MECHANISMS GENERATING CANCER GENOME COMPLEXITY FROM A SINGLE CELL
DIVISION ERROR

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Abstract

The chromosome breakage-fusion-bridge (BFB) cycle is a mutational process that produces gene amplification and genome instability. Signatures of BFB cycles can be observed in cancer genomes alongside chromothripsis, another catastrophic mutational phenomenon. Here, we explain this association by elucidating a mutational cascade that is triggered by a single cell division error—chromosome bridge formation—that rapidly increases genomic complexity. We show that actomyosin forces are required for initial bridge breakage, following which chromothripsis accumulates beginning with aberrant interphase replication of bridge DNA. This is then followed by an unexpected burst of DNA replication in the next mitosis, generating extensive DNA damage. During this second cell division, broken bridge chromosomes frequently mis-segregate and form micronuclei, promoting additional chromothripsis. We further show that iterations of this mutational cascade generate the continuing evolution and sub-clonal heterogeneity characteristic of many human cancers.

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DNA replication in eukaryotic cells.

Stephen Bell, Anindya Dutta (2002)

The maintenance of the eukaryotic genome requires precisely coordinated replication of the entire genome each time a cell divides. To achieve this coordination, eukaryotic cells use an ordered series of steps to form several key protein assemblies at origins of replication. Recent studies have identified many of the protein components of these complexes and the time during the cell cycle they assemble at the origin. Interestingly, despite distinct differences in origin structure, the identity and order of assembly of eukaryotic replication factors is highly conserved across all species. This review describes our current understanding of these events and how they are coordinated with cell cycle progression. We focus on bringing together the results from different organisms to provide a coherent model of the events of initiation. We emphasize recent progress in determining the function of the different replication factors once they have been assembled at the origin.

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Single-cell transcriptomes from human kidneys reveal the cellular identity of renal tumors

Matthew D. Young, Thomas J. Mitchell, Felipe A. Vieira Braga … (2018)

Understanding tumor origins and the similarities and differences between organ-specific cancers is important for determining treatment options. Young et al. generated more than 72,000 single-cell transcriptomes from healthy and cancerous human kidneys. From these data, they determined that Wilms tumor, a pediatric kidney cancer, originates from aberrant fetal cells, whereas adult kidney cancers are likely derived from a specific subtype of proximal convoluted tubular cell. Science , this issue p. [Related article:] 594 Single-cell mRNAs of normal and cancerous kidney cells reveal the cellular identity of childhood and adult tumors. Messenger RNA encodes cellular function and phenotype. In the context of human cancer, it defines the identities of malignant cells and the diversity of tumor tissue. We studied 72,501 single-cell transcriptomes of human renal tumors and normal tissue from fetal, pediatric, and adult kidneys. We matched childhood Wilms tumor with specific fetal cell types, thus providing evidence for the hypothesis that Wilms tumor cells are aberrant fetal cells. In adult renal cell carcinoma, we identified a canonical cancer transcriptome that matched a little-known subtype of proximal convoluted tubular cell. Analyses of the tumor composition defined cancer-associated normal cells and delineated a complex vascular endothelial growth factor (VEGF) signaling circuit. Our findings reveal the precise cellular identities and compositions of human kidney tumors.

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Patterns of somatic structural variation in human cancer genomes

Yilong Li, Nicola D. Roberts, Jeremiah A. Wala … (2020)

A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments that range in size from kilobases to whole chromosomes 1–7 . Here we develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumour types 8 . Sixteen signatures of structural variation emerged. Deletions have a multimodal size distribution, assort unevenly across tumour types and patients, are enriched in late-replicating regions and correlate with inversions. Tandem duplications also have a multimodal size distribution, but are enriched in early-replicating regions—as are unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy-number gains and frequent inverted rearrangements. One prominent structure consists of 2–7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, and—in liver cancer—frequently activate the telomerase gene TERT. A wide variety of rearrangement processes are active in cancer, which generate complex configurations of the genome upon which selection can act.

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Journal

Journal ID (nlm-journal-id): 0404511

Journal ID (pubmed-jr-id): 7473

Journal ID (nlm-ta): Science

Journal ID (iso-abbrev): Science

Title: Science (New York, N.Y.)

ISSN (Print): 0036-8075

ISSN (Electronic): 1095-9203

Publication date Nihms-submitted: 27 May 2020

Publication date (Print): 17 April 2020

Publication date PMC-release: 10 July 2020

Volume: 368

Issue: 6488

Electronic Location Identifier: eaba0712

Affiliations

[1. ]Howard Hughes Medical Institute, Chevy Chase, MD, USA

[2. ]Department of Cell Biology, Harvard Medical School, Boston, MA, USA

[3. ]Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

[4. ]Department of Biomedical Informatics, Harvard Medical School, Boston, MA, USA

[5. ]Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA

[6. ]Wellcome Sanger Institute, Hinxton, Cambridgeshire, CB10 1SA, UK

[7. ]Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK

[8. ]Single-Cell Sequencing Program, Dana-Farber Cancer Institute, Boston, MA, USA

[9. ]Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

Author notes

[*]

These authors contributed equally to this work

[‡]

These authors contributed equally to this work

AUTHOR CONTRIBUTIONS

D.P., N.T.U., and C.-Z.Z. conceived the project. D.P. and N.T.U. designed the biological experiments, which were performed by A.M.C., L.D.L. and N.T.U. D.P., N.T.U., and C.-Z.Z. designed the sequencing experiments, which were performed by L.S. and N.T.U. C.-Z.Z. designed and performed the analysis of single-cell and bulk sequencing data of RPE-1 samples, with help from L.J.B. Low-pass single-cell CNV analysis was performed by R.T. and H.F.A. T.J.M., and K.J. contributed the data and analysis in Fig. 5C. A.S. contributed the data in Figs. S15C and S16D, and to early experiments on the project. D.P. and N.T.U. wrote the manuscript with edits from other authors.

[† ]Corresponding authors: Correspondence regarding biological experiments and requests for materials should be addressed to neilt_umbreit@ 123456dfci.harvard.edu and to david_pellman@ 123456dfci.harvard.edu , Correspondence regarding sequencing analysis and requests for sequencing data should be addressed to cheng-zhong_zhang@ 123456dfci.harvard.edu

Article

Manuscript ID: NIHMS1597028

DOI: 10.1126/science.aba0712

PMC ID: 7347108

PubMed ID: 32299917

SO-VID: e43733d2-7379-4603-8a45-cc4e2bce1c2d

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This work is licensed under a Creative Commons Attribution 4.0 International (CC BY 4.0) license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/ . This license does not apply to figures/photos/artwork or other content included in the article that is credited to a third party; obtain authorization from the rights holder before using such material

MECHANISMS GENERATING CANCER GENOME COMPLEXITY FROM A SINGLE CELL DIVISION ERROR

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Genome Integrity

Most cited references 64

DNA replication in eukaryotic cells.

Single-cell transcriptomes from human kidneys reveal the cellular identity of renal tumors

Patterns of somatic structural variation in human cancer genomes

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