, visual inspection of mutation spectra indicated that this was likely due to misattribution of mutations to other MMR-deficiency signatures and that all cell lines with defective MMR (Table S4; Figure S2) continued to generate a subset of the corresponding signatures alongside the large numbers of small indels at short nucleotide repeats typical of this repair deficiency (Figure 3). The colorectal (SNU-81 and HT-115) and endometrial (ESS-1) cancer cell lines with mutations in POLE (Table S4) continued to generate the associated base substitution signatures. However, the relative contribution of SBS10b (composed predominantly of C>T mutations) compared to signature SBS10a (composed predominantly of C>A mutations) diminished markedly in vitro (Figure 3). Furthermore, signature 28, often found in cancers with mutations in POLE (Alexandrov et al., 2018Alexandrov L.B. Kim J. Haradhvala N.J. Huang M.N. Ng A.W.T. Boot A. Covington K.R. Gordenin D.A. Bergstrom E. Lopez-Bigas N. et al.The Repertoire of Mutational Signatures in Human Cancer.bioRxiv. 2018; https://doi.org/10.1101/322859Crossref Google Scholar), continued to be generated in all of these cell lines but not in the examined stomach cancer cell line (AGS) (Figure 3; Table S3). SBS3 is a relatively flat and featureless base substitution signature (Figure S1) that is associated with defective homologous recombination-based DNA repair and inactivating mutations of BRCA1 and BRCA2 (Alexandrov et al., 2013aAlexandrov L.B. Nik-Zainal S. Wedge D.C. Aparicio S.A. Behjati S. Biankin A.V. Bignell G.R. Bolli N. Borg A. Børresen-Dale A.L. et al.Australian Pancreatic Cancer Genome InitiativeICGC Breast Cancer ConsortiumICGC MMML-Seq ConsortiumICGC PedBrainSignatures of mutational processes in human cancer.Nature. 2013; 500: 415-421Crossref PubMed Scopus (6221) Google Scholar, Nik-Zainal et al., 2012aNik-Zainal S. Alexandrov L.B. Wedge D.C. Van Loo P. Greenman C.D. Raine K. Jones D. Hinton J. Marshall J. Stebbings L.A. et al.Breast Cancer Working Group of the International Cancer Genome ConsortiumMutational processes molding the genomes of 21 breast cancers.Cell. 2012; 149: 979-993Abstract Full Text Full Text PDF PubMed Scopus (1282) Google Scholar). It is usually accompanied by small deletions with overlapping microhomology at their boundaries and large numbers of rearrangements, including tandem duplications and deletions (Nik-Zainal et al., 2012aNik-Zainal S. Alexandrov L.B. Wedge D.C. Van Loo P. Greenman C.D. Raine K. Jones D. Hinton J. Marshall J. Stebbings L.A. et al.Breast Cancer Working Group of the International Cancer Genome ConsortiumMutational processes molding the genomes of 21 breast cancers.Cell. 2012; 149: 979-993Abstract Full Text Full Text PDF PubMed Scopus (1282) Google Scholar, Nik-Zainal et al., 2016Nik-Zainal S. Davies H. Staaf J. Ramakrishna M. Glodzik D. Zou X. Martincorena I. Alexandrov L.B. Martin S. Wedge D.C. et al.Landscape of somatic mutations in 560 breast cancer whole-genome sequences.Nature. 2016; 534: 47-54Crossref PubMed Scopus (1257) Google Scholar). The breast cancer cell line MDA-MB-436 is deficient in BRCA1 (Elstrodt et al., 2006Elstrodt F. Hollestelle A. Nagel J.H. Gorin M. Wasielewski M. van den Ouweland A. Merajver S.D. Ethier S.P. Schutte M. BRCA1 mutation analysis of 41 human breast cancer cell lines reveals three new deleterious mutants.Cancer Res. 2006; 66: 41-45Crossref PubMed Scopus (194) Google Scholar) and generated SBS3 during in vitro culture accompanied by the characteristic deletions with microhomology and large numbers of rearrangements (Figures 3 and S3A). SBS3 was also generated in the ovarian (OVCAR-8) and breast (HCC38) cancer cell lines (Figure 3), which have attenuated BRCA1 expression due to promoter methylation as well as in lung adenocarcinoma (NCI-H650) and breast cancer (AU565) cell lines, which did not show obvious deficiencies in BRCA1 or BRCA2 function (Figure S2; Table S4). In contrast to MDA-MB-436, however, SBS3 in these lines was not accompanied by substantial numbers of deletions with microhomology or rearrangements (Figure S3B). SBS1 and SBS5 have previously been attributed to processes generating mutations throughout life in normal tissues at constant rates in all individuals (Alexandrov et al., 2015Alexandrov L.B. Jones P.H. Wedge D.C. Sale J.E. Campbell P.J. Nik-Zainal S. Stratton M.R. Clock-like mutational processes in human somatic cells.Nat. Genet. 2015; 47: 1402-1407Crossref PubMed Scopus (546) Google Scholar). SBS5, which is of unknown origin, was identified in most clones (Figures 3B and 3C). SBS1, which is attributed to deamination of 5-methyl cytosine (Alexandrov et al., 2013aAlexandrov L.B. Nik-Zainal S. Wedge D.C. Aparicio S.A. Behjati S. Biankin A.V. Bignell G.R. Bolli N. Borg A. Børresen-Dale A.L. et al.Australian Pancreatic Cancer Genome InitiativeICGC Breast Cancer ConsortiumICGC MMML-Seq ConsortiumICGC PedBrainSignatures of mutational processes in human cancer.Nature. 2013; 500: 415-421Crossref PubMed Scopus (6221) Google Scholar, Pfeifer, 2006Pfeifer G.P. Mutagenesis at methylated CpG sequences.Curr. Top. Microbiol. Immunol. 2006; 301: 259-281Crossref PubMed Scopus (200) Google Scholar), was not detected by computational analysis among in vitro-generated mutations. However, the distinctive profile of SBS1, characterized by C>T mutations at NCG trinucleotides (mutated bases underlined and referred to by the pyrimidine partner of the mutated base pair; N any base) was clearly visible following normalization of mutation frequencies to account for depletion of NCG trinucleotides in the human genome (Figure S3B; STAR Methods), indicating that the under" @default.
• W2919337517 created "2019-03-11" @default.
• W2919337517 creator A5004776968 @default.
• W2919337517 creator A5006662985 @default.
• W2919337517 creator A5007140000 @default.
• W2919337517 creator A5008489368 @default.
• W2919337517 creator A5010808737 @default.
• W2919337517 creator A5011008959 @default.
• W2919337517 creator A5011152441 @default.
• W2919337517 creator A5021185845 @default.
• W2919337517 creator A5026738636 @default.
• W2919337517 creator A5026877917 @default.
• W2919337517 creator A5038578938 @default.
• W2919337517 creator A5039926199 @default.
• W2919337517 creator A5046527121 @default.
• W2919337517 creator A5049364024 @default.
• W2919337517 creator A5049418625 @default.
• W2919337517 creator A5051063130 @default.
• W2919337517 creator A5054166669 @default.
• W2919337517 creator A5054740288 @default.
• W2919337517 creator A5055883774 @default.
• W2919337517 creator A5056622062 @default.
• W2919337517 creator A5056697512 @default.
• W2919337517 creator A5058103562 @default.
• W2919337517 creator A5058862412 @default.
• W2919337517 creator A5067817335 @default.
• W2919337517 creator A5072873709 @default.
• W2919337517 creator A5077334183 @default.
• W2919337517 creator A5077753928 @default.
• W2919337517 creator A5078239086 @default.
• W2919337517 creator A5079365516 @default.
• W2919337517 creator A5080415325 @default.
• W2919337517 creator A5080997789 @default.
• W2919337517 creator A5081352687 @default.
• W2919337517 creator A5084431909 @default.
• W2919337517 creator A5085472676 @default.
• W2919337517 creator A5090434169 @default.
• W2919337517 date "2019-03-01" @default.
• W2919337517 modified "2023-10-17" @default.
• W2919337517 title "Characterizing Mutational Signatures in Human Cancer Cell Lines Reveals Episodic APOBEC Mutagenesis" @default.
• W2919337517 cites W1602188512 @default.
• W2919337517 cites W1912672559 @default.
• W2919337517 cites W1965151932 @default.
• W2919337517 cites W1971536112 @default.
• W2919337517 cites W1973950074 @default.
• W2919337517 cites W1978469053 @default.
• W2919337517 cites W1984236815 @default.
• W2919337517 cites W1987208099 @default.
• W2919337517 cites W1995070233 @default.
• W2919337517 cites W2000040814 @default.
• W2919337517 cites W2003665515 @default.
• W2919337517 cites W2008255210 @default.
• W2919337517 cites W2011728187 @default.
• W2919337517 cites W2021341670 @default.
• W2919337517 cites W2041699201 @default.
• W2919337517 cites W2044563319 @default.
• W2919337517 cites W2059300459 @default.
• W2919337517 cites W2064855999 @default.
• W2919337517 cites W2074446011 @default.
• W2919337517 cites W2077921362 @default.
• W2919337517 cites W2080309308 @default.
• W2919337517 cites W2096791516 @default.
• W2919337517 cites W2101836667 @default.
• W2919337517 cites W2104153021 @default.
• W2919337517 cites W2104549677 @default.
• W2919337517 cites W2109991075 @default.
• W2919337517 cites W2112907971 @default.
• W2919337517 cites W2117785761 @default.
• W2919337517 cites W2122732537 @default.
• W2919337517 cites W2122883276 @default.
• W2919337517 cites W2125789330 @default.
• W2919337517 cites W2129136620 @default.
• W2919337517 cites W2140729960 @default.
• W2919337517 cites W2141458291 @default.
• W2919337517 cites W2146948473 @default.
• W2919337517 cites W2146973661 @default.
• W2919337517 cites W2152061559 @default.
• W2919337517 cites W2154422767 @default.
• W2919337517 cites W2154974159 @default.
• W2919337517 cites W2160142678 @default.
• W2919337517 cites W2171690009 @default.
• W2919337517 cites W2173818354 @default.
• W2919337517 cites W2201808132 @default.
• W2919337517 cites W2204392137 @default.
• W2919337517 cites W2217642920 @default.
• W2919337517 cites W2269040222 @default.
• W2919337517 cites W2322936137 @default.
• W2919337517 cites W2344657883 @default.
• W2919337517 cites W2345503748 @default.
• W2919337517 cites W2461427403 @default.
• W2919337517 cites W2520234978 @default.
• W2919337517 cites W2522885072 @default.
• W2919337517 cites W2523216993 @default.
• W2919337517 cites W2524881570 @default.
• W2919337517 cites W2558715006 @default.
• W2919337517 cites W2564735272 @default.
• W2919337517 cites W2581568937 @default.
• W2919337517 cites W2606616407 @default.

• next