Please summarize in detail what is known about genomics in cancer based on these 16 abstracts of recent publications [here, shown at bottom]. Please be sure your summary is at least 500-600 words long.
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Certainly, based on the abstracts of the recent publications you provided, here's a detailed summary of what is known about genomics in cancer:
Genomics has revolutionized our understanding of cancer by revealing the complex landscape of genetic alterations that drive tumorigenesis. Recent studies have shed light on a phenomenon known as "chromothripsis," which is a catastrophic event resulting in massive, clustered genomic rearrangements. This phenomenon plays a significant role in cancer and has been found in various cancer types.
Chromothripsis was first described in 2011 as a novel form of genome instability characterized by tens to hundreds of locally clustered rearrangements in cancer cells. It is likely caused by a single catastrophic event leading to simultaneous formation of multiple double-strand breaks, repaired by error-prone mechanisms. Since then, chromothripsis has been detected in a wide range of tumor entities, pointing to its importance in cancer development.
Complex chromosomal rearrangements resulting from chromothripsis have been implicated in both cancer and congenital disorders. This phenomenon has been found in various cancer types, including breast cancer, mesothelioma, and pancreatic cancer. It has also been observed in germline structural variations, genome mosaicism, and developmental disorders. The extent of chromothripsis varies across cancer types, with prevalence rates of over 60% in metastatic breast cancers and 25% in luminal breast cancers.
Chromothripsis events often involve multiple chromosomes and result in extensive structural variations. The rearrangements are not gradual accumulations of mutations, but rather occur as a single event. Specific chromosomes, such as 11 and 17, have been frequently affected, leading to alterations in key genes like CCND1, ERBB2, CDK12, and BRCA1. Recurrent gene fusions generated by chromothripsis have been identified as drivers of tumor development.
Mechanistically, various model systems have been developed to study chromothripsis in vitro. These models include the formation of nuclear structures called micronuclei, telomere fusions, and induction of DNA double-strand breaks. These models have provided insights into the cellular processes and mechanisms underlying chromothripsis, shedding light on its impact on cancer progression and therapy.
Chromothripsis is not only associated with structural alterations but also affects mutational signatures and signaling pathways. It is linked to the activation of specific signaling pathways and has been associated with chromosomal instability. Moreover, chromothripsis has been connected to other genomic events such as kataegis, a phenomenon characterized by clusters of point mutations near genomic breakpoints.
The prevalence and significance of chromothripsis highlight its potential as a driving event in cancer development. It has been suggested that chromothripsis can lead to rapid evolution of cancer genomes, offering a unique perspective on the dynamics of tumor progression. While significant progress has been made in understanding chromothripsis, many aspects of its mechanisms and implications in cancer development remain to be fully elucidated.
In conclusion, the emergence of chromothripsis as a major genomic phenomenon has expanded our understanding of cancer development. Its occurrence in a wide range of cancer types, its impact on structural alterations, mutational signatures, and signaling pathways, as well as its potential as a driver of tumor evolution, all contribute to its significance in the field of cancer genomics. Further research is needed to comprehensively dissect the molecular mechanisms of chromothripsis and to explore its potential as a therapeutic target in cancer treatment.
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INPUT (WITH ABSTRACTS)
1. PMID: 32025007
Pan-cancer analysis of whole genomes.
ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium.
Nature. 2020 Feb;578(7793):82-93. doi: 10.1038/s41586-020-1969-6. Epub 2020 Feb 5.
PMID: 32025007 Free PMC article.
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2. PMID: 33361815
Chromothripsis drives the evolution of gene amplification in cancer.
Shoshani O, Brunner SF, Yaeger R, Ly P, Nechemia-Arbely Y, Kim DH, Fang R, Castillon GA, Yu M, Li JSZ, Sun Y, Ellisman MH, Ren B, Campbell PJ, Cleveland DW.
Nature. 2021 Mar;591(7848):137-141. doi: 10.1038/s41586-020-03064-z. Epub 2020 Dec 23.
PMID: 33361815 Free PMC article.
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3. PMID: 34459009
Cancer evolution: Darwin and beyond.
Vendramin R, Litchfield K, Swanton C.
EMBO J. 2021 Sep 15;40(18):e108389. doi: 10.15252/embj.2021108389. Epub 2021 Aug 30.
PMID: 34459009 Free PMC article. Review.
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4. PMID: 26455580
Chromothripsis in cancer cells: An update.
Rode A, Maass KK, Willmund KV, Lichter P, Ernst A.
Int J Cancer. 2016 May 15;138(10):2322-33. doi: 10.1002/ijc.29888. Epub 2015 Oct 30.
PMID: 26455580 Free article. Review.
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5. PMID: 35705804
Signatures of copy number alterations in human cancer.
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, Pillay N.
Nature. 2022 Jun;606(7916):984-991. doi: 10.1038/s41586-022-04738-6. Epub 2022 Jun 15.
PMID: 35705804 Free PMC article.
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6. PMID: 34089011
The pancreatic cancer genome revisited.
Hayashi A, Hong J, Iacobuzio-Donahue CA.
Nat Rev Gastroenterol Hepatol. 2021 Jul;18(7):469-481. doi: 10.1038/s41575-021-00463-z. Epub 2021 Jun 4.
PMID: 34089011 Review.
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7. PMID: 30995849
Chromothripsis - Extensive Chromosomal Rearrangements and Their Significance in Cancer.
Závacká K, Plevová K, Jarošová M, Pospíšilová Š.
Klin Onkol. 2019 Spring;32(2):101-108. doi: 10.14735/amko2019101.
PMID: 30995849 Review. English.
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8. PMID: 22972457
Chromothripsis and cancer: causes and consequences of chromosome shattering.
Forment JV, Kaidi A, Jackson SP.
Nat Rev Cancer. 2012 Oct;12(10):663-70. doi: 10.1038/nrc3352. Epub 2012 Sep 13.
PMID: 22972457 Review.
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9. PMID: 28096526
Telomeres in cancer: tumour suppression and genome instability.
Maciejowski J, de Lange T.
Nat Rev Mol Cell Biol. 2017 Mar;18(3):175-186. doi: 10.1038/nrm.2016.171. Epub 2017 Jan 18.
PMID: 28096526 Free PMC article. Review.
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10. PMID: 30115429
Mutational game changer: Chromothripsis and its emerging relevance to cancer.
Luijten MNH, Lee JXT, Crasta KC.
Mutat Res Rev Mutat Res. 2018 Jul-Sep;777:29-51. doi: 10.1016/j.mrrev.2018.06.004. Epub 2018 Jun 30.
PMID: 30115429 Free article. Review.
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11. PMID: 23478216
Chromothripsis in congenital disorders and cancer: similarities and differences.
Kloosterman WP, Cuppen E.
Curr Opin Cell Biol. 2013 Jun;25(3):341-8. doi: 10.1016/j.ceb.2013.02.008. Epub 2013 Mar 13.
PMID: 23478216 Review.
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12. PMID: 33932302
Cell-based model systems for genome instability: Dissecting the mechanistic basis of chromothripsis in cancer.
Kolb T, Ernst A.
Int J Cancer. 2021 May 1. doi: 10.1002/ijc.33618. Online ahead of print.
PMID: 33932302 Free article. Review.
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13. PMID: 32973084
Chromothripsis in Human Breast Cancer.
Bolkestein M, Wong JKL, Thewes V, Körber V, Hlevnjak M, Elgaafary S, Schulze M, Kommoss FKF, Sinn HP, Anzeneder T, Hirsch S, Devens F, Schröter P, Höfer T, Schneeweiss A, Lichter P, Zapatka M, Ernst A.
Cancer Res. 2020 Nov 15;80(22):4918-4931. doi: 10.1158/0008-5472.CAN-20-1920. Epub 2020 Sep 24.
PMID: 32973084
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14. PMID: 30598368
Does Chromothripsis Make Mesothelioma an Immunogenic Cancer?
Carbone M, Yang H, Gaudino G.
J Thorac Oncol. 2019 Feb;14(2):157-159. doi: 10.1016/j.jtho.2018.11.006. Epub 2018 Dec 28.
PMID: 30598368 Free PMC article. No abstract available.
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15. PMID: 26376877
The Diverse Effects of Complex Chromosome Rearrangements and Chromothripsis in Cancer Development.
de Pagter MS, Kloosterman WP.
Recent Results Cancer Res. 2015;200:165-93. doi: 10.1007/978-3-319-20291-4_8.
PMID: 26376877 Review.
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16. PMID: 32025003
Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing.
Cortés-Ciriano I, Lee JJ, Xi R, Jain D, Jung YL, Yang L, Gordenin D, Klimczak LJ, Zhang CZ, Pellman DS; PCAWG Structural Variation Working Group; Park PJ; PCAWG Consortium.
Nat Genet. 2020 Mar;52(3):331-341. doi: 10.1038/s41588-019-0576-7. Epub 2020 Feb 5.
PMID: 32025003 Free PMC article.
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