Identification of metastasis driver genes by massive parallel sequencing of successive steps of breast cancer progression

Anne Bruun Krøigård; Martin Jakob Larsen; Anne-Vibeke Lænkholm; Ann S Knoop; Jeanette Dupont Jensen; Martin Bak; Jan Mollenhauer; Mads Thomassen; Torben A Kruse

doi:10.1371/journal.pone.0189887

Identification of metastasis driver genes by massive parallel sequencing of successive steps of breast cancer progression

PLoS One. 2018 Jan 2;13(1):e0189887. doi: 10.1371/journal.pone.0189887. eCollection 2018.

Authors

Anne Bruun Krøigård^{1

2}, Martin Jakob Larsen^{1

2}, Anne-Vibeke Lænkholm³, Ann S Knoop⁴, Jeanette Dupont Jensen⁵, Martin Bak⁶, Jan Mollenhauer^{7

8}, Mads Thomassen^{1

2

7}, Torben A Kruse^{1

2

7}

Affiliations

¹ Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
² Human Genetics, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
³ Department of Pathology, Slagelse Hospital, Slagelse, Denmark.
⁴ Department of Oncology, Rigshospitalet, Copenhagen, Denmark.
⁵ Department of Oncology, Odense University Hospital, Odense, Denmark.
⁶ Department of Pathology, Odense University Hospital, Odense, Denmark.
⁷ Lundbeckfonden Center of Excellence NanoCAN, University of Southern Denmark, Odense, Denmark.
⁸ Molecular Oncology Group, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark.

Abstract

Cancer results from alterations at essential genomic sites and is characterized by uncontrolled cell proliferation, invasion and metastasis. Identification of driver genes of metastatic progression is essential, as metastases, not primary tumors, are fatal. To gain insight into the mutational concordance between different steps of malignant progression we performed exome sequencing and validation with targeted deep sequencing of successive steps of malignant progression from pre-invasive stages to asynchronous distant metastases in six breast cancer patients. Using the ratio of non-synonymous to synonymous mutations, a surprisingly large number of cancer driver genes, ranging between 3 and 145, were estimated to confer a selective advantage in the studied primary tumors. We report a substantial amount of metastasis specific mutations and a number of novel putative metastasis driver genes. Most notable are the DCC, ABCA13, TIAM2, CREBBP, BCL6B and ZNF185 genes, mainly mutated exclusively in metastases and highly likely driver genes of metastatic progression. We find different genes and pathways to be affected at different steps of malignant progression. The Adherens junction pathway is affected in four of the six studied patients and this pathway most likely plays a vital role in the metastatic process.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Breast Neoplasms / genetics
Breast Neoplasms / pathology*
Female
High-Throughput Nucleotide Sequencing / methods*
Humans
Neoplasm Metastasis / genetics*

Grants and funding

The project received funding from: Odense University Hospital Free Research Fund, Harboefonden, Aase og Ejnar Danielsen Fond, Fabrikant Einar Willumsens Mindelegat, Grosserer M. Brogaard og Hustrus Mindefond, Kong Christian Den Tiendes Fond, Dagmar Marshalls Fond, Axel Muusfeldts Fond, Kræftfonden, Raimond og Dagmar Ringgård-Bohns Fond, Grete og Sigurd Pedersens Fond, Syddansk Universitets Forskningsfond, Poul og Ellen Hertz’ Fond, Fonden til Lægevidenskabens Fremme, Grosserer A.V. Lykfeldt og Hustrus Legat, Familien Hede Nielsens Fond, Lykfeldts Legat, Dansk Kræftforskningsfond, Ulla og Mogens Folmer Andersens Fond, Ingeniør K. A. Rohde og Hustrus Legat, Krista og Viggo Petersens Fond, the Lundbeckfonden Center of Excellence NanoCAN grant, and the DAWN 2020 project grant from the SDU2020 Excellence program, Danish Strategic Research Counsil, DBCG-TIBCAT.