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Title: The topography of mutational processes in breast cancer genomes

Journal Article · · Nature Communications
DOI:https://doi.org/10.1038/ncomms11383· OSTI ID:1256099
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  1. European Bioinformatics Institute, Cambridgeshire (United Kingdom)
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Wellcome Trust Sanger Institute, Cambridge (United Kingdom)
  3. Wellcome Trust Sanger Institute, Cambridge (United Kingdom)
  4. Lund Univ., Lund (Sweden)
  5. Erasmus Univ. Medical Center, Rotterdam (The Netherlands)
  6. Radboud Univ., Nijmegen (The Netherlands)
  7. Hanyang Univ., Seoul (South Korea)
  8. Univ. Libre de Bruxelles, Brussels (Belgium)
  9. European Bioinformatics Institute, Cambridgeshire (United Kingdom); UT MD Anderson Cancer Center, Houston, TX (United States)
  10. Radboud Univ. Medical Center, Nijmegen (The Netherlands)
  11. Univ. of Antwerp, Antwerp (Belgium)
  12. Univ. of Queensland, Queensland (Australia); The Royal Brisbane and Women's Hospital, Queensland (Australia)
  13. Univ. of Iceland (Iceland)
  14. Univ. of Texas MD Anderson Cancer Center, Houston, TX (United States); Univ. of Dundee, Dundee (United Kingdom)
  15. Academic Medical Center, Amsterdam (The Netherlands)
  16. Oslo Univ. Hospital, The Norwegian Radium Hospital, Oslo (Norway); Univ. of Oslo, Oslo (Norway)
  17. Brigham and Women's Hospital, Boston, MA (United States); Dana-Farber Cancer Institute, Boston, MA (United States)
  18. Centre Leon Berard, Lyon Cedex (France)
  19. MRC Lab. of Molecular Biology, Cambridge (United Kingdom)
  20. Wellcome Trust Sanger Institute, Cambridge (United Kingdom); Cambridge Univ. Hospitals NHS Foundation Trust, Cambridge (United Kingdom)
+ Show Author Affiliations

Somatic mutations in human cancers show unevenness in genomic distribution that correlate with aspects of genome structure and function. These mutations are, however, generated by multiple mutational processes operating through the cellular lineage between the fertilized egg and the cancer cell, each composed of specific DNA damage and repair components and leaving its own characteristic mutational signature on the genome. Using somatic mutation catalogues from 560 breast cancer whole-genome sequences, here we show that each of 12 base substitution, 2 insertion/deletion (indel) and 6 rearrangement mutational signatures present in breast tissue, exhibit distinct relationships with genomic features relating to transcription, DNA replication and chromatin organization. This signature-based approach permits visualization of the genomic distribution of mutational processes associated with APOBEC enzymes, mismatch repair deficiency and homologous recombinational repair deficiency, as well as mutational processes of unknown aetiology. Lastly, it highlights mechanistic insights including a putative replication-dependent mechanism of APOBEC-related mutagenesis.

Research Organization:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
USDOE
Grant/Contract Number:
AC52-06NA25396
OSTI ID:
1256099
Report Number(s):
LA-UR-15-26421
Journal Information:
Nature Communications, Vol. 7; ISSN 2041-1723
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 169 works
Citation information provided by
Web of Science

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  • The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/wcvb-k036
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Cited By (98)

Intratumor heterogeneity defines treatment-resistant HER2+ breast tumors journal September 2018
Cancer chromosome breakpoints cluster in gene-rich genomic regions journal December 2018
Germline variants and somatic mutation signatures of breast cancer across populations of African and European ancestry in the US and Nigeria journal June 2019
Distribution and difference of APOBEC‐induced mutations in the TpCpW context of HBV DNA between HCC and non‐HCC journal August 2019
Landscape of somatic mutations in 560 breast cancer whole-genome sequences journal May 2016
The DNA cytosine deaminase APOBEC3H haplotype I likely contributes to breast and lung cancer mutagenesis journal September 2016
A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers journal January 2017
Reduced mutation rate in exons due to differential mismatch repair journal November 2017
HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures journal March 2017
Hereditary breast and ovarian cancer: new genes in confined pathways journal August 2016
Mutational processes contributing to the development of multiple myeloma journal August 2019
Mutational signatures reveal the dynamic interplay of risk factors and cellular processes during liver tumorigenesis journal November 2017
Validating the concept of mutational signatures with isogenic cell models journal May 2018
Characterization of Nigerian breast cancer reveals prevalent homologous recombination deficiency and aggressive molecular features journal October 2018
Replication timing and epigenome remodelling are associated with the nature of chromosomal rearrangements in cancer journal January 2019
Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation journal April 2019
Uncovering the signaling landscape controlling breast cancer cell migration identifies novel metastasis driver genes journal July 2019
The Rad51 paralogs facilitate a novel DNA strand specific damage tolerance pathway journal August 2019
5-Fluorouracil treatment induces characteristic T>G mutations in human cancer journal October 2019
The repertoire of mutational signatures in human cancer journal February 2020
The genomic landscape of metastatic breast cancer highlights changes in mutation and signature frequencies journal September 2019
The mutational footprints of cancer therapies journal November 2019
A practical framework and online tool for mutational signature analyses show intertissue variation and driver dependencies journal February 2020
Intragenomic variability and extended sequence patterns in the mutational signature of ultraviolet light journal September 2019
Computational approaches for discovery of mutational signatures in cancer journal July 2017
Detecting presence of mutational signatures in cancer with confidence journal September 2017
Error-prone bypass of DNA lesions during lagging strand replication is a common source of germline and cancer mutations posted_content May 2018
Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation journal November 2018
Modelling double strand break susceptibility to interrogate structural variation in cancer posted_content October 2018
Intragenomic variability and extended sequence patterns in the mutational signature of ultraviolet light posted_content May 2019
Mutational signatures are jointly shaped by DNA damage and repair posted_content February 2020
An integrative ENCODE resource for cancer genomics journal July 2019
Learning mutational signatures and their multidimensional genomic properties with TensorSignatures posted_content June 2020
APOBEC3A/B-induced mutagenesis is responsible for 20% of heritable mutations in the TpCpW context journal December 2016
Somatic evolution and global expansion of an ancient transmissible cancer lineage journal August 2019
APOBEC mutation drives early-onset squamous cell carcinomas in recessive dystrophic epidermolysis bullosa journal August 2018
Within-Host Variations of Human Papillomavirus Reveal APOBEC Signature Mutagenesis in the Viral Genome journal March 2018
Polyomavirus T Antigen Induces APOBEC3B Expression Using an LXCXE-Dependent and TP53-Independent Mechanism journal February 2019
Therapy-induced mutations drive the genomic landscape of relapsed acute lymphoblastic leukemia journal January 2020
Therapeutic landscape in mutational triple negative breast cancer journal July 2018
Reactivation of dormant anti-tumor immunity – a clinical perspective of therapeutic immune checkpoint modulation journal January 2017
Chromatin loop anchors are associated with genome instability in cancer and recombination hotspots in the germline journal July 2018
Mutational signature distribution varies with DNA replication timing and strand asymmetry journal September 2018
Recurrent mutations at estrogen receptor binding sites alter chromatin topology and distal gene expression in breast cancer journal November 2018
Modeling double strand break susceptibility to interrogate structural variation in cancer journal February 2019
Hidden Markov models lead to higher resolution maps of mutation signature activity in cancer journal July 2019
Network-based approaches elucidate differences within APOBEC and clock-like signatures in breast cancer journal May 2020
Correlation of gene expression and associated mutation profiles of APOBEC3A, APOBEC3B, REV1, UNG, and FHIT with chemosensitivity of cancer cell lines to drug treatment journal April 2018
Recent advances in understanding the complexities of metastasis journal January 2018
Recent advances in understanding the complexities of metastasis journal January 2018
Repair of multiple simultaneous double-strand breaks causes bursts of genome-wide clustered hypermutation journal September 2019
APOBEC3A is a prominent cytidine deaminase in breast cancer journal December 2019
The APOBEC3 genes and their role in cancer: insights from human papillomavirus journal May 2019
Perturbations in the Replication Program Contribute to Genomic Instability in Cancer journal May 2017
Chromatin Dynamics in Genome Stability: Roles in Suppressing Endogenous DNA Damage and Facilitating DNA Repair journal July 2017
Perturbation of base excision repair sensitizes breast cancer cells to APOBEC3 deaminase-mediated mutations journal January 2020
Error-prone bypass of DNA lesions during lagging-strand replication is a common source of germline and cancer mutations journal December 2018
APOBEC3A/B-induced mutagenesis is responsible for 20% of heritable mutations in the TpCpW context posted_content May 2016
Computational approaches for discovery of mutational signatures in cancer posted_content June 2017
Chromatin loop anchors are associated with genome instability in cancer and recombination hotspots in the germline journal July 2017
Polyomavirus T-Antigen Induces APOBEC3B Expression using a LXCXE-Dependent and TP53-Independent Mechanism journal May 2018
Network-based approaches elucidate differences within APOBEC and clock-like signatures in breast cancer posted_content May 2019
Detection and genomic characterization of a mammary-like adenocarcinoma journal September 2017
Landscape of somatic mutations in 560 breast cancer whole-genome sequences. journalarticle January 2016
HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. text January 2017
Recurrent Mutations At Estrogen Receptor Binding Sites Alter Chromatin Topology And Distal Gene Expression In Breast Cancer text January 2018
The mutational footprints of cancer therapies posted_content June 2019
BeWith: A Between-Within method to discover relationships between cancer modules via integrated analysis of mutual exclusivity, co-occurrence and functional interactions journal October 2017
Intratumor heterogeneity defines treatment-resistant HER2+ breast tumors. text January 2018
The repertoire of mutational signatures in human cancer text January 2020
Recurrent Mutations At Estrogen Receptor Binding Sites Alter Chromatin Topology And Distal Gene Expression In Breast Cancer text January 2018
Detecting presence of mutational signatures in cancer with confidence posted_content May 2017
Hidden Markov Models Lead to Higher Resolution Maps of Mutation Signature Activity in Cancer posted_content August 2018
Computational approaches for discovery of mutational signatures in cancer. text January 2019
Validating the concept of mutational signatures with isogenic cell models. text January 2018
A somatic-mutational process recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers in breast cancers text January 2017
Mutational signatures are jointly shaped by DNA damage and repair journal May 2020
An integrative ENCODE resource for cancer genomics journal July 2020
Mutational signatures are jointly shaped by DNA damage and repair. text January 2020
Multimodal Assessment of Estrogen Receptor mRNA Profiles to Quantify Estrogen Pathway Activity in Breast Tumors journal April 2017
The genomics of oxidative DNA damage, repair, and resulting mutagenesis journal January 2020
ESR1 mutations: Moving towards guiding treatment decision-making in metastatic breast cancer patients journal January 2017
A Sticky Multinomial Mixture Model of Strand-Coordinated Mutational Processes in Cancer journal March 2020
Replication stress response in cancer stem cells as a target for chemotherapy journal December 2018
Erratum: Whole-genome sequencing of chronic lymphocytic leukaemia reveals distinct differences in the mutational landscape between IgHVmut and IgHVunmut subgroups journal November 2017
Mismatch repair prefers exons journal November 2017
Nuclear topology modulates the mutational landscapes of cancer genomes journal October 2017
An integrative bioinformatics approach reveals coding and non-coding gene variants associated with gene expression profiles and outcome in breast cancer molecular subtypes journal March 2018
Author Correction: Characterization of Nigerian breast cancer reveals prevalent homologous recombination deficiency and aggressive molecular features journal January 2019
Breast cancers are rare diseases—and must be treated as such journal April 2017
The evolution of hematopoietic cells under cancer therapy journal October 2020
Uncovering the signaling landscape controlling breast cancer cell migration identifies splicing factor PRPF4B as a metastasis driver journal December 2018
DNA Repair Footprint Uncovers Contribution of DNA Repair Mechanism to Mutational Signatures conference November 2019
Progressive APOBEC3B mRNA expression in distant breast cancer metastases journal January 2017
From genome integrity to cancer. journalarticle January 2019
DNA Repair Pathway Alterations in Bladder Cancer journal March 2017
Risks at the DNA Replication Fork: Effects upon Carcinogenesis and Tumor Heterogeneity journal January 2017
BeWith: A Between-Within Method to Discover Relationships between Cancer Modules via Integrated Analysis of Mutual Exclusivity, Co-occurrence and Functional Interactions text January 2017

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