171 results on '"Alexandrov LB"'
Search Results
2. The evolutionary history of lethal metastatic prostate cancer
- Author
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Gundem, G, Van Loo, P, Kremeyer, B, Alexandrov, LB, Tubio, JMC, Papaemmanuil, E, Brewer, DS, Kallio, HML, Högnäs, G, Annala, M, Kivinummi, K, Goody, V, Latimer, C, O'Meara, S, Dawson, KJ, Isaacs, W, Emmert-Buck, MR, Nykter, M, Foster, C, Kote-Jarai, Z, Easton, D, Whitaker, HC, ICGC Prostate Group, Neal, DE, Cooper, CS, Eeles, RA, Visakorpi, T, Campbell, PJ, McDermott, U, Wedge, DC, Bova, GS, Easton, Douglas [0000-0003-2444-3247], and Apollo - University of Cambridge Repository
- Subjects
Male ,Receptors, Androgen ,DNA Mutational Analysis ,Androgens ,Disease Progression ,Humans ,Prostatic Neoplasms ,Cell Lineage ,Genes, Tumor Suppressor ,Neoplasm Metastasis ,Clone Cells ,Epigenesis, Genetic ,Signal Transduction - Abstract
Cancers emerge from an ongoing Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour. This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths. However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. Although the hypothesis that each metastasis originates from a single tumour cell is generally supported, recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and interclonal cooperation between multiple subclones. Here we sought definitive evidence for the existence of polyclonal seeding in human malignancy and to establish the clonal relationship among different metastases in the context of androgen-deprived metastatic prostate cancer. Using whole-genome sequencing, we characterized multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subclonal architecture revealed the patterns of metastatic spread in unprecedented detail. Metastasis-to-metastasis spread was found to be common, either through de novo monoclonal seeding of daughter metastases or, in five cases, through the transfer of multiple tumour clones between metastatic sites. Lesions affecting tumour suppressor genes usually occur as single events, whereas mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases. Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen-deprivation therapy in prostate cancer.
- Published
- 2015
3. Erratum: Corrigendum: Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue
- Author
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Cooper, CS, Eeles, R, Wedge, DC, Van Loo, P, Gundem, G, Alexandrov, LB, Kremeyer, B, Butler, A, Lynch, AG, Camacho, N, Massie, CE, Kay, J, Luxton, HJ, Edwards, S, Kote-Jarai, Z, Dennis, N, Merson, S, Leongamornlert, D, Zamora, J, Corbishley, C, Thomas, S, Nik-Zainal, S, Ramakrishna, M, O'Meara, S, Matthews, L, Clark, J, Hurst, R, Mithen, R, Bristow, RG, Boutros, PC, Fraser, M, Cooke, S, Raine, K, Jones, D, Menzies, A, Stebbings, L, Hinton, J, Teague, J, McLaren, S, Mudie, L, Hardy, C, Anderson, E, Joseph, O, Goody, V, Robinson, B, Maddison, M, Gamble, S, Greenman, C, Berney, D, Hazell, S, Livni, N, ICGC Prostate Group, Fisher, C, Ogden, C, Kumar, P, Thompson, A, Woodhouse, C, Nicol, D, Mayer, E, Dudderidge, T, Shah, NC, Gnanapragasam, V, Voet, T, Campbell, P, Futreal, A, Easton, D, Warren, AY, Foster, CS, Stratton, MR, Whitaker, HC, McDermott, U, Brewer, DS, and Neal, DE
- Subjects
Genetics ,Prostate cancer ,medicine.anatomical_structure ,Phylogenetics ,Prostate ,ICGC Prostate Group ,medicine ,11 Medical And Health Sciences ,06 Biological Sciences ,Biology ,medicine.disease ,Developmental Biology - Published
- 2015
4. Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer
- Author
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Hong, MKH, Macintyre, G, Wedge, DC, Van Loo, P, Patel, K, Lunke, S, Alexandrov, LB, Sloggett, C, Cmero, M, Marass, F, Tsui, D, Mangiola, S, Lonie, A, Naeem, H, Sapre, N, Phal, PM, Kurganovs, N, Chin, X, Kerger, M, Warren, AY, Neal, D, Gnanapragasam, V, Rosenfeld, N, Pedersen, JS, Ryan, A, Haviv, I, Costello, AJ, Corcoran, NM, and Hovens, CM
- Subjects
Male ,DNA Copy Number Variations ,Brain Neoplasms ,Prostatic Neoplasms ,Bone Neoplasms ,Sequence Analysis, DNA ,Adenocarcinoma ,Middle Aged ,Polymorphism, Single Nucleotide ,3. Good health ,Mutation ,Disease Progression ,Humans ,Longitudinal Studies ,RNA, Messenger ,Neoplasm Metastasis ,Tumor Suppressor Protein p53 ,Aged - Abstract
Tumour heterogeneity in primary prostate cancer is a well-established phenomenon. However, how the subclonal diversity of tumours changes during metastasis and progression to lethality is poorly understood. Here we reveal the precise direction of metastatic spread across four lethal prostate cancer patients using whole-genome and ultra-deep targeted sequencing of longitudinally collected primary and metastatic tumours. We find one case of metastatic spread to the surgical bed causing local recurrence, and another case of cross-metastatic site seeding combining with dynamic remoulding of subclonal mixtures in response to therapy. By ultra-deep sequencing end-stage blood, we detect both metastatic and primary tumour clones, even years after removal of the prostate. Analysis of mutations associated with metastasis reveals an enrichment of TP53 mutations, and additional sequencing of metastases from 19 patients demonstrates that acquisition of TP53 mutations is linked with the expansion of subclones with metastatic potential which we can detect in the blood.
5. A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers
- Author
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Glodzik, D, Morganella, S, Davies, H, Simpson, PT, Li, Y, Zou, X, Diez-Perez, J, Staaf, J, Alexandrov, LB, Smid, M, Brinkman, AB, Rye, IH, Russnes, H, Raine, K, Purdie, CA, Lakhani, Thompson, AM, Birney, E, Stunnenberg, HG, Van De Vijver, MJ, Martens, JWM, Børresen-Dale, A-L, Richardson, AL, Kong, G, Viari, A, Easton, D, Evan, G, Campbell, PJ, Stratton, MR, and Nik-Zainal, S
- Subjects
breast cancer ,genetics research ,genomics ,3. Good health - Abstract
Somatic rearrangements contribute to the mutagenized landscape of cancer genomes. Here, we systematically interrogated rearrangements in 560 breast cancers by using a piecewise constant fitting approach. We identified 33 hotspots of large (>100 kb) tandem duplications, a mutational signature associated with homologous-recombination-repair deficiency. Notably, these tandem-duplication hotspots were enriched in breast cancer germline susceptibility loci (odds ratio (OR) = 4.28) and breast-specific 'super-enhancer' regulatory elements (OR = 3.54). These hotspots may be sites of selective susceptibility to double-strand-break damage due to high transcriptional activity or, through incrementally increasing copy number, may be sites of secondary selective pressure. The transcriptomic consequences ranged from strong individual oncogene effects to weak but quantifiable multigene expression effects. We thus present a somatic-rearrangement mutational process affecting coding sequences and noncoding regulatory elements and contributing a continuum of driver consequences, from modest to strong effects, thereby supporting a polygenic model of cancer development.
6. Mutational signatures of ionizing radiation in second malignancies
- Author
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Behjati, S, Gundem, G, Wedge, DC, Roberts, ND, Tarpey, PS, Cooke, SL, Van Loo, P, Alexandrov, LB, Ramakrishna, M, Davies, H, Nik-Zainal, S, Hardy, C, Latimer, C, Raine, KM, Stebbings, L, Menzies, A, Jones, D, Shepherd, R, Butler, AP, Teague, JW, Jorgensen, M, Khatri, B, Pillay, N, Shlien, A, Futreal, PA, Badie, C, ICGC Prostate Group, McDermott, U, Bova, GS, Richardson, AL, Flanagan, AM, Stratton, MR, and Campbell, PJ
- Subjects
Male ,Osteosarcoma ,Radiation, Ionizing ,Mutation ,Humans ,Prostatic Neoplasms ,Breast Neoplasms ,Female ,Neoplasms, Second Primary ,Gene Deletion ,Germ-Line Mutation ,3. Good health ,DNA Damage - Abstract
Ionizing radiation is a potent carcinogen, inducing cancer through DNA damage. The signatures of mutations arising in human tissues following in vivo exposure to ionizing radiation have not been documented. Here, we searched for signatures of ionizing radiation in 12 radiation-associated second malignancies of different tumour types. Two signatures of somatic mutation characterize ionizing radiation exposure irrespective of tumour type. Compared with 319 radiation-naive tumours, radiation-associated tumours carry a median extra 201 deletions genome-wide, sized 1-100 base pairs often with microhomology at the junction. Unlike deletions of radiation-naive tumours, these show no variation in density across the genome or correlation with sequence context, replication timing or chromatin structure. Furthermore, we observe a significant increase in balanced inversions in radiation-associated tumours. Both small deletions and inversions generate driver mutations. Thus, ionizing radiation generates distinctive mutational signatures that explain its carcinogenic potential.
7. Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue
- Author
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Cooper, CS, Eeles, R, Wedge, DC, Van Loo, P, Gundem, G, Alexandrov, LB, Kremeyer, B, Butler, A, Lynch, AG, Camacho, N, Massie, CE, Kay, J, Lmcton, HJ, Edwards, S, Kote-Jarai, Z, Dennis, N, Merson, S, Leongamornlert, D, Zamora, J, Corbishley, C, Thomas, S, Nik-Zainal, S, Ramakrishna, M, O'Meara, S, Matthews, L, Clark, J, Hurst, R, Mithen, R, Bristow, RG, Boutros, PC, Fraser, M, Cooke, S, Raine, K, Jones, D, Menzies, A, Stebbings, L, Hinton, J, Teague, J, McLaren, S, Mudie, L, Hardy, C, Anderson, E, Joseph, O, Goody, V, Robinson, B, Maddison, M, Gamble, S, Greenman, C, Berney, D, Hazell, S, Livni, N, Fisher, C, Ogden, C, Kumar, P, Thompson, A, Woodhouse, C, Nicol, D, Mayer, E, Dudderidge, T, Shah, NC, Gnanapragasam, V, Voet, T, Campbell, P, Futreal, A, Easton, D, Warren, AY, Foster, CS, Stratton, MR, Whitaker, HC, McDermott, U, Brewer, DS, Neal, DE, and Grp, ICGCP
- Subjects
DNA sequencing ,prostate cancer ,3. Good health - Abstract
Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases., This work was funded by Cancer Research UK (grant C5047/A14835), the Dallaglio Foundation and the Wellcome Trust. We also acknowledge support from the Bob Champion Cancer Trust, the Orchid Cancer Appeal, the RoseTrees Trust, the North West Cancer Research Fund, Big C, the King family, the Grand Charity of Freemasons, and the Research Foundation Flanders (FWO). We thank D. Holland from the Infrastructure Management Team and P. Clapham from the Informatics Systems Group at the Wellcome Trust Sanger Institute. We acknowledge the Biomedical Research Centre at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, supported by the National Institute for Health Research. We acknowledge support from the National Cancer Research Prostate Cancer: Mechanisms of Progression and Treatment (PROMPT) collaborative (grant G0500966/75466). We thank the National Institute for Health Research, Hutchison Whampoa Limited and the Human Research Tissue Bank (Addenbrooke's Hospital), the Cancer Research UK Cambridge Research Institute Histopathology, the In-situ Hybridisation Core Facility, the Genomics Core Facility Cambridge and the Cambridge University Hospitals Media Studio.
8. The evolutionary history of lethal metastatic prostate cancer
- Author
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Gundem, G, Van Loo, P, Kremeyer, B, Alexandrov, LB, Tubio, JMC, Papaemmanuil, E, Brewer, DS, Kallio, HML, Högnäs, G, Annala, M, Kivinummi, K, Goody, V, Latimer, C, O'Meara, S, Dawson, KJ, Isaacs, W, Emmert-Buck, MR, Nykter, M, Foster, C, Kote-Jarai, Z, Easton, D, Whitaker, HC, ICGC Prostate Group, Neal, DE, Cooper, CS, Eeles, RA, Visakorpi, T, Campbell, PJ, McDermott, U, Wedge, DC, and Bova, GS
- Subjects
Male ,DNA Mutational Analysis ,Prostatic Neoplasms ,3. Good health ,Clone Cells ,Epigenesis, Genetic ,Receptors, Androgen ,Androgens ,Disease Progression ,Humans ,Cell Lineage ,Genes, Tumor Suppressor ,Neoplasm Metastasis ,Signal Transduction - Abstract
Cancers emerge from an ongoing Darwinian evolutionary process, often leading to multiple competing subclones within a single primary tumour. This evolutionary process culminates in the formation of metastases, which is the cause of 90% of cancer-related deaths. However, despite its clinical importance, little is known about the principles governing the dissemination of cancer cells to distant organs. Although the hypothesis that each metastasis originates from a single tumour cell is generally supported, recent studies using mouse models of cancer demonstrated the existence of polyclonal seeding from and interclonal cooperation between multiple subclones. Here we sought definitive evidence for the existence of polyclonal seeding in human malignancy and to establish the clonal relationship among different metastases in the context of androgen-deprived metastatic prostate cancer. Using whole-genome sequencing, we characterized multiple metastases arising from prostate tumours in ten patients. Integrated analyses of subclonal architecture revealed the patterns of metastatic spread in unprecedented detail. Metastasis-to-metastasis spread was found to be common, either through de novo monoclonal seeding of daughter metastases or, in five cases, through the transfer of multiple tumour clones between metastatic sites. Lesions affecting tumour suppressor genes usually occur as single events, whereas mutations in genes involved in androgen receptor signalling commonly involve multiple, convergent events in different metastases. Our results elucidate in detail the complex patterns of metastatic spread and further our understanding of the development of resistance to androgen-deprivation therapy in prostate cancer.
9. Preclinical evaluation of avutometinib and defactinib in high-grade endometrioid endometrial cancer.
- Author
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Hartwich TMP, Mansolf M, Demirkiran C, Greenman M, Bellone S, McNamara B, Nandi SP, Alexandrov LB, Yang-Hartwich Y, Coma S, Pachter J, and Santin AD
- Subjects
- Female, Humans, Animals, Mice, Cell Line, Tumor, Carcinoma, Endometrioid drug therapy, Carcinoma, Endometrioid pathology, Carcinoma, Endometrioid genetics, Carcinoma, Endometrioid metabolism, Exome Sequencing, Antineoplastic Combined Chemotherapy Protocols pharmacology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cell Proliferation drug effects, Neoplasm Grading, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Focal Adhesion Kinase 1 metabolism, Focal Adhesion Kinase 1 antagonists & inhibitors, Oxazepines, Sulfonamides, Pyrazines, Benzamides, Imidazoles, Endometrial Neoplasms drug therapy, Endometrial Neoplasms pathology, Endometrial Neoplasms genetics, Xenograft Model Antitumor Assays
- Abstract
Background: High-grade endometrial cancers (EAC) are aggressive tumors with a high risk of progression after treatment. As EAC may harbor mutations in the RAS/MAPK pathways, we evaluated the preclinical in vitro and in vivo efficacy of avutometinib, a RAF/MEK clamp, in combination with the focal adhesion kinase (FAK) inhibitors defactinib or VS-4718, against multiple primary EAC cell lines and xenografts., Methods: Whole-exome sequencing (WES) was used to evaluate the genetic landscape of five primary EAC cell lines. The in vitro activity of avutometinib and defactinib as single agents and in combination was evaluated using cell viability, cell cycle, and cytotoxicity assays. Mechanistic studies were performed using Western blot assays while in vivo experiments were completed in UTE10 engrafted mice treated with either vehicle, avutometinib, VS-4718, or their combination through oral gavage., Results: WES results demonstrated multiple EAC cell lines to harbor genetic derangements in the RAS/MAPK pathway including KRAS/PTEN/PIK3CA/BRAF/ARID1A, potentially sensitizing to FAK and RAF/MEK inhibition. Five out of five of the EAC cell lines demonstrated in vitro sensitivity to FAK and/or RAF/MEK inhibition. By Western blot assays, exposure of EAC cell lines to defactinib, avutometinib, and their combination demonstrated decreased phosphorylated FAK (p-FAK) as well as decreased p-MEK and p-ERK. In vivo the combination of avutometinib/VS-4718 demonstrated superior tumor growth inhibition compared to single-agent treatment and controls starting at Day 9 (p < 0.02 and p < 0.04) in UTE10 xenografts., Conclusions: Avutometinib, defactinib, and to a larger extent their combinations, demonstrated promising in vitro and in vivo activity against EAC cell lines and xenografts. These preclinical data support the potential clinical evaluation of this combination in high-grade EAC patients., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)
- Published
- 2024
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10. The genomic landscape of 2,023 colorectal cancers.
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Cornish AJ, Gruber AJ, Kinnersley B, Chubb D, Frangou A, Caravagna G, Noyvert B, Lakatos E, Wood HM, Thorn S, Culliford R, Arnedo-Pac C, Househam J, Cross W, Sud A, Law P, Leathlobhair MN, Hawari A, Woolley C, Sherwood K, Feeley N, Gül G, Fernandez-Tajes J, Zapata L, Alexandrov LB, Murugaesu N, Sosinsky A, Mitchell J, Lopez-Bigas N, Quirke P, Church DN, Tomlinson IPM, Sottoriva A, Graham TA, Wedge DC, and Houlston RS
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- Humans, Female, Male, Microsatellite Instability, Whole Genome Sequencing, Prognosis, United Kingdom epidemiology, Chromosomal Instability genetics, Genome, Human genetics, DNA Copy Number Variations genetics, HLA Antigens genetics, Colorectal Neoplasms genetics, Mutation, Genomics
- Abstract
Colorectal carcinoma (CRC) is a common cause of mortality
1 , but a comprehensive description of its genomic landscape is lacking2-9 . Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurrent changes outside the coding genome. We extend the molecular pathways involved in CRC development, define four new common subgroups of microsatellite-stable CRC based on genomic features and show that these groups have independent prognostic associations. We also characterize several rare molecular CRC subgroups, some with potential clinical relevance, including cancers with both microsatellite and chromosomal instability. We demonstrate a spectrum of mutational profiles across the colorectum, which reflect aetiological differences. These include the role of Escherichia colipks+ colibactin in rectal cancers10 and the importance of the SBS93 signature11-13 , which suggests that diet or smoking is a risk factor. Immune-escape driver mutations14 are near-ubiquitous in hypermutant tumours and occur in about half of microsatellite-stable CRCs, often in the form of HLA copy number changes. Many driver mutations are actionable, including those associated with rare subgroups (for example, BRCA1 and IDH1), highlighting the role of whole-genome sequencing in optimizing patient care., (© 2024. The Author(s).)- Published
- 2024
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11. Enhanced precision in immunotherapy.
- Author
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Bergstrom EN and Alexandrov LB
- Subjects
- Humans, Neoplasms therapy, Neoplasms immunology, Immunotherapy methods, Precision Medicine methods
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- 2024
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12. Deep Learning Artificial Intelligence Predicts Homologous Recombination Deficiency and Platinum Response From Histologic Slides.
- Author
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Bergstrom EN, Abbasi A, Díaz-Gay M, Galland L, Ladoire S, Lippman SM, and Alexandrov LB
- Abstract
Purpose: Cancers with homologous recombination deficiency (HRD) can benefit from platinum salts and poly(ADP-ribose) polymerase inhibitors. Standard diagnostic tests for detecting HRD require molecular profiling, which is not universally available., Methods: We trained DeepHRD, a deep learning platform for predicting HRD from hematoxylin and eosin (H&E)-stained histopathological slides, using primary breast (n = 1,008) and ovarian (n = 459) cancers from The Cancer Genome Atlas (TCGA). DeepHRD was compared with four standard HRD molecular tests using breast (n = 349) and ovarian (n = 141) cancers from multiple independent data sets, including platinum-treated clinical cohorts with RECIST progression-free survival (PFS), complete response (CR), and overall survival (OS) endpoints., Results: DeepHRD predicted HRD from held-out H&E-stained breast cancer slides in TCGA with an AUC of 0.81 (95% CI, 0.77 to 0.85). This performance was confirmed in two independent primary breast cancer cohorts (AUC, 0.76 [95% CI, 0.71 to 0.82]). In an external platinum-treated metastatic breast cancer cohort, samples predicted as HRD had higher complete CR (AUC, 0.76 [95% CI, 0.54 to 0.93]) with 3.7-fold increase in median PFS (14.4 v 3.9 months; P = .0019) and hazard ratio (HR) of 0.45 ( P = .0047). There were no significant differences in nonplatinum treatment outcome by predicted HRD status in three breast cancer cohorts, including CR (AUC, 0.39) and PFS (HR, 0.98, P = .95) in taxane-treated metastatic breast cancer. Through transfer learning to high-grade serous ovarian cancer, DeepHRD-predicted HRD samples had better OS after first-line (HR, 0.46; P = .030) and neoadjuvant (HR, 0.49; P = .015) platinum therapy in two cohorts., Conclusion: DeepHRD can predict HRD in breast and ovarian cancers directly from routine H&E slides across multiple external cohorts, slide scanners, and tissue fixation variables. When compared with molecular testing, DeepHRD classified 1.8- to 3.1-fold more patients with HRD, which exhibited better OS in high-grade serous ovarian cancer and platinum-specific PFS in metastatic breast cancer.
- Published
- 2024
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13. Detecting HRD in whole-genome and whole-exome sequenced breast and ovarian cancers.
- Author
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Abbasi A, Steele CD, Bergstrom EN, Khandekar A, Farswan A, Mckay RR, Pillay N, and Alexandrov LB
- Abstract
Breast and ovarian cancers harboring homologous recombination deficiency (HRD) are sensitive to PARP inhibitors and platinum chemotherapy. Conventionally, detecting HRD involves screening for defects in BRCA1 , BRCA2 , and other relevant genes. Recent analyses have shown that HRD cancers exhibit characteristic mutational patterns due to the activities of HRD-associated mutational signatures. At least three machine learning tools exist for detecting HRD based on mutational patterns. Here, using sequencing data from 1,043 breast and 182 ovarian cancers, we trained Homologous Recombination Proficiency Profiler (HRProfiler), a machine learning method for detecting HRD using six mutational features. HRProfiler's performance is assessed against prior approaches using additional independent datasets of 417 breast and 115 ovarian cancers, including retrospective data from a clinical trial involving patients treated with PARP inhibitors. Our results demonstrate that HRProfiler is the only tool that robustly and consistently predicts clinical response from whole-exome sequenced breast and ovarian cancers., Competing Interests: Competing interests LBA is a co-founder, CSO, scientific advisory member, and consultant for io9, has equity and receives income. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. LBA’s spouse is an employee of Biotheranostics. ENB is a consultant for io9, has equity, and receives income. AA and LBA declare U.S. provisional patent application filed with UCSD with serial numbers 63/366,392 for detecting homologous recombination deficiency from genomics data. ENB and LBA declare U.S. provisional patent application filed with UCSD with serial numbers 63/269,033 for artificial intelligence architecture for predicting cancer biomarkers, including homologous recombination deficiency. LBA also declares U.S. provisional applications with serial numbers: 63/289,601; 63/483,237; 63/412,835; and 63/492,348. All other authors declare that they have no competing interests.
- Published
- 2024
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14. Human cancer genomes harbor the mutational signature of tobacco-specific nitrosamines NNN and NNK.
- Author
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Korenjak M, Temiz NA, Keita S, Chavanel B, Renard C, Sirand C, Cahais V, Mayel T, Vevang KR, Jacobs FC, Guo J, Smith WE, Oram MK, Tăbăran FA, Ahlat O, Cornax I, O'Sullivan MG, Das S, Nandi SP, Cheng Y, Alexandrov LB, Balbo S, Hecht SS, Senkin S, Virard F, Peterson LA, and Zavadil J
- Abstract
Tobacco usage is linked to multiple cancer types and accounts for a quarter of all cancer-related deaths. Tobacco smoke contains various carcinogenic compounds, including polycyclic aromatic hydrocarbons (PAH), though the mutagenic potential of many tobacco-related chemicals remains largely unexplored. In particular, the highly carcinogenic tobacco-specific nitrosamines NNN and NNK form pre-mutagenic pyridyloxobutyl (POB) DNA adducts. In the study presented here, we identified genome-scale POB-induced mutational signatures in cell lines and rat tumors, while also investigating their role in human cancer. These signatures are characterized by T>N and C>T mutations forming from specific POB adducts damaging dT and dC residues. Analysis of 2,780 cancer genomes uncovered POB signatures in ∼180 tumors; from cancer types distinct from the ones linked to smoking-related signatures SBS4 and SBS92. This suggests that, unlike PAH compounds, the POB pathway may contribute uniquely to the mutational landscapes of certain hematological malignancies and cancers of the kidney, breast, prostate and pancreas.
- Published
- 2024
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15. The mutagenic forces shaping the genomic landscape of lung cancer in never smokers.
- Author
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Díaz-Gay M, Zhang T, Hoang PH, Khandekar A, Zhao W, Steele CD, Otlu B, Nandi SP, Vangara R, Bergstrom EN, Kazachkova M, Pich O, Swanton C, Hsiung CA, Chang IS, Wong MP, Leung KC, Sang J, McElderry J, Yang L, Nowak MA, Shi J, Rothman N, Wedge DC, Homer R, Yang SR, Lan Q, Zhu B, Chanock SJ, Alexandrov LB, and Landi MT
- Abstract
Lung cancer in never smokers (LCINS) accounts for up to 25% of all lung cancers and has been associated with exposure to secondhand tobacco smoke and air pollution in observational studies. Here, we evaluate the mutagenic exposures in LCINS by examining deep whole-genome sequencing data from a large international cohort of 871 treatment-naïve LCINS recruited from 28 geographical locations within the Sherlock- Lung study. KRAS mutations were 3.8-fold more common in adenocarcinomas of never smokers from North America and Europe, while a 1.6-fold higher prevalence of EGFR and TP53 mutations was observed in adenocarcinomas from East Asia. Signature SBS40a, with unknown cause, was found in most samples and accounted for the largest proportion of single base substitutions in adenocarcinomas, being enriched in EGFR -mutated cases. Conversely, the aristolochic acid signature SBS22a was almost exclusively observed in patients from Taipei. Even though LCINS exposed to secondhand smoke had an 8.3% higher mutational burden and 5.4% shorter telomeres, passive smoking was not associated with driver mutations in cancer driver genes or the activities of individual mutational signatures. In contrast, patients from regions with high levels of air pollution were more likely to have TP53 mutations while exhibiting shorter telomeres and an increase in most types of somatic mutations, including a 3.9-fold elevation of signature SBS4 (q-value=3.1 × 10
-5 ), previously linked mainly to tobacco smoking, and a 76% increase of clock-like signature SBS5 (q-value=5.0 × 10-5 ). A positive dose-response effect was observed with air pollution levels, which correlated with both a decrease in telomere length and an elevation in somatic mutations, notably attributed to signatures SBS4 and SBS5. Our results elucidate the diversity of mutational processes shaping the genomic landscape of lung cancer in never smokers., Competing Interests: COMPETING INTERESTS LBA is a co-founder, CSO, scientific advisory member, and consultant for io9, has equity and receives income. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. LBA is also a compensated member of the scientific advisory board of Inocras. LBA’s spouse is an employee of Biotheranostics. ENB and LBA declare U.S. provisional patent application filed with UCSD with serial numbers 63/269,033. LBA also declares U.S. provisional applications filed with UCSD with serial numbers: 63/366,392; 63/289,601; 63/483,237; 63/412,835; and 63/492,348. LBA is also an inventor of a US Patent 10,776,718 for source identification by non-negative matrix factorization. SRY has received consulting fees from AstraZeneca, Sanofi, Amgen, AbbVie, and Sanofi; received speaking fees from AstraZeneca, Medscape, PRIME Education, and Medical Learning Institute. All other authors declare that they have no competing interests.- Published
- 2024
- Full Text
- View/download PDF
16. Geographic variation of mutagenic exposures in kidney cancer genomes.
- Author
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Senkin S, Moody S, Díaz-Gay M, Abedi-Ardekani B, Cattiaux T, Ferreiro-Iglesias A, Wang J, Fitzgerald S, Kazachkova M, Vangara R, Le AP, Bergstrom EN, Khandekar A, Otlu B, Cheema S, Latimer C, Thomas E, Atkins JR, Smith-Byrne K, Cortez Cardoso Penha R, Carreira C, Chopard P, Gaborieau V, Keski-Rahkonen P, Jones D, Teague JW, Ferlicot S, Asgari M, Sangkhathat S, Attawettayanon W, Świątkowska B, Jarmalaite S, Sabaliauskaite R, Shibata T, Fukagawa A, Mates D, Jinga V, Rascu S, Mijuskovic M, Savic S, Milosavljevic S, Bartlett JMS, Albert M, Phouthavongsy L, Ashton-Prolla P, Botton MR, Silva Neto B, Bezerra SM, Curado MP, Zequi SC, Reis RM, Faria EF, de Menezes NS, Ferrari RS, Banks RE, Vasudev NS, Zaridze D, Mukeriya A, Shangina O, Matveev V, Foretova L, Navratilova M, Holcatova I, Hornakova A, Janout V, Purdue MP, Rothman N, Chanock SJ, Ueland PM, Johansson M, McKay J, Scelo G, Chanudet E, Humphreys L, de Carvalho AC, Perdomo S, Alexandrov LB, Stratton MR, and Brennan P
- Subjects
- Female, Humans, Male, Aristolochic Acids adverse effects, Genome, Human genetics, Genomics, Hypertension epidemiology, Incidence, Japan epidemiology, Obesity epidemiology, Risk Factors, Romania epidemiology, Serbia epidemiology, Thailand epidemiology, Tobacco Smoking adverse effects, Tobacco Smoking genetics, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell epidemiology, Carcinoma, Renal Cell chemically induced, Environmental Exposure adverse effects, Environmental Exposure analysis, Geography, Kidney Neoplasms genetics, Kidney Neoplasms epidemiology, Kidney Neoplasms chemically induced, Mutagens adverse effects, Mutation
- Abstract
International differences in the incidence of many cancer types indicate the existence of carcinogen exposures that have not yet been identified by conventional epidemiology make a substantial contribution to cancer burden
1 . In clear cell renal cell carcinoma, obesity, hypertension and tobacco smoking are risk factors, but they do not explain the geographical variation in its incidence2 . Underlying causes can be inferred by sequencing the genomes of cancers from populations with different incidence rates and detecting differences in patterns of somatic mutations. Here we sequenced 962 clear cell renal cell carcinomas from 11 countries with varying incidence. The somatic mutation profiles differed between countries. In Romania, Serbia and Thailand, mutational signatures characteristic of aristolochic acid compounds were present in most cases, but these were rare elsewhere. In Japan, a mutational signature of unknown cause was found in more than 70% of cases but in less than 2% elsewhere. A further mutational signature of unknown cause was ubiquitous but exhibited higher mutation loads in countries with higher incidence rates of kidney cancer. Known signatures of tobacco smoking correlated with tobacco consumption, but no signature was associated with obesity or hypertension, suggesting that non-mutagenic mechanisms of action underlie these risk factors. The results of this study indicate the existence of multiple, geographically variable, mutagenic exposures that potentially affect tens of millions of people and illustrate the opportunities for new insights into cancer causation through large-scale global cancer genomics., (© 2024. The Author(s).)- Published
- 2024
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17. Integrated mutational landscape analysis of poorly differentiated high-grade neuroendocrine carcinoma of the uterine cervix.
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Bellone S, Jeong K, Halle MK, Krakstad C, McNamara B, Greenman M, Mutlu L, Demirkiran C, Hartwich TMP, Yang-Hartwich Y, Zipponi M, Buza N, Hui P, Raspagliesi F, Lopez S, Paolini B, Milione M, Perrone E, Scambia G, Altwerger G, Ravaggi A, Bignotti E, Huang GS, Andikyan V, Clark M, Ratner E, Azodi M, Schwartz PE, Quick CM, Angioli R, Terranova C, Zaidi S, Nandi S, Alexandrov LB, Siegel ER, Choi J, Schlessinger J, and Santin AD
- Subjects
- Humans, Female, Afatinib, Phylogeny, Phosphatidylinositol 3-Kinases genetics, Mutation, Class I Phosphatidylinositol 3-Kinases genetics, DNA Mutational Analysis, Uterine Cervical Neoplasms genetics, Uterine Cervical Neoplasms pathology, Neuroendocrine Tumors, Adenocarcinoma, Carcinoma, Neuroendocrine genetics, Carcinoma, Neuroendocrine pathology
- Abstract
High-grade neuroendocrine cervical cancers (NETc) are exceedingly rare, highly aggressive tumors. We analyzed 64 NETc tumor samples by whole-exome sequencing (WES). Human papillomavirus DNA was detected in 65.6% (42/64) of the tumors. Recurrent mutations were identified in PIK3CA, KMT2D/MLL2, K-RAS, ARID1A, NOTCH2, and RPL10. The top mutated genes included RB1, ARID1A, PTEN, KMT2D / MLL2, and WDFY3, a gene not yet implicated in NETc. Somatic CNV analysis identified two copy number gains (3q27.1 and 19q13.12) and five copy number losses (1p36.21/5q31.3/6p22.2/9q21.11/11p15.5). Also, gene fusions affecting the ACLY-CRHR1 and PVT1-MYC genes were identified in one of the eight samples subjected to RNA sequencing. To resolve evolutionary history, multiregion WES in NETc admixed with adenocarcinoma cells was performed (i.e., mixed-NETc). Phylogenetic analysis of mixed-NETc demonstrated that adenocarcinoma and neuroendocrine elements derive from a common precursor with mutations typical of adenocarcinomas. Over one-third (22/64) of NETc demonstrated a mutator phenotype of C > T at CpG consistent with deficiencies in MBD4 , a member of the base excision repair (BER) pathway. Mutations in the PI3K/AMPK pathways were identified in 49/64 samples. We used two patient-derived-xenografts (PDX) (i.e., NET19 and NET21) to evaluate the activity of pan-HER (afatinib), PIK3CA (copanlisib), and ATR (elimusertib) inhibitors, alone and in combination. PDXs harboring alterations in the ERBB2/PI3K/AKT/mTOR/ATR pathway were sensitive to afatinib, copanlisib, and elimusertib ( P < 0.001 vs. controls). However, combinations of copanlisib/afatinib and copanlisib/elimusertib were significantly more effective in controlling NETc tumor growth. These findings define the genetic landscape of NETc and suggest that a large subset of these highly lethal malignancies might benefit from existing targeted therapies., Competing Interests: Competing interests statement:A.D.S. is listed as author in a paper (i.e., N. Engl. J. Med. 2022; 386:437–448, DOI: 10.1056/NEJMoa2108330) where G.E.K. is listed as group author. A.D.S. had no interactions with G.E.K. (or any other of the 309-KEYNOTE-775 multicenter clinical trial Investigators) over the course of the research and writing of this paper.
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- 2024
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18. The Complexity of Tobacco Smoke-Induced Mutagenesis in Head and Neck Cancer.
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Torrens L, Moody S, de Carvalho AC, Kazachkova M, Abedi-Ardekani B, Cheema S, Senkin S, Cattiaux T, Cortez Cardoso Penha R, Atkins JR, Gaborieau V, Chopard P, Carreira C, Abbasi A, Bergstrom EN, Vangara R, Wang J, Fitzgerald S, Latimer C, Diaz-Gay M, Jones D, Teague J, Ribeiro Pinto F, Kowalski LP, Polesel J, Giudici F, de Oliveira JC, Lagiou P, Lagiou A, Vilensky M, Mates D, Mates IN, Arantes LM, Reis R, Podesta JRV, von Zeidler SV, Holcatova I, Curado MP, Canova C, Fabianova E, Rodríguez-Urrego PA, Humphreys L, Alexandrov LB, Brennan P, Stratton MR, and Perdomo S
- Abstract
Tobacco smoke, alone or combined with alcohol, is the predominant cause of head and neck cancer (HNC). Here, we further explore how tobacco exposure contributes to cancer development by mutational signature analysis of 265 whole-genome sequenced HNC from eight countries. Six tobacco-associated mutational signatures were detected, including some not previously reported. Differences in HNC incidence between countries corresponded with differences in mutation burdens of tobacco-associated signatures, consistent with the dominant role of tobacco in HNC causation. Differences were found in the burden of tobacco-associated signatures between anatomical subsites, suggesting that tissue-specific factors modulate mutagenesis. We identified an association between tobacco smoking and three additional alcohol-related signatures indicating synergism between the two exposures. Tobacco smoking was associated with differences in the mutational spectra and repertoire of driver mutations in cancer genes, and in patterns of copy number change. Together, the results demonstrate the multiple pathways by which tobacco smoke can influence the evolution of cancer cell clones.
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- 2024
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19. APOBEC shapes tumor evolution and age at onset of lung cancer in smokers.
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Zhang T, Sang J, Hoang PH, Zhao W, Rosenbaum J, Johnson KE, Klimczak LJ, McElderry J, Klein A, Wirth C, Bergstrom EN, Díaz-Gay M, Vangara R, Colon-Matos F, Hutchinson A, Lawrence SM, Cole N, Zhu B, Przytycka TM, Shi J, Caporaso NE, Homer R, Pesatori AC, Consonni D, Imielinski M, Chanock SJ, Wedge DC, Gordenin DA, Alexandrov LB, Harris RS, and Landi MT
- Abstract
APOBEC enzymes are part of the innate immunity and are responsible for restricting viruses and retroelements by deaminating cytosine residues
1,2 . Most solid tumors harbor different levels of somatic mutations attributed to the off-target activities of APOBEC3A (A3A) and/or APOBEC3B (A3B)3-6 . However, how APOBEC3A/B enzymes shape the tumor evolution in the presence of exogenous mutagenic processes is largely unknown. Here, by combining deep whole-genome sequencing with multi-omics profiling of 309 lung cancers from smokers with detailed tobacco smoking information, we identify two subtypes defined by low ( LAS ) and high ( HAS ) APOBEC mutagenesis. LAS are enriched for A3B-like mutagenesis and KRAS mutations, whereas HAS for A3A-like mutagenesis and TP53 mutations. Unlike APOBEC3A , APOBEC3B expression is strongly associated with an upregulation of the base excision repair pathway. Hypermutation by unrepaired A3A and tobacco smoking mutagenesis combined with TP53 -induced genomic instability can trigger senescence7 , apoptosis8 , and cell regeneration9 , as indicated by high expression of pulmonary healing signaling pathway, stemness markers and distal cell-of-origin in HAS. The expected association of tobacco smoking variables (e.g., time to first cigarette) with genomic/epigenomic changes are not observed in HAS, a plausible consequence of frequent cell senescence or apoptosis. HAS have more neoantigens, slower clonal expansion, and older age at onset compared to LAS, particularly in heavy smokers, consistent with high proportions of newly generated, unmutated cells and frequent immuno-editing. These findings show how heterogeneity in mutational burden across co-occurring mutational processes and cell types contributes to tumor development, with important clinical implications., Competing Interests: ETHICS DECLARATIONS LBA is a compensated consultant and has equity interest in io9, LLC. His spouse is an employee of Biotheranostics, Inc. LBA is also an inventor of a US Patent 10,776,718 for source identification by non-negative matrix factorization. ENB and LBA declare U.S. provisional patent applications with serial numbers 63/289,601 and 63/269,033. LBA also declares U.S. provisional patent applications with serial numbers: 63/366,392; 63/367,846; and 63/412,835. All other authors declare no competing interests.- Published
- 2024
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20. The Mutographs biorepository: A unique genomic resource to study cancer around the world.
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Perdomo S, Abedi-Ardekani B, de Carvalho AC, Ferreiro-Iglesias A, Gaborieau V, Cattiaux T, Renard H, Chopard P, Carreira C, Spanu A, Nikmanesh A, Cardoso Penha RC, Antwi SO, Ashton-Prolla P, Canova C, Chitapanarux T, Cox R, Curado MP, de Oliveira JC, Dzamalala C, Fabianova E, Ferri L, Fitzgerald R, Foretova L, Gallinger S, Goldstein AM, Holcatova I, Huertas A, Janout V, Jarmalaite S, Kaneva R, Kowalski LP, Kulis T, Lagiou P, Lissowska J, Malekzadeh R, Mates D, McCorrmack V, Menya D, Mhatre S, Mmbaga BT, de Moricz A, Nyirády P, Ognjanovic M, Papadopoulou K, Polesel J, Purdue MP, Rascu S, Rebolho Batista LM, Reis RM, Ribeiro Pinto LF, Rodríguez-Urrego PA, Sangkhathat S, Sangrajrang S, Shibata T, Stakhovsky E, Świątkowska B, Vaccaro C, Vasconcelos de Podesta JR, Vasudev NS, Vilensky M, Yeung J, Zaridze D, Zendehdel K, Scelo G, Chanudet E, Wang J, Fitzgerald S, Latimer C, Moody S, Humphreys L, Alexandrov LB, Stratton MR, and Brennan P
- Subjects
- Humans, Genomics, Databases, Factual, Delivery of Health Care, Biological Specimen Banks, Neoplasms diagnosis
- Abstract
Large-scale biorepositories and databases are essential to generate equitable, effective, and sustainable advances in cancer prevention, early detection, cancer therapy, cancer care, and surveillance. The Mutographs project has created a large genomic dataset and biorepository of over 7,800 cancer cases from 30 countries across five continents with extensive demographic, lifestyle, environmental, and clinical information. Whole-genome sequencing is being finalized for over 4,000 cases, with the primary goal of understanding the causes of cancer at eight anatomic sites. Genomic, exposure, and clinical data will be publicly available through the International Cancer Genome Consortium Accelerating Research in Genomic Oncology platform. The Mutographs sample and metadata biorepository constitutes a legacy resource for new projects and collaborations aiming to increase our current research efforts in cancer genomic epidemiology globally., Competing Interests: Declaration of interests M.R.S. is founder of, consultant to, and stockholder in Quotient Therapeutics. L.B.A. is a compensated consultant and has equity interest in io9, LLC, and Genome Insight. His spouse is an employee of Biotheranostics, Inc. L.B.A. is also an inventor of a US patent 10,776,718 for source identification by non-negative matrix factorization. L.B.A. declares US provisional applications with serial numbers 63/289,601; 63/269,033; and 63/483,237. L.B.A. also declares US provisional applications with serial numbers 63/366,392; 63/367,846; 63/412,835; and 63/492,348., (Copyright © 2024. Published by Elsevier Inc.)
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- 2024
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21. Evaluating topography of mutational signatures with SigProfilerTopography.
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Otlu B and Alexandrov LB
- Abstract
The mutations found in a cancer genome are shaped by diverse processes, each displaying a characteristic mutational signature that may be influenced by the genome's architecture. While prior analyses have evaluated the effect of topographical genomic features on mutational signatures, there has been no computational tool that can comprehensively examine this interplay. Here, we present SigProfilerTopography, a Python package that allows evaluating the effect of chromatin organization, histone modifications, transcription factor binding, DNA replication, and DNA transcription on the activities of different mutational processes. SigProfilerTopography elucidates the unique topographical characteristics of mutational signatures, unveiling their underlying biological and molecular mechanisms., Competing Interests: Competing interests: LBA is a co-founder, CSO, scientific advisory member, and consultant for io9, has equity and receives income. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. LBA’s spouse is an employee of Biotheranostics. LBA declares U.S. provisional applications with serial numbers: 63/289,601; 63/269,033; 63/483,237; 63/366,392; 63/412,835; and 63/492,348. BO declares no known competing interests or personal relationships that could have appeared to influence the work reported in this paper.
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- 2024
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22. Nivolumab for Patients With High-Risk Oral Leukoplakia: A Nonrandomized Controlled Trial.
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Hanna GJ, Villa A, Nandi SP, Shi R, ONeill A, Liu M, Quinn CT, Treister NS, Sroussi HY, Vacharotayangul P, Goguen LA, Annino DJ Jr, Rettig EM, Jo VY, Wong KS, Lizotte P, Paweletz CP, Uppaluri R, Haddad RI, Cohen EEW, Alexandrov LB, William WN Jr, Lippman SM, and Woo SB
- Subjects
- Humans, Female, Middle Aged, Male, Nivolumab adverse effects, Nivolumab administration & dosage, Programmed Cell Death 1 Receptor immunology, B7-H1 Antigen, Immunotherapy, Leukoplakia, Oral drug therapy, Leukoplakia, Oral chemically induced, Tumor Microenvironment, Carcinoma, Squamous Cell drug therapy, Mouth Neoplasms drug therapy, Precancerous Conditions
- Abstract
Importance: Proliferative verrucous leukoplakia (PVL) is an aggressive oral precancerous disease characterized by a high risk of transformation to invasive oral squamous cell carcinoma (OSCC), and no therapies have been shown to affect its natural history. A recent study of the PVL immune landscape revealed a cytotoxic T-cell-rich microenvironment, providing strong rationale to investigate immune checkpoint therapy., Objective: To determine the safety and clinical activity of anti-programmed cell death 1 protein (PD-1) therapy to treat high-risk PVL., Design, Setting, and Participants: This nonrandomized, open-label, phase 2 clinical trial was conducted from January 2019 to December 2021 at a single academic medical center; median (range) follow-up was 21.1 (5.4-43.6) months. Participants were a population-based sample of patients with PVL (multifocal, contiguous, or a single lesion ≥4 cm with any degree of dysplasia)., Intervention: Patients underwent pretreatment biopsy (1-3 sites) and then received 4 doses of nivolumab (480 mg intravenously) every 28 days, followed by rebiopsy and intraoral photographs at each visit., Main Outcomes and Measures: The primary end point was the change in composite score (size and degree of dysplasia) from before to after treatment (major response [MR]: >80% decrease in score; partial response: 40%-80% decrease). Secondary analyses included immune-related adverse events, cancer-free survival (CFS), PD-1 ligand 1 (PD-L1) expression, 9p21.3 deletion, and other exploratory immunologic and genomic associations of response., Results: A total of 33 patients were enrolled (median [range] age, 63 [32-80] years; 18 [55%] were female), including 8 (24%) with previously resected early-stage OSCC. Twelve patients (36%) (95% CI, 20.4%-54.8%) had a response by composite score (3 MRs [9%]), 4 had progressive disease (>10% composite score increase, or cancer). Nine patients (27%) developed OSCC during the trial, with a 2-year CFS of 73% (95% CI, 53%-86%). Two patients (6%) discontinued because of toxic effects; 7 (21%) experienced grade 3 to 4 immune-related adverse events. PD-L1 combined positive scores were not associated with response or CFS. Of 20 whole-exome sequenced patients, all 6 patients who had progression to OSCC after nivolumab treatment exhibited 9p21.3 somatic copy-number loss on pretreatment biopsy, while only 4 of the 14 patients (29%) who did not develop OSCC had 9p21.3 loss., Conclusions and Relevance: This immune checkpoint therapy precancer nonrandomized clinical trial met its prespecified response end point, suggesting potential clinical activity for nivolumab in high-risk PVL. Findings identified immunogenomic associations to inform future trials in this precancerous disease with unmet medical need that has been difficult to study., Trial Registration: ClinicalTrials.gov Identifier: NCT03692325.
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- 2024
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23. Arsenic is a potent co-mutagen of ultraviolet light.
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Speer RM, Nandi SP, Cooper KL, Zhou X, Yu H, Guo Y, Hudson LG, Alexandrov LB, and Liu KJ
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- Animals, Mice, Humans, Ultraviolet Rays adverse effects, Mutagens, Skin, Arsenic toxicity, Skin Neoplasms genetics, Skin Neoplasms pathology
- Abstract
Arsenic enhances the carcinogenicity of ultraviolet radiation (UVR). However, the mechanisms of arsenic-driven oncogenesis are not well understood. Here, we utilize experimental systems to investigate the carcinogenic and mutagenic properties of co-exposure to arsenic and UVR. In vitro and in vivo exposures indicate that, by itself, arsenic is not mutagenic. However, in combination with UVR, arsenic exposure has a synergistic effect leading to an accelerated mouse skin carcinogenesis and to more than 2-fold enrichment of UVR mutational burden. Notably, mutational signature ID13, previously found only in UVR-associated human skin cancers, is observed exclusively in mouse skin tumors and cell lines jointly exposed to arsenic and UVR. This signature was not observed in any model system exposed purely to arsenic or purely to UVR, making ID13, to the best of our knowledge, the first co-exposure signature to be reported using controlled experimental conditions. Analysis of existing skin cancer genomics data reveals that only a subset of cancers harbor ID13 and these exhibit an elevated UVR mutagenesis. Our results report a unique mutational signature caused by a co-exposure to two environmental carcinogens and provide comprehensive evidence that arsenic is a potent co-mutagen and co-carcinogen of UVR., (© 2023. The Author(s).)
- Published
- 2023
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24. Breakage fusion bridge cycles drive high oncogene copy number, but not intratumoral genetic heterogeneity or rapid cancer genome change.
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Dehkordi SR, Wong IT, Ni J, Luebeck J, Zhu K, Prasad G, Krockenberger L, Xu G, Chowdhury B, Rajkumar U, Caplin A, Muliaditan D, Coruh C, Jin Q, Turner K, Teo SX, Pang AWC, Alexandrov LB, Chua CEL, Furnari FB, Paulson TG, Law JA, Chang HY, Yue F, DasGupta R, Zhao J, Mischel PS, and Bafna V
- Abstract
Oncogene amplification is a major driver of cancer pathogenesis. Breakage fusion bridge (BFB) cycles, like extrachromosomal DNA (ecDNA), can lead to high copy numbers of oncogenes, but their impact on intratumoral heterogeneity, treatment response, and patient survival are not well understood due to difficulty in detecting them by DNA sequencing. We describe a novel algorithm that detects and reconstructs BFB amplifications using optical genome maps (OGMs), called OM2BFB. OM2BFB showed high precision (>93%) and recall (92%) in detecting BFB amplifications in cancer cell lines, PDX models and primary tumors. OM-based comparisons demonstrated that short-read BFB detection using our AmpliconSuite (AS) toolkit also achieved high precision, albeit with reduced sensitivity. We detected 371 BFB events using whole genome sequences from 2,557 primary tumors and cancer lines. BFB amplifications were preferentially found in cervical, head and neck, lung, and esophageal cancers, but rarely in brain cancers. BFB amplified genes show lower variance of gene expression, with fewer options for regulatory rewiring relative to ecDNA amplified genes. BFB positive (BFB (+)) tumors showed reduced heterogeneity of amplicon structures, and delayed onset of resistance, relative to ecDNA(+) tumors. EcDNA and BFB amplifications represent contrasting mechanisms to increase the copy numbers of oncogene with markedly different characteristics that suggest different routes for intervention.
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- 2023
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25. Assigning mutational signatures to individual samples and individual somatic mutations with SigProfilerAssignment.
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Díaz-Gay M, Vangara R, Barnes M, Wang X, Islam SMA, Vermes I, Duke S, Narasimman NB, Yang T, Jiang Z, Moody S, Senkin S, Brennan P, Stratton MR, and Alexandrov LB
- Subjects
- Humans, Mutation, Algorithms, Genome, Neoplasms genetics
- Abstract
Motivation: Analysis of mutational signatures is a powerful approach for understanding the mutagenic processes that have shaped the evolution of a cancer genome. To evaluate the mutational signatures operative in a cancer genome, one first needs to quantify their activities by estimating the number of mutations imprinted by each signature., Results: Here we present SigProfilerAssignment, a desktop and an online computational framework for assigning all types of mutational signatures to individual samples. SigProfilerAssignment is the first tool that allows both analysis of copy-number signatures and probabilistic assignment of signatures to individual somatic mutations. As its computational engine, the tool uses a custom implementation of the forward stagewise algorithm for sparse regression and nonnegative least squares for numerical optimization. Analysis of 2700 synthetic cancer genomes with and without noise demonstrates that SigProfilerAssignment outperforms four commonly used approaches for assigning mutational signatures., Availability and Implementation: SigProfilerAssignment is available under the BSD 2-clause license at https://github.com/AlexandrovLab/SigProfilerAssignment with a web implementation at https://cancer.sanger.ac.uk/signatures/assignment/., (© The Author(s) 2023. Published by Oxford University Press.)
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- 2023
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26. APOBEC3B regulates R-loops and promotes transcription-associated mutagenesis in cancer.
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McCann JL, Cristini A, Law EK, Lee SY, Tellier M, Carpenter MA, Beghè C, Kim JJ, Sanchez A, Jarvis MC, Stefanovska B, Temiz NA, Bergstrom EN, Salamango DJ, Brown MR, Murphy S, Alexandrov LB, Miller KM, Gromak N, and Harris RS
- Subjects
- Humans, DNA, Single-Stranded genetics, Genome-Wide Association Study, Mutagenesis, Cytidine Deaminase genetics, Minor Histocompatibility Antigens genetics, Minor Histocompatibility Antigens metabolism, R-Loop Structures, Neoplasms genetics, Neoplasms pathology
- Abstract
The single-stranded DNA cytosine-to-uracil deaminase APOBEC3B is an antiviral protein implicated in cancer. However, its substrates in cells are not fully delineated. Here APOBEC3B proteomics reveal interactions with a surprising number of R-loop factors. Biochemical experiments show APOBEC3B binding to R-loops in cells and in vitro. Genetic experiments demonstrate R-loop increases in cells lacking APOBEC3B and decreases in cells overexpressing APOBEC3B. Genome-wide analyses show major changes in the overall landscape of physiological and stimulus-induced R-loops with thousands of differentially altered regions, as well as binding of APOBEC3B to many of these sites. APOBEC3 mutagenesis impacts genes overexpressed in tumors and splice factor mutant tumors preferentially, and APOBEC3-attributed kataegis are enriched in RTCW motifs consistent with APOBEC3B deamination. Taken together with the fact that APOBEC3B binds single-stranded DNA and RNA and preferentially deaminates DNA, these results support a mechanism in which APOBEC3B regulates R-loops and contributes to R-loop mutagenesis in cancer., (© 2023. The Author(s).)
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- 2023
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27. Topography of mutational signatures in human cancer.
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Otlu B, Díaz-Gay M, Vermes I, Bergstrom EN, Zhivagui M, Barnes M, and Alexandrov LB
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- Humans, Mutation genetics, Genomics, Base Sequence, Genome, Human, Neoplasms genetics
- Abstract
The somatic mutations found in a cancer genome are imprinted by different mutational processes. Each process exhibits a characteristic mutational signature, which can be affected by the genome architecture. However, the interplay between mutational signatures and topographical genomic features has not been extensively explored. Here, we integrate mutations from 5,120 whole-genome-sequenced tumors from 40 cancer types with 516 topographical features from ENCODE to evaluate the effect of nucleosome occupancy, histone modifications, CTCF binding, replication timing, and transcription/replication strand asymmetries on the cancer-specific accumulation of mutations from distinct mutagenic processes. Most mutational signatures are affected by topographical features, with signatures of related etiologies being similarly affected. Certain signatures exhibit periodic behaviors or cancer-type-specific enrichments/depletions near topographical features, revealing further information about the processes that imprinted them. Our findings, disseminated via the COSMIC (Catalog of Somatic Mutations in Cancer) signatures database, provide a comprehensive online resource for exploring the interactions between mutational signatures and topographical features across human cancer., Competing Interests: Declaration of interests L.B.A. is a compensated consultant and has equity interest in io9, LLC, and Genome Insight. His spouse is an employee of Biotheranostics, Inc. L.B.A. is also an inventor of US patent 10,776,718 for source identification by non-negative matrix factorization. E.N.B. and L.B.A. declare US provisional applications with serial numbers 63/289,601, 63/269,033, and 63/483,237. L.B.A. also declares US provisional applications with serial numbers 63/366,392, 63/412,835, and 63/492,348., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2023
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28. Visualizing and exploring patterns of large mutational events with SigProfilerMatrixGenerator.
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Khandekar A, Vangara R, Barnes M, Díaz-Gay M, Abbasi A, Bergstrom EN, Steele CD, Pillay N, and Alexandrov LB
- Subjects
- Humans, Mutation, Algorithms, Computational Biology
- Abstract
Background: All cancers harbor somatic mutations in their genomes. In principle, mutations affecting between one and fifty base pairs are generally classified as small mutational events. Conversely, large mutational events affect more than fifty base pairs, and, in most cases, they encompass copy-number and structural variants affecting many thousands of base pairs. Prior studies have demonstrated that examining patterns of somatic mutations can be leveraged to provide both biological and clinical insights, thus, resulting in an extensive repertoire of tools for evaluating small mutational events. Recently, classification schemas for examining large-scale mutational events have emerged and shown their utility across the spectrum of human cancers. However, there has been no computationally efficient bioinformatics tool that allows visualizing and exploring these large-scale mutational events., Results: Here, we present a new version of SigProfilerMatrixGenerator that now delivers integrated capabilities for examining large mutational events. The tool provides support for examining copy-number variants and structural variants under two previously developed classification schemas and it supports data from numerous algorithms and data modalities. SigProfilerMatrixGenerator is written in Python with an R wrapper package provided for users that prefer working in an R environment., Conclusions: The new version of SigProfilerMatrixGenerator provides the first standardized bioinformatics tool for optimized exploration and visualization of two previously developed classification schemas for copy number and structural variants. The tool is freely available at https://github.com/AlexandrovLab/SigProfilerMatrixGenerator with an extensive documentation at https://osf.io/s93d5/wiki/home/ ., (© 2023. BioMed Central Ltd., part of Springer Nature.)
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- 2023
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29. Mitotic tethering enables inheritance of shattered micronuclear chromosomes.
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Trivedi P, Steele CD, Au FKC, Alexandrov LB, and Cleveland DW
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- Humans, Neoplasms genetics, Chromatin genetics, Cell Nucleus genetics, Cell Nucleus metabolism, Chromosome Segregation, Chromosomes, Human, Chromothripsis, Mitosis
- Abstract
Chromothripsis, the shattering and imperfect reassembly of one (or a few) chromosome(s)
1 , is an ubiquitous2 mutational process generating localized and complex chromosomal rearrangements that drive genome evolution in cancer. Chromothripsis can be initiated by mis-segregation errors in mitosis3,4 or DNA metabolism5-7 that lead to entrapment of chromosomes within micronuclei and their subsequent fragmentation in the next interphase or following mitotic entry6,8-10 . Here we use inducible degrons to demonstrate that chromothriptically produced pieces of a micronucleated chromosome are tethered together in mitosis by a protein complex consisting of mediator of DNA damage checkpoint 1 (MDC1), DNA topoisomerase II-binding protein 1 (TOPBP1) and cellular inhibitor of PP2A (CIP2A), thereby enabling en masse segregation to the same daughter cell. Such tethering is shown to be crucial for the viability of cells undergoing chromosome mis-segregation and shattering after transient inactivation of the spindle assembly checkpoint. Transient, degron-induced reduction in CIP2A following chromosome micronucleation-dependent chromosome shattering is shown to drive acquisition of segmental deletions and inversions. Analyses of pancancer tumour genomes showed that expression of CIP2A and TOPBP1 was increased overall in cancers with genomic rearrangements, including copy number-neutral chromothripsis with minimal deletions, but comparatively reduced in cancers with canonical chromothripsis in which deletions were frequent. Thus, chromatin-bound tethers maintain the proximity of fragments of a shattered chromosome enabling their re-encapsulation into, and religation within, a daughter cell nucleus to form heritable, chromothriptically rearranged chromosomes found in the majority of human cancers., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2023
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30. Control-independent mosaic single nucleotide variant detection with DeepMosaic.
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Yang X, Xu X, Breuss MW, Antaki D, Ball LL, Chung C, Shen J, Li C, George RD, Wang Y, Bae T, Cheng Y, Abyzov A, Wei L, Alexandrov LB, Sebat JL, and Gleeson JG
- Subjects
- Whole Genome Sequencing methods, Exome Sequencing, High-Throughput Nucleotide Sequencing methods, Polymorphism, Single Nucleotide genetics, Nucleotides, Software, Exome
- Abstract
Mosaic variants (MVs) reflect mutagenic processes during embryonic development and environmental exposure, accumulate with aging and underlie diseases such as cancer and autism. The detection of noncancer MVs has been computationally challenging due to the sparse representation of nonclonally expanded MVs. Here we present DeepMosaic, combining an image-based visualization module for single nucleotide MVs and a convolutional neural network-based classification module for control-independent MV detection. DeepMosaic was trained on 180,000 simulated or experimentally assessed MVs, and was benchmarked on 619,740 simulated MVs and 530 independent biologically tested MVs from 16 genomes and 181 exomes. DeepMosaic achieved higher accuracy compared with existing methods on biological data, with a sensitivity of 0.78, specificity of 0.83 and positive predictive value of 0.96 on noncancer whole-genome sequencing data, as well as doubling the validation rate over previous best-practice methods on noncancer whole-exome sequencing data (0.43 versus 0.18). DeepMosaic represents an accurate MV classifier for noncancer samples that can be implemented as an alternative or complement to existing methods., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
- Published
- 2023
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31. Germline modifiers of the tumor immune microenvironment implicate drivers of cancer risk and immunotherapy response.
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Pagadala M, Sears TJ, Wu VH, Pérez-Guijarro E, Kim H, Castro A, Talwar JV, Gonzalez-Colin C, Cao S, Schmiedel BJ, Goudarzi S, Kirani D, Au J, Zhang T, Landi T, Salem RM, Morris GP, Harismendy O, Patel SP, Alexandrov LB, Mesirov JP, Zanetti M, Day CP, Fan CC, Thompson WK, Merlino G, Gutkind JS, Vijayanand P, and Carter H
- Subjects
- Germ Cells, Germ-Line Mutation, Inhibition, Psychological, Macrophages, Tumor Microenvironment genetics, Immunotherapy, Neoplasms genetics, Neoplasms therapy
- Abstract
With the continued promise of immunotherapy for treating cancer, understanding how host genetics contributes to the tumor immune microenvironment (TIME) is essential to tailoring cancer screening and treatment strategies. Here, we study 1084 eQTLs affecting the TIME found through analysis of The Cancer Genome Atlas and literature curation. These TIME eQTLs are enriched in areas of active transcription, and associate with gene expression in specific immune cell subsets, such as macrophages and dendritic cells. Polygenic score models built with TIME eQTLs reproducibly stratify cancer risk, survival and immune checkpoint blockade (ICB) response across independent cohorts. To assess whether an eQTL-informed approach could reveal potential cancer immunotherapy targets, we inhibit CTSS, a gene implicated by cancer risk and ICB response-associated polygenic models; CTSS inhibition results in slowed tumor growth and extended survival in vivo. These results validate the potential of integrating germline variation and TIME characteristics for uncovering potential targets for immunotherapy., (© 2023. The Author(s).)
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- 2023
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32. Chromosomal fragile site breakage by EBV-encoded EBNA1 at clustered repeats.
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Li JSZ, Abbasi A, Kim DH, Lippman SM, Alexandrov LB, and Cleveland DW
- Subjects
- Humans, Binding Sites, DNA Breaks, Double-Stranded, Chromosomes, Human, Pair 11 chemistry, Chromosomes, Human, Pair 11 genetics, Chromosomes, Human, Pair 11 metabolism, Genomic Instability, Mitosis, DNA chemistry, DNA metabolism, Herpesvirus 4, Human genetics, Herpesvirus 4, Human metabolism, Herpesvirus 4, Human pathogenicity, Viral Proteins genetics, Viral Proteins metabolism, Chromosome Breakage
- Abstract
Epstein-Barr virus (EBV) is an oncogenic herpesvirus associated with several cancers of lymphocytic and epithelial origin
1-3 . EBV encodes EBNA1, which binds to a cluster of 20 copies of an 18-base-pair palindromic sequence in the EBV genome4-6 . EBNA1 also associates with host chromosomes at non-sequence-specific sites7 , thereby enabling viral persistence. Here we show that the sequence-specific DNA-binding domain of EBNA1 binds to a cluster of tandemly repeated copies of an EBV-like, 18-base-pair imperfect palindromic sequence encompassing a region of about 21 kilobases at human chromosome 11q23. In situ visualization of the repetitive EBNA1-binding site reveals aberrant structures on mitotic chromosomes characteristic of inherently fragile DNA. We demonstrate that increasing levels of EBNA1 binding trigger dose-dependent breakage at 11q23, producing a fusogenic centromere-containing fragment and an acentric distal fragment, with both mis-segregated into micronuclei in the next cell cycles. In cells latently infected with EBV, elevating EBNA1 abundance by as little as twofold was sufficient to trigger breakage at 11q23. Examination of whole-genome sequencing of EBV-associated nasopharyngeal carcinomas revealed that structural variants are highly enriched on chromosome 11. Presence of EBV is also shown to be associated with an enrichment of chromosome 11 rearrangements across 2,439 tumours from 38 cancer types. Our results identify a previously unappreciated link between EBV and genomic instability, wherein EBNA1-induced breakage at 11q23 triggers acquisition of structural variations in chromosome 11., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2023
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33. Extrachromosomal DNA in the cancerous transformation of Barrett's oesophagus.
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Luebeck J, Ng AWT, Galipeau PC, Li X, Sanchez CA, Katz-Summercorn AC, Kim H, Jammula S, He Y, Lippman SM, Verhaak RGW, Maley CC, Alexandrov LB, Reid BJ, Fitzgerald RC, Paulson TG, Chang HY, Wu S, Bafna V, and Mischel PS
- Subjects
- Humans, Case-Control Studies, Whole Genome Sequencing, Cohort Studies, Biopsy, Oncogenes, Immunomodulation, DNA Copy Number Variations, Gene Amplification, Adenocarcinoma genetics, Adenocarcinoma pathology, Barrett Esophagus genetics, Barrett Esophagus pathology, DNA genetics, Esophageal Neoplasms genetics, Esophageal Neoplasms pathology, Carcinogenesis genetics, Disease Progression, Early Detection of Cancer methods
- Abstract
Oncogene amplification on extrachromosomal DNA (ecDNA) drives the evolution of tumours and their resistance to treatment, and is associated with poor outcomes for patients with cancer
1-6 . At present, it is unclear whether ecDNA is a later manifestation of genomic instability, or whether it can be an early event in the transition from dysplasia to cancer. Here, to better understand the development of ecDNA, we analysed whole-genome sequencing (WGS) data from patients with oesophageal adenocarcinoma (EAC) or Barrett's oesophagus. These data included 206 biopsies in Barrett's oesophagus surveillance and EAC cohorts from Cambridge University. We also analysed WGS and histology data from biopsies that were collected across multiple regions at 2 time points from 80 patients in a case-control study at the Fred Hutchinson Cancer Center. In the Cambridge cohorts, the frequency of ecDNA increased between Barrett's-oesophagus-associated early-stage (24%) and late-stage (43%) EAC, suggesting that ecDNA is formed during cancer progression. In the cohort from the Fred Hutchinson Cancer Center, 33% of patients who developed EAC had at least one oesophageal biopsy with ecDNA before or at the diagnosis of EAC. In biopsies that were collected before cancer diagnosis, higher levels of ecDNA were present in samples from patients who later developed EAC than in samples from those who did not. We found that ecDNAs contained diverse collections of oncogenes and immunomodulatory genes. Furthermore, ecDNAs showed increases in copy number and structural complexity at more advanced stages of disease. Our findings show that ecDNA can develop early in the transition from high-grade dysplasia to cancer, and that ecDNAs progressively form and evolve under positive selection., (© 2023. The Author(s).)- Published
- 2023
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34. Multiomic analysis of malignant pleural mesothelioma identifies molecular axes and specialized tumor profiles driving intertumor heterogeneity.
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Mangiante L, Alcala N, Sexton-Oates A, Di Genova A, Gonzalez-Perez A, Khandekar A, Bergstrom EN, Kim J, Liu X, Blazquez-Encinas R, Giacobi C, Le Stang N, Boyault S, Cuenin C, Tabone-Eglinger S, Damiola F, Voegele C, Ardin M, Michallet MC, Soudade L, Delhomme TM, Poret A, Brevet M, Copin MC, Giusiano-Courcambeck S, Damotte D, Girard C, Hofman V, Hofman P, Mouroux J, Cohen C, Lacomme S, Mazieres J, de Montpreville VT, Perrin C, Planchard G, Rousseau N, Rouquette I, Sagan C, Scherpereel A, Thivolet F, Vignaud JM, Jean D, Ilg AGS, Olaso R, Meyer V, Boland-Auge A, Deleuze JF, Altmuller J, Nuernberg P, Ibáñez-Costa A, Castaño JP, Lantuejoul S, Ghantous A, Maussion C, Courtiol P, Hernandez-Vargas H, Caux C, Girard N, Lopez-Bigas N, Alexandrov LB, Galateau-Salle F, Foll M, and Fernandez-Cuesta L
- Subjects
- Humans, Multiomics, Biomarkers, Tumor genetics, Mesothelioma, Malignant genetics, Mesothelioma, Malignant complications, Mesothelioma genetics, Mesothelioma pathology, Pleural Neoplasms genetics, Pleural Neoplasms pathology, Lung Neoplasms pathology
- Abstract
Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing data, integrated with transcriptomic and epigenomic data using multiomics factor analysis, we demonstrate that the current World Health Organization classification only accounts for up to 10% of interpatient molecular differences. Instead, the MESOMICS project paves the way for a morphomolecular classification of MPM based on four dimensions: ploidy, tumor cell morphology, adaptive immune response and CpG island methylator profile. We show that these four dimensions are complementary, capture major interpatient molecular differences and are delimited by extreme phenotypes that-in the case of the interdependent tumor cell morphology and adapted immune response-reflect tumor specialization. These findings unearth the interplay between MPM functional biology and its genomic history, and provide insights into the variations observed in the clinical behavior of patients with MPM., (© 2023. The Author(s).)
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- 2023
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35. Author Correction: DNA damage and somatic mutations in mammalian cells after irradiation with a nail polish dryer.
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Zhivagui M, Hoda A, Valenzuela N, Yeh YY, Dai J, He Y, Nandi SP, Otlu B, Van Houten B, and Alexandrov LB
- Published
- 2023
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36. Author Correction: The repertoire of mutational signatures in human cancer.
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Alexandrov LB, Kim J, Haradhvala NJ, Huang MN, Tian Ng AW, Wu Y, Boot A, Covington KR, Gordenin DA, Bergstrom EN, Islam SMA, Lopez-Bigas N, Klimczak LJ, McPherson JR, Morganella S, Sabarinathan R, Wheeler DA, Mustonen V, Getz G, Rozen SG, and Stratton MR
- Published
- 2023
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37. Comprehensive analysis of mutational signatures reveals distinct patterns and molecular processes across 27 pediatric cancers.
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Thatikonda V, Islam SMA, Autry RJ, Jones BC, Gröbner SN, Warsow G, Hutter B, Huebschmann D, Fröhling S, Kool M, Blattner-Johnson M, Jones DTW, Alexandrov LB, Pfister SM, and Jäger N
- Subjects
- Adult, Humans, Child, Mutation, Oncogenes, INDEL Mutation, DNA Repair, Neoplasms genetics
- Abstract
Analysis of mutational signatures can reveal underlying molecular mechanisms of the processes that have imprinted the somatic mutations found in cancer genomes. Here, we analyze single base substitutions and small insertions and deletions in pediatric cancers encompassing 785 whole-genome sequenced tumors from 27 molecularly defined cancer subtypes. We identified only a small number of mutational signatures active in pediatric cancers, compared with previously analyzed adult cancers. Further, we report a significant difference in the proportion of pediatric tumors showing homologous recombination repair defect signatures compared with previous analyses. In pediatric leukemias, we identified an indel signature, not previously reported, characterized by long insertions in nonrepeat regions, affecting mainly intronic and intergenic regions, but also exons of known cancer genes. We provide a systematic overview of COSMIC v.3 mutational signatures active across pediatric cancers, which is highly relevant for understanding tumor biology and enabling future research in defining biomarkers of treatment response., (© 2023. The Author(s).)
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- 2023
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38. Ovarian and uterine carcinosarcomas are sensitive in vitro and in vivo to elimusertib, a novel ataxia-telangiectasia and Rad3-related (ATR) kinase inhibitor.
- Author
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Manavella DD, McNamara B, Harold J, Bellone S, Hartwich TMP, Yang-Hartwich Y, Mutlu L, Zipponi M, Demirkiran C, Verzosa MS, Altwerger G, Ratner E, Huang GS, Clark M, Andikyan V, Azodi M, Schwartz PE, Dottino PR, Choi J, Alexandrov LB, Buza N, Hui P, and Santin AD
- Subjects
- Female, Animals, Humans, Ovary, Ataxia Telangiectasia Mutated Proteins genetics, Cell Line, Tumor, Ataxia Telangiectasia drug therapy, Antineoplastic Agents therapeutic use, Uterine Neoplasms drug therapy, Uterine Neoplasms genetics, Carcinosarcoma drug therapy, Carcinosarcoma genetics
- Abstract
Background: Carcinosarcoma of the ovary (OCS) and uterus (UCS) are rare highly aggressive malignancies. Ataxia-telangiectasia-and-Rad3-related (ATR) kinase and homologous recombination play a pivotal role in DNA damage repair. Homologous recombination deficiency (HRD) has been demonstrated in >30% of OCS/UCS. We investigated the preclinical activity of elimusertib, a selective ATR kinase inhibitor, against carcinosarcoma (CS) cell lines and xenografts., Methods: Sensitivity to elimusertib was evaluated in vitro against nine whole exome-sequenced (WES) primary CS cell lines and in vivo against HRD CS xenografts. Western blots were performed to determine baseline ATR and p-ATR protein expression in CS, and ATR pathway downstream effectors and apoptosis markers in CS HRD cell lines after Elimusertib treatment., Results: Out of the 9 CS cell lines, 3 harbored HRD and 6 homologous recombination proficient (HRP) features. Most of CS (i.e., 7/9 = 85%) were found to be sensitive to Elimusertib in vitro. Among the 5 primary CS cell lines with a high-grade pure serous epithelial component, HRD cell lines were more sensitive to elimusertib than HRP tumors (mean IC
50 ± SEM HRD CS = 61.3 nM ±15.2 vs HRP = 361.6 nM ±24.4 (p = 0.01)). Baseline ATR and p-ATR protein expression was higher in HRD CS cell lines. Elimusertib showed tumor growth inhibition in HRD CS xenografts (p < 0.0001) and increased overall animal survival (p < 0.0001). Western blot demonstrated dose-dependent inhibition of ATR, p-ATR and its downstream effector p-CHK1, and a dose-dependent increase in caspase-3 expression., Conclusions: Elimusertib is preclinically active in vitro and in vivo against primary CS cell lines and xenografts, respectively. CS models harboring HRD or with pure/mixed endometrioid histology demonstrated higher sensitivity to ATR inhibition. Clinical trials with elimusertib in CS patients are warranted., Competing Interests: Declaration of Competing Interest A.D.S. reports grants from PUMA, grants from IMMUNOMEDICS, grants from GILEAD, grants from SYNTHON, grants and personal fees from MERCK, grants from BOEHINGER-INGELHEIM, grants from GENENTECH, grants and personal fees from TESARO and grants and personal fees from EISAI and R-Pharm US. L.B.A. is a compensated consultant and has equity interest in io9, LLC. His spouse is an employee of Biotheranostics, Inc. L.B.A. is also an inventor of a US Patent 10,776,718 for source identification by non-negative matrix factorization. L.B.A. declares U.S. provisional applications with serial numbers: 63/289,601; 63/269,033; 63/366,392; 63/367,846; 63/412,835. The other authors declare no conflict of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)- Published
- 2023
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39. Unraveling the impact of a germline heterozygous POLD1 frameshift variant in serrated polyposis syndrome.
- Author
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Bonjoch L, Soares de Lima Y, Díaz-Gay M, Dotti I, Muñoz J, Moreira L, Carballal S, Ocaña T, Cuatrecasas M, Ortiz O, Castells A, Pellisé M, Balaguer F, Salas A, Alexandrov LB, and Castellví-Bel S
- Abstract
Serrated polyposis syndrome (SPS) is one of the most frequent polyposis syndromes characterized by an increased risk for developing colorectal cancer (CRC). Although SPS etiology has been mainly associated with environmental factors, germline predisposition to SPS could also be relevant for cases with familial aggregation or a family history of SPS/CRC. After whole-exome sequencing of 39 SPS patients from 16 families, we identified a heterozygous germline frameshift variant in the POLD1 gene (c.1941delG, p.(Lys648fs*46)) in a patient with SPS and CRC. Tumor presented an ultra-hypermutated phenotype and microsatellite instability. The POLD1 germline variant segregated in three additional SPS-affected family members. We attempted to create yeast and cellular models for this variant but were no viable. Alternatively, we generated patient-derived organoids (PDOs) from healthy rectal tissue of the index case, as well as from a control donor. Then, we challenged PDOs with a DNA-damaging agent to induce replication stress. No significant differences were observed in the DNA damage response between control and POLD1 -Lys648fs PDOs, nor specific mutational signatures were observed. Our results do not support the pathogenicity of the analyzed POLD1 frameshift variant. One possible explanation is that haplosufficiency of the wild-type allele may be compensating for the absence of expression of the frameshift allele. Overall, future work is required to elucidate if functional consequences could be derived from POLD1 alterations different from missense variants in their proofreading domain. To our knowledge, our study presents the first organoid model for germline POLD1 variants and establishes the basis for its use as a model for disease in SPS, CRC and other malignancies., Competing Interests: LA is a compensated consultant and has equity interest in io9, LLC. His spouse is an employee of Biotheranostics, Inc. LA is an inventor of a U.S. Patent 10,776,718 and he also declares U.S. provisional patent applications with serial numbers: 63/289,601, 63/269,033, 63/412,835, 63/366,392, and 63/367,846. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Bonjoch, Soares de Lima, Díaz-Gay, Dotti, Muñoz, Moreira, Carballal, Ocaña, Cuatrecasas, Ortiz, Castells, Pellisé, Balaguer, Salas, Alexandrov and Castellví-Bel.)
- Published
- 2023
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40. DNA damage and somatic mutations in mammalian cells after irradiation with a nail polish dryer.
- Author
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Zhivagui M, Hoda A, Valenzuela N, Yeh YY, Dai J, He Y, Nandi SP, Otlu B, Van Houten B, and Alexandrov LB
- Subjects
- Animals, Humans, Mice, Keratinocytes radiation effects, Mammals, Mutation radiation effects, Reactive Oxygen Species metabolism, Nails, DNA Damage, Fibroblasts, Ultraviolet Rays adverse effects
- Abstract
Ultraviolet A light is commonly emitted by UV-nail polish dryers with recent reports suggesting that long-term use may increase the risk for developing skin cancer. However, no experimental evaluation has been conducted to reveal the effect of radiation emitted by UV-nail polish dryers on mammalian cells. Here, we show that irradiation by a UV-nail polish dryer causes high levels of reactive oxygen species, consistent with 8-oxo-7,8-dihydroguanine damage and mitochondrial dysfunction. Analysis of somatic mutations reveals a dose-dependent increase of C:G>A:T substitutions in irradiated samples with mutagenic patterns similar to mutational signatures previously attributed to reactive oxygen species. In summary, this study demonstrates that radiation emitted by UV-nail polish dryers can both damage DNA and permanently engrave mutations on the genomes of primary mouse embryonic fibroblasts, human foreskin fibroblasts, and human epidermal keratinocytes., (© 2023. The Author(s).)
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- 2023
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41. Germline TP53 mutations undergo copy number gain years prior to tumor diagnosis.
- Author
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Light N, Layeghifard M, Attery A, Subasri V, Zatzman M, Anderson ND, Hatkar R, Blay S, Chen D, Novokmet A, Fuligni F, Tran J, de Borja R, Agarwal H, Waldman L, Abegglen LM, Albertson D, Finlay JL, Hansford JR, Behjati S, Villani A, Gerstung M, Alexandrov LB, Somers GR, Schiffman JD, Rotter V, Malkin D, and Shlien A
- Subjects
- Humans, Tumor Suppressor Protein p53 genetics, Genetic Predisposition to Disease, DNA Copy Number Variations genetics, Phosphatidylinositol 3-Kinases genetics, Phylogeny, Germ-Line Mutation genetics, Mutation, Li-Fraumeni Syndrome diagnosis, Li-Fraumeni Syndrome genetics, Neoplastic Syndromes, Hereditary
- Abstract
Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with germline TP53 pathogenic variants. Here, we perform whole-genome sequence (WGS) analysis of tumors from 22 patients with TP53 germline pathogenic variants. We observe somatic mutations affecting Wnt, PI3K/AKT signaling, epigenetic modifiers and homologous recombination genes as well as mutational signatures associated with prior chemotherapy. We identify near-ubiquitous early loss of heterozygosity of TP53, with gain of the mutant allele. This occurs earlier in these tumors compared to tumors with somatic TP53 mutations, suggesting the timing of this mark may distinguish germline from somatic TP53 mutations. Phylogenetic trees of tumor evolution, reconstructed from bulk and multi-region WGS, reveal that LFS tumors exhibit comparatively limited heterogeneity. Overall, our study delineates early copy number gains of mutant TP53 as a characteristic mutational process in LFS tumorigenesis, likely arising years prior to tumor diagnosis., (© 2023. The Author(s).)
- Published
- 2023
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42. Somatic 9p24.1 alterations in HPV - head and neck squamous cancer dictate immune microenvironment and anti-PD-1 checkpoint inhibitor activity.
- Author
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Zhao X, Cohen EEW, William WN Jr, Bianchi JJ, Abraham JP, Magee D, Spetzler DB, Gutkind JS, Alexandrov LB, Cavenee WK, Lippman SM, and Davoli T
- Subjects
- Humans, Tumor Microenvironment genetics, Immune Checkpoint Inhibitors, Squamous Cell Carcinoma of Head and Neck drug therapy, Squamous Cell Carcinoma of Head and Neck genetics, Papillomavirus Infections genetics, Carcinoma, Squamous Cell, Head and Neck Neoplasms drug therapy, Head and Neck Neoplasms genetics
- Abstract
Somatic copy number alterations (SCNAs), generally (1) losses containing interferons and interferon-pathway genes, many on chromosome 9p, predict immune-cold, immune checkpoint therapy (ICT)-resistant tumors (2); however, genomic regions mediating these effects are unclear and probably tissue specific. Previously, 9p21.3 loss was found to be an early genetic driver of human papillomavirus-negative (HPV
- ) head and neck squamous cancer (HNSC), associated with an immune-cold tumor microenvironment (TME) signal, and recent evidence suggested that this TME-cold phenotype was greatly enhanced with 9p21 deletion size, notably encompassing band 9p24.1 (3). Here, we report multi-omic, -threshold and continuous-variable dissection of 9p21 and 9p24 loci (including depth and degree of somatic alteration of each band at each locus, and each gene at each band) and TME of four HPV- HNSC cohorts. Preferential 9p24 deletion, CD8 T-cell immune-cold associations were observed, driven by 9p24.1 loss, and in turn by an essential telomeric regulatory gene element, JAK2-CD274 . Surprisingly, same genetic region gains were immune hot. Related 9p21-TME analyses were less evident. Inherent 9p-band-level influences on anti-PD1 ICT survival rates, coincident with TME patterns, were also observed. At a 9p24.1 whole-transcriptome expression threshold of 60th percentile, ICT survival rate exceeded that of lower expression percentiles and of chemotherapy; below this transcript threshold, ICT survival was inferior to chemotherapy, the latter unaffected by 9p24.1 expression level ( P- values < 0.01, including in a PD-L1 immunohistochemistry-positive patient subgroup). Whole-exome analyses of 10 solid-tumor types suggest that these 9p-related ICT findings could be relevant to squamous cancers, in which 9p24.1 gain/immune-hot associations exist.- Published
- 2022
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43. Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor.
- Author
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Islam SMA, Díaz-Gay M, Wu Y, Barnes M, Vangara R, Bergstrom EN, He Y, Vella M, Wang J, Teague JW, Clapham P, Moody S, Senkin S, Li YR, Riva L, Zhang T, Gruber AJ, Steele CD, Otlu B, Khandekar A, Abbasi A, Humphreys L, Syulyukina N, Brady SW, Alexandrov BS, Pillay N, Zhang J, Adams DJ, Martincorena I, Wedge DC, Landi MT, Brennan P, Stratton MR, Rozen SG, and Alexandrov LB
- Abstract
Mutational signature analysis is commonly performed in cancer genomic studies. Here, we present SigProfilerExtractor, an automated tool for de novo extraction of mutational signatures, and benchmark it against another 13 bioinformatics tools by using 34 scenarios encompassing 2,500 simulated signatures found in 60,000 synthetic genomes and 20,000 synthetic exomes. For simulations with 5% noise, reflecting high-quality datasets, SigProfilerExtractor outperforms other approaches by elucidating between 20% and 50% more true-positive signatures while yielding 5-fold less false-positive signatures. Applying SigProfilerExtractor to 4,643 whole-genome- and 19,184 whole-exome-sequenced cancers reveals four novel signatures. Two of the signatures are confirmed in independent cohorts, and one of these signatures is associated with tobacco smoking. In summary, this report provides a reference tool for analysis of mutational signatures, a comprehensive benchmarking of bioinformatics tools for extracting signatures, and several novel mutational signatures, including one putatively attributed to direct tobacco smoking mutagenesis in bladder tissues., Competing Interests: M.V. is an employee of NVIDIA corporation. L.B.A. is a compensated consultant and has equity interest in io9, LLC. His spouse is an employee of Biotheranostics, Inc. L.B.A. and B.S.A. are inventors of a US patent 10,776,718. E.N.B. and L.B.A. declare US provisional applications with serial numbers 63/289,601 and 63/269,033. L.B.A. and A.A. declare US provisional patent applications with serial numbers 63/366,392 and 63/367,846. All other authors declare no competing interests., (© 2022 The Author(s).)
- Published
- 2022
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44. AI-assisted discovery of an ethnicity-influenced driver of cell transformation in esophageal and gastroesophageal junction adenocarcinomas.
- Author
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Ghosh P, Campos VJ, Vo DT, Guccione C, Goheen-Holland V, Tindle C, Mazzini GS, He Y, Alexandrov LB, Lippman SM, Gurski RR, Das S, Yadlapati R, Curtius K, and Sahoo D
- Subjects
- Artificial Intelligence, Case-Control Studies, Cell Transformation, Neoplastic genetics, Cross-Sectional Studies, Esophagogastric Junction metabolism, Esophagogastric Junction pathology, Ethnicity, Humans, Interleukin-8 genetics, Tumor Microenvironment, Adenocarcinoma pathology, Barrett Esophagus genetics, Barrett Esophagus pathology, Esophageal Neoplasms pathology
- Abstract
Although Barrett's metaplasia of the esophagus (BE) is the only known precursor lesion to esophageal adenocarcinomas (EACs), drivers of cellular transformation in BE remain incompletely understood. We use an artificial intelligence-guided network approach to study EAC initiation and progression. Key predictions are subsequently validated in a human organoid model, in patient-derived biopsy specimens of BE, a case-control study of genomics of BE progression, and in a cross-sectional study of 113 patients with BE and EACs. Our model classified healthy esophagus from BE and BE from EACs in several publicly available gene expression data sets (n = 932 samples). The model confirmed that all EACs must originate from BE and pinpointed a CXCL8/IL8↔neutrophil immune microenvironment as a driver of cellular transformation in EACs and gastroesophageal junction adenocarcinomas. This driver is prominent in White individuals but is notably absent in African Americans (AAs). Network-derived gene signatures, independent signatures of neutrophil processes, CXCL8/IL8 expression, and an absolute neutrophil count (ANC) are associated with risk of progression. SNPs associated with changes in ANC by ethnicity (e.g., benign ethnic neutropenia [BEN]) modify that risk. Findings define a racially influenced immunological basis for cell transformation and suggest that BEN in AAs may be a deterrent to BE→EAC progression.
- Published
- 2022
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45. Synergistic activity of neratinib in combination with olaparib in uterine serous carcinoma overexpressing HER2/neu.
- Author
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Yadav G, Roque DM, Bellone S, Manavella DD, Hartwich TMP, Zipponi M, Harold J, Tymon-Rosario J, Mutlu L, Altwerger G, Menderes G, Ratner E, Buza N, Hui P, Huang GS, Andikyan V, Clark M, Azodi M, Schwartz PE, Alexandrov LB, and Santin AD
- Subjects
- Cell Line, Tumor, Female, Humans, Phthalazines, Piperazines, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Quinolines, Receptor, ErbB-2 metabolism, Xenograft Model Antitumor Assays, Cystadenocarcinoma, Serous drug therapy, Cystadenocarcinoma, Serous genetics, Cystadenocarcinoma, Serous pathology, Uterine Neoplasms drug therapy, Uterine Neoplasms genetics, Uterine Neoplasms metabolism
- Abstract
Introduction: Uterine serous carcinoma (USC) is an aggressive variant of endometrial cancer with a poor prognosis. Approximately 30% of USC overexpress HER2/neu, a recognized target for trastuzumab in advanced/recurrent HER2/neu-positive USC. We evaluated the efficacy of the pan-c-erb inhibitor neratinib and the poly (ADP-ribose)-polymerase (PARP) inhibitor olaparib as single agents and in combination against USC cell lines and xenografts., Methods: In-vitro cell-viability assays with olaparib, neratinib, and olaparib/neratinib were assessed using flow-cytometry based assays against a panel of USC cell lines with high and low HER2/neu expression. Homologous recombination deficiency (HRD) signatures were evaluated as described by Alexandrov et al. (Nature;2020;578:94-101) while downstream signaling affected by neratinib/olaparib exposure was assessed with immunoblotting. Efficacy of single- versus dual-agent inhibition was evaluated in-vivo using two USC-xenografts with 3+ HER2/neu expression., Results: Neratinib was more potent than olaparib in suppression of in-vitro growth of HER2/neu 3+ cell lines (ARK1: p = 0.0047; ARK2: p = 0.0428) while no difference was noted against HER2/neu 1+ tumors (ARK4). Importantly, the combination of olaparib with neratinib synergistically improved tumor suppression compared to either single-agent in vitro. USC cells exposed to olaparib upregulated HER2/neu expression, while neratinib treatment increased PARP activity (ARK1: p < 0.0001; ARK2: p < 0.0001). Single-agent neratinib transiently inhibited in vivo growth of USC xenografts harboring HER2/neu gene amplification (ARK1: p < 0.05; ARK2: p < 0.05). In contrast, the combination of the two inhibitors caused a stronger and durable growth inhibition in both USC xenografts (ARK1: p < 0.05; ARK2: p < 0.05)., Conclusion: The combination of olaparib and neratinib is active and synergistic against primary HER2/neu + USC. This combination may represent a novel therapeutic option for USC patients with HER2/neu+, homologous recombination-proficient tumors resistant to chemotherapy., Competing Interests: Declaration of Competing Interest Dr. Santin reports grants from PUMA, GILEAD, SYNTHON, BOEHINGER-INGELHEIM, GENENTECH and grants and personal fees from MERCK, TESARO, and EISAI. The remaining authors declare no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2022
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46. Mechanisms of APOBEC3 mutagenesis in human cancer cells.
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Petljak M, Dananberg A, Chu K, Bergstrom EN, Striepen J, von Morgen P, Chen Y, Shah H, Sale JE, Alexandrov LB, Stratton MR, and Maciejowski J
- Subjects
- Cell Line, Tumor, DNA-Directed DNA Polymerase metabolism, Gene Deletion, Genome, Human, Humans, Uracil-DNA Glycosidase metabolism, APOBEC Deaminases deficiency, APOBEC Deaminases genetics, APOBEC Deaminases metabolism, Mutagenesis genetics, Neoplasms enzymology, Neoplasms genetics, Neoplasms pathology
- Abstract
The APOBEC3 family of cytosine deaminases has been implicated in some of the most prevalent mutational signatures in cancer
1-3 . However, a causal link between endogenous APOBEC3 enzymes and mutational signatures in human cancer genomes has not been established, leaving the mechanisms of APOBEC3 mutagenesis poorly understood. Here, to investigate the mechanisms of APOBEC3 mutagenesis, we deleted implicated genes from human cancer cell lines that naturally generate APOBEC3-associated mutational signatures over time4 . Analysis of non-clustered and clustered signatures across whole-genome sequences from 251 breast, bladder and lymphoma cancer cell line clones revealed that APOBEC3A deletion diminished APOBEC3-associated mutational signatures. Deletion of both APOBEC3A and APOBEC3B further decreased APOBEC3 mutation burdens, without eliminating them. Deletion of APOBEC3B increased APOBEC3A protein levels, activity and APOBEC3A-mediated mutagenesis in some cell lines. The uracil glycosylase UNG was required for APOBEC3-mediated transversions, whereas the loss of the translesion polymerase REV1 decreased overall mutation burdens. Together, these data represent direct evidence that endogenous APOBEC3 deaminases generate prevalent mutational signatures in human cancer cells. Our results identify APOBEC3A as the main driver of these mutations, indicate that APOBEC3B can restrain APOBEC3A-dependent mutagenesis while contributing its own smaller mutation burdens and dissect mechanisms that translate APOBEC3 activities into distinct mutational signatures., (© 2022. The Author(s).)- Published
- 2022
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47. An overview of mutational and copy number signatures in human cancer.
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Steele CD, Pillay N, and Alexandrov LB
- Subjects
- DNA Damage, Genomics, Humans, Mutation, DNA Copy Number Variations, Neoplasms genetics
- Abstract
The genome of each cell in the human body is constantly under assault from a plethora of exogenous and endogenous processes that can damage DNA. If not successfully repaired, DNA damage generally becomes permanently imprinted in cells, and all their progenies, as somatic mutations. In most cases, the patterns of these somatic mutations contain the tell-tale signs of the mutagenic processes that have imprinted and are termed mutational signatures. Recent pan-cancer genomic analyses have elucidated the compendium of mutational signatures for all types of small mutational events, including (1) single base substitutions, (2) doublet base substitutions, and (3) small insertions/deletions. In contrast to small mutational events, where, in most cases, DNA damage is a prerequisite, aneuploidy, which refers to the abnormal number of chromosomes in a cell, usually develops from mistakes during DNA replication. Such mistakes include DNA replication stress, mitotic errors caused by faulty microtubule dynamics, or cohesion defects that contribute to chromosomal breakage and can lead to copy number (CN) alterations (CNAs) or even to structural rearrangements. These aberrations also leave behind genomic scars which can be inferred from sequencing as CN signatures and rearrangement signatures. The analyses of mutational signatures of small mutational events have been extensively reviewed, so we will not comprehensively re-examine them here. Rather, our focus will be on summarising the existing knowledge for mutational signatures of CNAs. As studying CN signatures is an emerging field, we briefly summarise the utility that mutational signatures of small mutational events have provided in basic science, cancer treatment, and cancer prevention, and we emphasise the future role that CN signatures may play in each of these fields. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland., (© 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.)
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- 2022
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48. Homologous recombination deficiency (HRD) signature-3 in ovarian and uterine carcinosarcomas correlates with preclinical sensitivity to Olaparib, a poly (adenosine diphosphate [ADP]- ribose) polymerase (PARP) inhibitor.
- Author
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Tymon-Rosario JR, Manara P, Manavella DD, Bellone S, Hartwich TMP, Harold J, Yang-Hartwich Y, Zipponi M, Choi J, Jeong K, Mutlu L, Yang K, Altwerger G, Menderes G, Ratner E, Huang GS, Clark M, Andikyan V, Azodi M, Schwartz PE, Alexandrov LB, and Santin AD
- Subjects
- Adenosine Diphosphate therapeutic use, Animals, Cell Line, Tumor, Female, Homologous Recombination, Humans, Ovary pathology, Phthalazines pharmacology, Phthalazines therapeutic use, Piperazines, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use, Poly(ADP-ribose) Polymerases, Ribose therapeutic use, Carcinosarcoma drug therapy, Carcinosarcoma genetics, Ovarian Neoplasms drug therapy, Ovarian Neoplasms genetics, Ovarian Neoplasms pathology
- Abstract
Objectives: Carcinosarcoma (CS) of the ovary and uterus are highly aggressive malignancies associated with poor survival. Poly(ADP-ribose)-polymerase inhibitors (PARPi) are targeted agents impairing DNA repair via homologous-recombination-deficiency (HRD) mechanisms. We used whole-exome-sequencing (WES) data from a cohort of fresh tumor samples of ovarian (OCS) and uterine carcinosarcoma (UCS), primary cell lines and xenografts to investigate the role for olaparib in CSs., Methods: WES data from 73 CS samples (48 UCS and 25 OCS) were analyzed for HRD signatures. Olaparib activity was evaluated using cell-viability, cell-cycle, apoptosis and cytotoxicity assays against primary CS cell lines. Olaparib antitumor activity was tested in vivo against HRD CS xenografts., Results: Signature-3 (i.e. HRD-related signature) was identified in 60% of OCS (15 of 25) vs 25% of UCS (12 of 48) (p = 0.005). CS cell lines harboring Signature-3/HRD (3 OCS/1 UCS) were significantly more sensitive to olaparib when compared to HRP cell lines (5 UCS/1 OCS) [mean IC
50 ± SEM = 2.94 μM ± 0.07 vs mean ± SEM = 23.3 μM ± 0.09, (p = 0.02), respectively]. PARPi suppressed CS cell growth through cell cycle arrest in the G2/M phase and caused more apoptosis in HRD vs HRP primary tumors (p < 0.0001). In vivo, olaparib significantly impaired HRD CS xenografts tumor growth (p = 0.0008) and increased overall animal survival (p < 0.0001)., Conclusions: OCS and UCS cell lines harboring HRD signature-3 were significantly more sensitive to olaparib in vitro and in vivo when compared to HRP CS. Clinical studies with PARPi in CS patients with a dominant signature 3 (HRD-related) are warranted., (Published by Elsevier Inc.)- Published
- 2022
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49. Examining clustered somatic mutations with SigProfilerClusters.
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Bergstrom EN, Kundu M, Tbeileh N, and Alexandrov LB
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- Humans, Mutation, Genome, Software, Neoplasms genetics
- Abstract
Motivation: Clustered mutations are found in the human germline as well as in the genomes of cancer and normal somatic cells. Clustered events can be imprinted by a multitude of mutational processes, and they have been implicated in both cancer evolution and development disorders. Existing tools for identifying clustered mutations have been optimized for a particular subtype of clustered event and, in most cases, relied on a predefined inter-mutational distance (IMD) cutoff combined with a piecewise linear regression analysis., Results: Here, we present SigProfilerClusters, an automated tool for detecting all types of clustered mutations by calculating a sample-dependent IMD threshold using a simulated background model that takes into account extended sequence context, transcriptional strand asymmetries and regional mutation densities. SigProfilerClusters disentangles all types of clustered events from non-clustered mutations and annotates each clustered event into an established subclass, including the widely used classes of doublet-base substitutions, multi-base substitutions, omikli and kataegis. SigProfilerClusters outputs non-clustered mutations and clustered events using standard data formats as well as provides multiple visualizations for exploring the distributions and patterns of clustered mutations across the genome., Availability and Implementation: SigProfilerClusters is supported across most operating systems and made freely available at https://github.com/AlexandrovLab/SigProfilerClusters with an extensive documentation located at https://osf.io/qpmzw/wiki/home/., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2022. Published by Oxford University Press.)
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- 2022
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50. Signatures of copy number alterations in human cancer.
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Steele CD, Abbasi A, Islam SMA, Bowes AL, Khandekar A, Haase K, Hames-Fathi S, Ajayi D, Verfaillie A, Dhami P, McLatchie A, Lechner M, Light N, Shlien A, Malkin D, Feber A, Proszek P, Lesluyes T, Mertens F, Flanagan AM, Tarabichi M, Van Loo P, Alexandrov LB, and Pillay N
- Subjects
- Aneuploidy, Chromothripsis, Haploidy, Homologous Recombination genetics, Humans, Loss of Heterozygosity genetics, Mutation, Exome Sequencing, DNA Copy Number Variations genetics, DNA Mutational Analysis, Neoplasms genetics, Neoplasms pathology
- Abstract
Gains and losses of DNA are prevalent in cancer and emerge as a consequence of inter-related processes of replication stress, mitotic errors, spindle multipolarity and breakage-fusion-bridge cycles, among others, which may lead to chromosomal instability and aneuploidy
1,2 . These copy number alterations contribute to cancer initiation, progression and therapeutic resistance3-5 . Here we present a conceptual framework to examine the patterns of copy number alterations in human cancer that is widely applicable to diverse data types, including whole-genome sequencing, whole-exome sequencing, reduced representation bisulfite sequencing, single-cell DNA sequencing and SNP6 microarray data. Deploying this framework to 9,873 cancers representing 33 human cancer types from The Cancer Genome Atlas6 revealed a set of 21 copy number signatures that explain the copy number patterns of 97% of samples. Seventeen copy number signatures were attributed to biological phenomena of whole-genome doubling, aneuploidy, loss of heterozygosity, homologous recombination deficiency, chromothripsis and haploidization. The aetiologies of four copy number signatures remain unexplained. Some cancer types harbour amplicon signatures associated with extrachromosomal DNA, disease-specific survival and proto-oncogene gains such as MDM2. In contrast to base-scale mutational signatures, no copy number signature was associated with many known exogenous cancer risk factors. Our results synthesize the global landscape of copy number alterations in human cancer by revealing a diversity of mutational processes that give rise to these alterations., (© 2022. The Author(s).)- Published
- 2022
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