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A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns

Notta, Faiyaz ; Chan-Seng-Yue, Michelle ; Lemire, Mathieu ; Li, Yilong ; Wilson, Gavin W ; Connor, Ashton A ; Denroche, Robert E ; Liang, Sheng-Ben ; Brown, Andrew MK ; Kim, Jaeseung C ; Wang, Tao ; Simpson, Jared T ; Beck, Timothy ; Borgida, Ayelet ; Buchner, Nicholas ; Chadwick, Dianne ; Hafezi-Bakhtiari, Sara ; Dick, John E ; Heisler, Lawrence ; Hollingsworth, Michael A ; Ibrahimov, Emin ; Jang, Gun Ho ; Johns, Jeremy ; Jorgensen, Lars GT ; Law, Calvin ; Ludkovski, Olga ; Lungu, Ilinca ; Ng, Karen ; Pasternack, Danielle ; Petersen, Gloria M ; Shlush, Liran I ; Timms, Lee ; Tsao, Ming-Sound ; Wilson, Julie M ; Yung, Christina K ; Zogopoulos, George ; Bartlett, John MS ; Alexandrov, Ludmil B ; Real, Francisco X ; Cleary, Sean P ; Roehrl, Michael H ; McPherson, John D ; Stein, Lincoln D ; Hudson, Thomas J ; Campbell, Peter J ; Gallinger, Steven

Nature, 2016-10, Vol.538 (7625), p.378-382

eScholarship, University of California

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Título:
A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns
Autor: Notta, Faiyaz ; Chan-Seng-Yue, Michelle ; Lemire, Mathieu ; Li, Yilong ; Wilson, Gavin W ; Connor, Ashton A ; Denroche, Robert E ; Liang, Sheng-Ben ; Brown, Andrew MK ; Kim, Jaeseung C ; Wang, Tao ; Simpson, Jared T ; Beck, Timothy ; Borgida, Ayelet ; Buchner, Nicholas ; Chadwick, Dianne ; Hafezi-Bakhtiari, Sara ; Dick, John E ; Heisler, Lawrence ; Hollingsworth, Michael A ; Ibrahimov, Emin ; Jang, Gun Ho ; Johns, Jeremy ; Jorgensen, Lars GT ; Law, Calvin ; Ludkovski, Olga ; Lungu, Ilinca ; Ng, Karen ; Pasternack, Danielle ; Petersen, Gloria M ; Shlush, Liran I ; Timms, Lee ; Tsao, Ming-Sound ; Wilson, Julie M ; Yung, Christina K ; Zogopoulos, George ; Bartlett, John MS ; Alexandrov, Ludmil B ; Real, Francisco X ; Cleary, Sean P ; Roehrl, Michael H ; McPherson, John D ; Stein, Lincoln D ; Hudson, Thomas J ; Campbell, Peter J ; Gallinger, Steven
Assuntos: 2.1 Biological and endogenous factors ; 5.1 Pharmaceuticals ; Aetiology ; Biological ; Biological Sciences ; Biomedical and Clinical Sciences ; Biotechnology ; Cancer ; Carcinogenesis ; Carcinoma in Situ ; Chromothripsis ; Development of treatments and therapeutic interventions ; Digestive Diseases ; Disease Progression ; DNA Copy Number Variations ; Evolution ; Female ; Gene Rearrangement ; General Science & Technology ; Genes ; Genetics ; Genome ; Human ; Human Genome ; Humans ; Male ; Mitosis ; Molecular ; Mutagenesis ; Mutation ; Neoplasm ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Oncology and Carcinogenesis ; Orphan Drug ; Pancreatic Cancer ; Pancreatic Neoplasms ; Polyploidy ; Precancerous Conditions ; Rare Diseases
É parte de: Nature, 2016-10, Vol.538 (7625), p.378-382
Notas: 378 - 382
Nature, vol 538, iss 7625
Descrição: Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the classically held view of stepwise cancer development. The current model of tumorigenesis, based on analyses of precursor lesions, termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: first, that pancreatic cancer develops through a particular sequence of genetic alterations (KRAS, followed by CDKN2A, then TP53 and SMAD4); and second, that the evolutionary trajectory of pancreatic cancer progression is gradual because each alteration is acquired independently. A shortcoming of this model is that clonally expanded precursor lesions do not always belong to the tumour lineage, indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing model of tumorigenesis has contributed to the clinical notion that pancreatic cancer evolves slowly and presents at a late stage. However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes, despite efforts aimed at early detection, suggest that pancreatic cancer progression is not gradual. Here, using newly developed informatics tools, we tracked changes in DNA copy number and their associated rearrangements in tumour-enriched genomes and found that pancreatic cancer tumorigenesis is neither gradual nor follows the accepted mutation order. Two-thirds of tumours harbour complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory. In a subset of cases, the consequence of such errors is the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that are likely to set-off invasive cancer growth. These findings challenge the current progression model of pancreatic cancer and provide insights into the mutational processes that give rise to these aggressive tumours.
Editor: eScholarship, University of California
Idioma: Inglês

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A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns

eScholarship, University of California

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