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The breast pre-cancer atlas illustrates the molecular and micro-environmental diversity of ductal carcinoma in situ

View ORCID ProfileDaniela Nachmanson, Adam Officer, View ORCID ProfileHidetoshi Mori, Jonathan Gordon, Mark F. Evans, Joseph Steward, Huazhen Yao, Thomas O’Keefe, Farnaz Hasteh, Gary S. Stein, Kristen Jepsen, Donald L. Weaver, View ORCID ProfileGillian L. Hirst, Brian L. Sprague, View ORCID ProfileLaura J. Esserman, Alexander D. Borowsky, Janet L. Stein, View ORCID ProfileOlivier Harismendy
doi: https://doi.org/10.1101/2021.05.11.443641
Daniela Nachmanson
1Bioinformatics and Systems Biology Graduate Program, University of California San Diego
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Adam Officer
1Bioinformatics and Systems Biology Graduate Program, University of California San Diego
2Division of Biomedical Informatics, Department of Medicine, University of California San Diego
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Hidetoshi Mori
3Department of Pathology and Laboratory Medicine, Center for Immunology and Infectious Diseases, School of Medicine, University of California Davis
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Jonathan Gordon
4University of Vermont Cancer Center
5Department of Biochemistry, University of Vermont
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Mark F. Evans
4University of Vermont Cancer Center
6Department of Pathology and Laboratory Medicine, University of Vermont
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Joseph Steward
7Moores Cancer Center, University of California San Diego
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Huazhen Yao
8Institute for Genomic Medicine, University of California San Diego
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Thomas O’Keefe
9Department of Surgery, University of California San Diego
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Farnaz Hasteh
7Moores Cancer Center, University of California San Diego
10Department of Pathology, University of California San Diego
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Gary S. Stein
4University of Vermont Cancer Center
5Department of Biochemistry, University of Vermont
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Kristen Jepsen
8Institute for Genomic Medicine, University of California San Diego
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Donald L. Weaver
4University of Vermont Cancer Center
6Department of Pathology and Laboratory Medicine, University of Vermont
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Gillian L. Hirst
11Helen Diller Family Comprehensive Cancer Center, University of California San Francisco
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  • ORCID record for Gillian L. Hirst
Brian L. Sprague
4University of Vermont Cancer Center
12Department of Surgery, University of Vermont
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Laura J. Esserman
11Helen Diller Family Comprehensive Cancer Center, University of California San Francisco
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Alexander D. Borowsky
3Department of Pathology and Laboratory Medicine, Center for Immunology and Infectious Diseases, School of Medicine, University of California Davis
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Janet L. Stein
4University of Vermont Cancer Center
5Department of Biochemistry, University of Vermont
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Olivier Harismendy
2Division of Biomedical Informatics, Department of Medicine, University of California San Diego
7Moores Cancer Center, University of California San Diego
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  • ORCID record for Olivier Harismendy
  • For correspondence: oharismendy@ucsd.edu
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Abstract

Micro-environmental and molecular factors mediating the progression of Breast Ductal Carcinoma In Situ (DCIS) are not well understood, impeding the development of prevention strategies and the safe testing of treatment de-escalation. We addressed methodological barriers and characterized the mutational, transcriptional, histological and microenvironmental landscape across 85 multiple micro-dissected regions from 39 cases. Most somatic alterations, including whole genome duplications, were clonal, but genetic divergence increased with physical distance. Phenotypic and subtype heterogeneity frequently associated with underlying genetic heterogeneity and regions with low-risk features preceded those with high-risk features according to the inferred phylogeny. B- and T-lymphocytes spatial analysis identified 3 immune states, including an epithelial excluded state located preferentially at DCIS regions, and characterized by histological and molecular features of immune escape, independently from molecular subtypes. Such breast pre-cancer atlas with uniquely integrated observations will help scope future expansion studies and build finer models of outcomes and progression risk.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • updated abstract added missing references

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted June 07, 2021.
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The breast pre-cancer atlas illustrates the molecular and micro-environmental diversity of ductal carcinoma in situ
Daniela Nachmanson, Adam Officer, Hidetoshi Mori, Jonathan Gordon, Mark F. Evans, Joseph Steward, Huazhen Yao, Thomas O’Keefe, Farnaz Hasteh, Gary S. Stein, Kristen Jepsen, Donald L. Weaver, Gillian L. Hirst, Brian L. Sprague, Laura J. Esserman, Alexander D. Borowsky, Janet L. Stein, Olivier Harismendy
bioRxiv 2021.05.11.443641; doi: https://doi.org/10.1101/2021.05.11.443641
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The breast pre-cancer atlas illustrates the molecular and micro-environmental diversity of ductal carcinoma in situ
Daniela Nachmanson, Adam Officer, Hidetoshi Mori, Jonathan Gordon, Mark F. Evans, Joseph Steward, Huazhen Yao, Thomas O’Keefe, Farnaz Hasteh, Gary S. Stein, Kristen Jepsen, Donald L. Weaver, Gillian L. Hirst, Brian L. Sprague, Laura J. Esserman, Alexander D. Borowsky, Janet L. Stein, Olivier Harismendy
bioRxiv 2021.05.11.443641; doi: https://doi.org/10.1101/2021.05.11.443641

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