Exploring the landscape of focal amplifications in cancer using AmpliconArchitect

Deshpande, Viraj; Luebeck, Jens; Nguyen, Nam; Bakhtiari, Mehrdad; Turner, Kristen M.; Schwab, Richard B.; Carter, Hannah; Mischel, Paul S.; Bafna, Vineet

doi:10.1038/s41467-018-08200-y

Cited by 225 publications

(340 citation statements)

References 35 publications

(40 reference statements)

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“…EcDNA can arise during genome reshuffling events like chromothripsis and are subsequently amplified 2,3 . This partially explains why such circular DNAs can consist of several coding and non-coding distant parts of one or more chromosomes 4 .…”

Section: Introductionmentioning

confidence: 99%

Enhancer hijacking determines intra- and extrachromosomal circularMYCNamplicon architecture in neuroblastoma

Helmsauer

Валиева

Ali

et al. 2019

Preprint

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MYCN amplification drives one in six cases of neuroblastoma. The supernumerary gene copies are commonly found on highly rearranged, extrachromosomal circular DNA. The exact amplicon structure has not been described thus far and the functional relevance of its rearrangements is unknown. Here, we analyzed the MYCN amplicon structure and its chromatin landscape. This revealed two distinct classes of amplicons which explain the regulatory requirements for MYCN overexpression. The first class always co-amplified a proximal enhancer driven by the noradrenergic core regulatory circuit (CRC). The second class of MYCN amplicons was characterized by high structural complexity, lacked key local enhancers, and instead contained distal chromosomal fragments, which harbored CRC-driven enhancers. Thus, ectopic enhancer hijacking can compensate for the loss of local gene regulatory elements and explains a large component of the structural diversity observed in MYCN amplification.

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Section: Introductionmentioning

confidence: 99%

Enhancer hijacking determines intra- and extrachromosomal circularMYCNamplicon architecture in neuroblastoma

Helmsauer

Валиева

Ali

et al. 2019

Preprint

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“…Performance-wise, low-coverage WGS consistently showed high concordance with microarray and high-coverage WGS in our analysis. It As WGS studies become less expensive, we foresee that in the future low-coverage WGS may prove to be replacing clinical microarray testing for cancers 33 , developmental disabilities, congenital anomalies [34][35][36] , autism spectrum disorder 37 , and many other genetic diseases 29 . Citing the benefits of WGS, a recent study compared the performance of low-coverage WGS versus microarrays on rare and undiagnosed cases.…”

Section: Discussionmentioning

confidence: 99%

Whole genome analysis identifies the association of TP53 genomic deletions with lower survival in Stage III colorectal cancer

Xia

Hummelen

Kubit

et al. 2019

Preprint

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DNA copy number aberrations (CNA) were frequently observed in colorectal cancers (CRC).There is an urgent call for CNA-based biomarkers in clinics, in particular for Stage III CRC, if combined with imaging or pathologic evidence, promise more precise care at the timing. We conducted this Stage III specific biomarker discovery with a cohort of 134 CRCs, and with a newly developed high-efficiency CNA profiling protocol. Specifically, we developed the profiling protocol for tumor-normal matched tissue samples based on low-coverage clinical wholegenome sequencing (WGS). We demonstrated the protocol's accuracy and robustness by a systematic benchmark with microarray, high-coverage whole-exome and -genome approaches, where the low-coverage WGS-derived CNA segments were highly accordant (PCC>0.95) with those derived from microarray, and they were substantially less variable if compared to exome-derived segments. A lasso-based model and multivariate cox regression analysis identified a chromosome 17p loss, containing the TP53 tumor suppressor gene, that was significantly associated with reduced survival (P=0.0139, HR=1.688, 95% CI = [1.112-2.562]), which was validated by an independent cohort of 187 Stage III CRCs. In summary, the new low-coverage WGS protocol has high sensitivity, high resolution and low cost and the identified 17p-loss is an effective poor prognosis marker for Stage III patients.

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“…Recent genome profiling studies of both healthy and cancerous human tissues found a high prevalence of nuclear extra-chromosomal DNA (ecDNA) [1,2,3,4]. ecDNA occurs during episodes of chromosomal instability and contributes to cancer initiation and treatment resistance [5,6,7,8,9].…”

Section: Introductionmentioning

confidence: 99%

“…ecDNA occurs during episodes of chromosomal instability and contributes to cancer initiation and treatment resistance [5,6,7,8,9]. Double minute oncogene amplifications exist in 31.7% of all neuroblastoma and highly amplified extra-chromosomal KRAS copies appear at relapse of anti-EGFR targeted therapies [1,4,9]. Yet, the evolutionary fade Figure 1.…”

Section: Introductionmentioning

confidence: 99%

Stochastic dynamics of extra-chromosomal DNA

Pichugin

Huang

Werner

2019

Preprint

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Nuclear extra-chromosomal DNA (ecDNA) is highly prevalent in human tumours. ecDNA amplifications can promote accessible chromatin, oncogen over-expression and imply a worse clinical prognosis.Yet, little is known about the evolutionary process of ecDNA in human cancers. Here, we develop the theoretical foundation of the ecDNA somatic evolutionary process combining mathematical, computational and experimental approaches. We show that random ecDNA segregation leads to unintuitive dynamics even if ecDNA is under very strong positive selection. Patterns of inter-and intra-tumour ecDNA and chromosomal heterogeneity differ markedly and standard approaches are not directly applicable to quantify ecDNA evolution. We show that evolutionary informed modelling leads to testable predictions on how to distinguish positively selected from neutral ecDNA dynamics. Our predictions describe the dynamics of circular amplicons in GBM39 cell line experiments, suggesting a 300% fitness increase due to circular extra-chromosomal EGFRvI I I amplifications. Our work lies the basis for further studies to quantitate ecDNA somatic evolutionary processes.

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Exploring the landscape of focal amplifications in cancer using AmpliconArchitect

Cited by 225 publications

References 35 publications

Enhancer hijacking determines intra- and extrachromosomal circularMYCNamplicon architecture in neuroblastoma

Enhancer hijacking determines intra- and extrachromosomal circularMYCNamplicon architecture in neuroblastoma

Whole genome analysis identifies the association of TP53 genomic deletions with lower survival in Stage III colorectal cancer

Stochastic dynamics of extra-chromosomal DNA

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