Distinct Classes of Complex Structural Variation Uncovered across Thousands of Cancer Genome Graphs

Hadi, Kevin; Yao, Xiaotong; Behr, Julie M.; Deshpande, Aditya; Xanthopoulakis, Charalampos; Tian, Huasong; Kudman, Sarah; Rosiene, Joel; Darmofal, Madison; DeRose, Joseph; Mortensen, Rick; Adney, Emily M.; Shaiber, Alon; Gajic, Zoran; Sigouros, Michael; K, Eng; Wala, Jeremiah A.; Wrzeszczyński, Kazimierz O.; Arora, Kanika; Shah, Minita; Emde, Anne Katrin; Felice, Vanessa; Frank, Mayu O.; Darnell, Robert B.; Ghandi, Mahmoud; Huang, Franklin W.; Dewhurst, Sally M.; Maciejowski, John; Lange, Titia de; Setton, J.; Riaz, Nadeem; Reis‐Filho, Jorge S.; Powell, Simon N.; Knowles, David A.; Reznik, Ed; Mishra, Bud; Beroukhim, Rameen; Zody, Michael C.; Robine, Nicolas; Oman, Kenji; Sanchez, Carissa A.; Kuhner, Mary K.; Smith, Lucian P.; Galipeau, Patricia C.; Paulson, Thomas G.; Reid, Brian J.; Xiao-hong, LI; Wilkes, David; Sboner, Andrea; Mosquera, Juan Miguel; Elemento, Olivier; Imieliński, Marcin

doi:10.1016/j.cell.2020.08.006

Cited by 181 publications

(271 citation statements)

References 70 publications

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“…SV features figure prominently in ESAD cases 23 . Using the same SV calling pipeline, we compared the SV features between NCO and CO with data from 416 ESAD cases 13,23 . SV burden was significantly higher in ESAD compared to CO, which was significantly higher than NCO (Fig.…”

Section: Development Of Complex Chromosomal Structural Variants Durinmentioning

confidence: 93%

Somatic whole genome dynamics of precancer in Barrett’s Esophagus

Paulson

Galipeau

Oman

et al. 2021

Preprint

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While the genomes of normal tissues undergo dynamic changes over time, little is understood about the temporal-spatial dynamics of genomes in premalignant tissues that progress to cancer compared to those that remain cancer-free. Here we use whole genome sequencing to contrast genomic alterations in 427 longitudinal samples from 40 patients with stable Barrett’s esophagus compared to 40 Barrett’s patients who progressed to esophageal adenocarcinoma (ESAD). We show the same somatic mutational processes were active in Barrett’s tissue regardless of outcome, with high levels of mutation, ESAD gene and focal chromosomal alterations, and similar mutational signatures. The critical distinction between stable Barrett’s versus those who progress to cancer is acquisition and expansion of TP53-/- cell populations having complex structural variants and high-level amplifications, which were detectable up to six years prior to a cancer diagnosis. These findings reveal the timing of common somatic genome dynamics in stable Barrett’s esophagus and define key genomic features specific to progression to esophageal adenocarcinoma, both of which are critical for cancer prevention and early detection strategies.

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Section: Development Of Complex Chromosomal Structural Variants Durinmentioning

confidence: 93%

Somatic whole genome dynamics of precancer in Barrett’s Esophagus

Paulson

Galipeau

Oman

et al. 2021

Preprint

Self Cite

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“…Current approaches for identifying these complex SVs require expense and time commitment because of the need for either the manual curation of WGS data or the use of computational tools requiring both CN and SV data to predict chromothripsis 1,8,9,34 . In order to circumvent these issues, we investigated CN signature approach for predicting the presence of chromothripsis.…”

Section: Discussionmentioning

confidence: 99%

“…Although the biological impact is likely similar across various malignancies, in MM and in other hematological malignancies, the structural complexity of each chromothripsis event is typically lower than seen in the solid cancers 1,4,5 . Specifically, the total focal CN gains within the regions of chromothripsis is lower than in solid organ cancer and in MM there is a lack of enrichment for double-minutes and other more catastrophic events such as typhonas 1,8 .…”

Section: Introductionmentioning

confidence: 98%

“…Chromothripsis, a catastrophic chromosomal shattering event associated with random rejoining, is emerging as strong and independent prognostic factor across multiple malignancies 1-7 . Reliable detection of chromothripsis requires whole genome sequencing (WGS) and the integration of both structural variants (SVs) and copy number (CN) data 1,2,4,8 .…”

Section: Introductionmentioning

confidence: 99%

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Copy number signatures predict chromothripsis and associate with poor clinical outcomes in patients with newly diagnosed multiple myeloma

Derkach

et al. 2020

Preprint

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Chromothripsis is detectable in 20-30% of newly diagnosed multiple myeloma (NDMM) patients and is emerging as a new independent adverse prognostic factor. In this study, we interrogate 752 NDMM patients using whole genome sequencing (WGS) to study the relationship of copy number (CN) signatures to chromothripsis and show they are highly associated. CN signatures are highly predictive of the presence of chromothripsis (AUC=0.90) and can be used to identify its adverse prognostic impact. The ability of CN signatures to predict the presence of chromothripsis was confirmed in a validation series of WGS comprised of 235 hematological cancers (AUC=0.97) and an independent series of 34 NDMM (AUC=0.87). We show that CN signatures can also be derived from whole exome data (WES) and using 677 cases from the same series of NDMM, we were able to predict both the presence of chromothripsis (AUC=0.82) and its adverse prognostic impact. CN signatures constitute a flexible tool to identify the presence of chromothripsis and is applicable to WES and WGS data.

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“…A key step in completing the puzzle of the aetiology of replication stress-derived CNAs will be resolving the copy number breakpoints and any associated structural genomic variations at base-pair resolution, which will provide important clues to the molecular pathways connecting replication stress to genomic instability. In turn such analyses will be important to discover the aetiology of disease-associated copy number and structural variations currently being uncovered at rapid rates from genome sequencing studies 48,49 .…”

Section: Discussionmentioning

confidence: 99%

DNA Replication Stress Generates Distinctive Landscapes of DNA Copy Number Alterations and Chromosome Scale Losses

Mazzagatti

Shaikh

Bakker

et al. 2019

Preprint

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Replication stress can drive genetic instability and is associated with chromosomal instability in cancer and during reprogramming of stem cells, however the exact mechanisms connecting replication stress to chromosome aberrations are not known. Here we use single cell DNA sequencing to precisely map DNA copy number alterations (CNAs) after one cell division cycle under replication stress in two diploid cell types to megabase pair resolution.Unexpectedly, we find that replication stress generates several distinct classes of CNAs, and that specific genomic regions convert to particular classes of CNA. By combining analyses of single cell replication timing and bulk gene expression from both cell types, we provide a comprehensive picture of the features and mechanisms converting replication stress to DNA copy number alterations. The breakpoints of large CNAs tend to be associated with late DNA replication timing, low surrounding gene expression and proximity to large or giant genes. By contrast, small amplifications show contrasting associations and may represent a new class of replication stress induced CNAs.These findings provide a platform to further dissect molecular mechanisms involved in the replication stress response and to gain insights into how replication stress can drive chromosomal instability in cancer.

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Distinct Classes of Complex Structural Variation Uncovered across Thousands of Cancer Genome Graphs

Cited by 181 publications

References 70 publications

Somatic whole genome dynamics of precancer in Barrett’s Esophagus

Somatic whole genome dynamics of precancer in Barrett’s Esophagus

Copy number signatures predict chromothripsis and associate with poor clinical outcomes in patients with newly diagnosed multiple myeloma

DNA Replication Stress Generates Distinctive Landscapes of DNA Copy Number Alterations and Chromosome Scale Losses

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