Genome doubling shapes the evolution and prognosis of advanced cancers

Bielski, Craig M.; Zehir, Ahmet; Penson, A.; Donoghue, Mark T.A.; Chatila, Walid K.; Armenia, Joshua; Chang, Matthew T.; Schram, Alison M.; Jonsson, Philip; Bandlamudi, Chaitanya; Razavi, Pedram; Iyer, Gopa; Robson, Mark E.; Stadler, Zsofia K.; Schultz, Nikolaus; Baselga, José; Solit, David B.; Hyman, David M.; Berger, Michael F.; Taylor, Barry S.

doi:10.1038/s41588-018-0165-1

Cited by 449 publications

(595 citation statements)

References 38 publications

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“…One solution is to exclude regions containing CNAs and build phylogenies from SNVs in diploid, or copy-neutral, regions. However, ≈90% of solid tumors are highly aneuploid 26 , containing extensive CNAs, and ≈30% of solid tumors have whole-genome duplications 27 . Identifying collections of SNVs with no possibility of overlapping CNAs during evolution of such tumors may be challenging.…”

Section: Missionmentioning

confidence: 99%

Single-cell tumor phylogeny inference with copy-number constrained mutation losses

Satas

Zaccaria

Mon

et al. 2019

Preprint

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Motivation: Single-cell DNA sequencing enables the measurement of somatic mutations in individual tumor cells, and provides data to reconstruct the evolutionary history of the tumor. Nearly all existing methods to construct phylogenetic trees from single-cell sequencing data use single-nucleotide variants (SNVs) as markers. However, most solid tumors contain copy-number aberrations (CNAs) which can overlap loci containing SNVs. Particularly problematic are CNAs that delete an SNV, thus returning the SNV locus to the unmutated state. Such mutation losses are allowed in some models of SNV evolution, but these models are generally too permissive, allowing mutation losses without evidence of a CNA overlapping the locus. Results:We introduce a novel loss-supported evolutionary model, a generalization of the infinite sites and Dollo models, that constrains mutation losses to loci with evidence of a decrease in copy number.We design a new algorithm, Single-Cell Algorithm for Reconstructing the Loss-supported Evolution of Tumors (SCARLET), that infers phylogenies from single-cell tumor sequencing data using the losssupported model and a probabilistic model of sequencing errors and allele dropout. On simulated data, we show that SCARLET outperforms current single-cell phylogeny methods, recovering more accurate trees and correcting errors in SNV data. On single-cell sequencing data from a metastatic colorectal cancer patient, SCARLET constructs a phylogeny that is both more consistent with the observed copynumber data and also reveals a simpler monooclonal seeding of the metastasis, contrasting with published reports of polyclonal seeding in this patient. SCARLET substantially improves single-cell phylogeny inference in tumors with CNAs, yielding new insights into the analysis of tumor evolution.Availability: Software is available at

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Section: Missionmentioning

confidence: 99%

Single-cell tumor phylogeny inference with copy-number constrained mutation losses

Satas

Zaccaria

Mon

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…[39][40][41] Whole genome sequencing of cancer showed that whole genome doubling (WGD) was an early event in over 40% of breast cancers and occurred significantly more frequently in TP53 mutated compared to TP53 wild type tumors. 42 Thus, in our HMEC models, p53 inactivation did not result in structural rearrangements, but favored genetic plasticity and laid the ground for genetic anomalies that occurred upon oncogene expression. Noticeably, shp53-CCNE1 and shp53-WNT1 became aneuploid and showed a significant increase in rearrangement levels after soft agar cloning.…”

Section: Discussionmentioning

confidence: 83%

“…Tetraploidy is considered as a prelude to large scale chromosomal aberrations in cancer . Whole genome sequencing of cancer showed that whole genome doubling (WGD) was an early event in over 40% of breast cancers and occurred significantly more frequently in TP53 mutated compared to TP53 wild type tumors . Thus, in our HMEC models, p53 inactivation did not result in structural rearrangements, but favored genetic plasticity and laid the ground for genetic anomalies that occurred upon oncogene expression.…”

Section: Discussionmentioning

confidence: 88%

Distinct oncogenes drive different genome and epigenome alterations in human mammary epithelial cells

Fonti

Saumet

Abi-Khalil

et al. 2019

Intl Journal of Cancer

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Molecular subtypes of breast cancer are defined on the basis of gene expression and genomic/epigenetic pattern differences. Different subtypes are thought to originate from distinct cell lineages, but the early activation of an oncogene could also play a role. It is difficult to discriminate the respective inputs of oncogene activation or cell type of origin. In this work, we wished to determine whether activation of distinct oncogenic pathways in human mammary epithelial cells (HMEC) could lead to different patterns of genetic and epigenetic changes. To this aim, we transduced shp53 immortalized HMECs in parallel with the CCNE1, WNT1 and RASv12 oncogenes which activate distinct oncogenic pathways and characterized them at sequential stages of transformation for changes in their genetic and epigenetic profiles. We show that initial activation of CCNE1, WNT1 and RASv12, in shp53 HMECs results in different and reproducible changes in mRNA and micro‐RNA expression, copy number alterations (CNA) and DNA methylation profiles. Noticeably, HMECs transformed by RAS bore very specific profiles of CNAs and DNA methylation, clearly distinct from those shown by CCNE1 and WNT1 transformed HMECs. Genes impacted by CNAs and CpG methylation in the RAS and the CCNE1/WNT1 clusters showed clear differences, illustrating the activation of distinct pathways. Our data show that early activation of distinct oncogenic pathways leads to active adaptive events resulting in specific sets of CNAs and DNA methylation changes. We, thus, propose that activation of different oncogenes could have a role in reshaping the genetic landscape of breast cancer subtypes.

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“…This suggests that cytokinesis failure is not the only mechanistic explanation for extra centrosome accumulation, or that there are yet unidentified centrosome reduction mechanisms at play. Moreover, even if not statistically significant, low CNI seems to be associated with WGD and hence with worse clinical prognosis 40 .…”

Section: The Cni Does Not Correlate With Proliferation Mitotic Indexmentioning

confidence: 97%

“…WGD-positive (near tetraploid) tumors contain a ploidy of 3.31 on average, while ploidy is closer to ~1.99 (near diploid) for WGD-negative tumors 41 . Centrosome amplification and WGD are hallmarks that have been associated, as both can be produced via the same mechanisms such as cytokinesis failure 40 . We therefore examined if CNI correlated with ploidy in our tumor cohort.…”

Section: The Cni Does Not Correlate With Proliferation Mitotic Indexmentioning

confidence: 99%

Low centrosome numbers correlate with higher aggressivity in ovarian cancer

Morretton

Herbette

Cosson

et al. 2019

Preprint

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Centrosome amplification has been described as a common feature of human cancers and it is known to promote tumorigenesis when induced in animals.However, little is known about the real status of centrosome numbers in human cancers and whether numerical alterations are solely associated with poor prognosis. To address this question, we have analyzed a large cohort of human epithelial ovarian cancers (EOCs) from 100 patients using state-of-the-art microscopy to determine the Centrosome-Nucleus Index (CNI) of each tumor. We found that EOCs are highly heterogeneous, with infrequent but strong centrosome amplifications leading to higher CNI than in healthy tissues. Strikingly, while a correlation between CNI and genomic alterations, such as aneuploidy or chromosome rearrangements could not be established, we found that high CNI correlates with increased patient survival and sensitivity to chemotherapy. Using ovarian cancer cellular models to manipulate centrosome numbers and Patient-Derived Xenografts (PDXs), we found that higher CNIs can positively impact the response to chemotherapy and inhibit cell dissemination. Our findings highlight a novel paradigm linking centrosome amplification to the inhibition of tumor progression.

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Genome doubling shapes the evolution and prognosis of advanced cancers

Cited by 449 publications

References 38 publications

Single-cell tumor phylogeny inference with copy-number constrained mutation losses

Single-cell tumor phylogeny inference with copy-number constrained mutation losses

Distinct oncogenes drive different genome and epigenome alterations in human mammary epithelial cells

Low centrosome numbers correlate with higher aggressivity in ovarian cancer

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