Oncotarget

Research Papers:

Remarkable similarities of chromosomal rearrangements between primary human breast cancers and matched distant metastases as revealed by whole-genome sequencing

Man-Hung Eric Tang _, Malin Dahlgren, Christian Brueffer, Tamara Tjitrowirjo, Christof Winter, Yilun Chen, Eleonor Olsson, Kun Wang, Therese Törngren, Martin Sjöström, Dorthe Grabau, Pär-Ola Bendahl, Lisa Rydén, Emma Niméus, Lao H. Saal, Åke Borg and Sofia K. Gruvberger-Saal

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Oncotarget. 2015; 6:37169-37184. https://doi.org/10.18632/oncotarget.5951

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Abstract

Man-Hung Eric Tang1,*, Malin Dahlgren1,*, Christian Brueffer1, Tamara Tjitrowirjo1, Christof Winter1, Yilun Chen1, Eleonor Olsson1, Kun Wang1, Therese Törngren1, Martin Sjöström1,2, Dorthe Grabau3, Pär-Ola Bendahl1, Lisa Rydén2, Emma Niméus1,2, Lao H. Saal1,4, Åke Borg1,4 and Sofia K. Gruvberger-Saal1

1 Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden

2 Division of Surgery, Department of Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden

3 Department of Pathology, Skåne University Hospital, Lund, Sweden

4 CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden

* These authors have contributed equally to this work

Correspondence to:

Sofia K. Gruvberger-Saal, email:

Keywords: breast cancer, metastasis, whole-genome sequencing, chromosomal rearrangements, chromothripsis

Received: May 02, 2015 Accepted: September 17, 2015 Published: October 02, 2015

Abstract

To better understand and characterize chromosomal structural variation during breast cancer progression, we enumerated chromosomal rearrangements for 11 patients by performing low-coverage whole-genome sequencing of 11 primary breast tumors and their 13 matched distant metastases. The tumor genomes harbored a median of 85 (range 18-404) rearrangements per tumor, with a median of 82 (26-310) in primaries compared to 87 (18-404) in distant metastases. Concordance between paired tumors from the same patient was high with a median of 89% of rearrangements shared (range 61-100%), whereas little overlap was found when comparing all possible pairings of tumors from different patients (median 3%). The tumors exhibited diverse genomic patterns of rearrangements: some carried events distributed throughout the genome while others had events mostly within densely clustered chromothripsis-like foci at a few chromosomal locations. Irrespectively, the patterns were highly conserved between the primary tumor and metastases from the same patient. Rearrangements occurred more frequently in genic areas than expected by chance and among the genes affected there was significant enrichment for cancer-associated genes including disruption of TP53, RB1, PTEN, and ESR1, likely contributing to tumor development. Our findings are most consistent with chromosomal rearrangements being early events in breast cancer progression that remain stable during the development from primary tumor to distant metastasis.


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