Integrated genomic and epigenomic analysis of breast cancer brain metastasis

Bodour Salhia, Jeff Kiefer, Julianna T D Ross, Raghu Metapally, Rae Anne Martinez, Kyle N. Johnson, Danielle M. DiPerna, Kimberly M. Paquette, Sungwon Jung, Sara Nasser, Garrick Wallstrom, Waibhav Tembe, Angela Baker, John Carpten, Jim Resau, Timothy Ryken, Zita Sibenaller, Emanuel F. Petricoin, Lance A. Liotta, Ramesh K. RamanathanMichael E. Berens, Nhan L. Tran

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

The brain is a common site of metastatic disease in patients with breast cancer, which has few therapeutic options and dismal outcomes. The purpose of our study was to identify common and rare events that underlie breast cancer brain metastasis. We performed deep genomic profiling, which integrated gene copy number, gene expression and DNA methylation datasets on a collection of breast brain metastases. We identified frequent large chromosomal gains in 1q, 5p, 8q, 11q, and 20q and frequent broad-level deletions involving 8p, 17p, 21p and Xq. Frequently amplified and overexpressed genes included ATAD2, BRAF, DERL1, DNMTRB and NEK2A. The ATM, CRYAB and HSPB2 genes were commonly deleted and underexpressed. Knowledge mining revealed enrichment in cell cycle and G2/M transition pathways, which contained AURKA, AURKB and FOXM1. Using the PAM50 breast cancer intrinsic classifier, Luminal B, Her2+/ER negative, and basal-like tumors were identified as the most commonly represented breast cancer subtypes in our brain metastasis cohort. While overall methylation levels were increased in breast cancer brain metastasis, basal-like brain metastases were associated with significantly lower levels of methylation. Integrating DNA methylation data with gene expression revealed defects in cell migration and adhesion due to hypermethylation and downregulation of PENK, EDN3, and ITGAM. Hypomethylation and upregulation of KRT8 likely affects adhesion and permeability. Genomic and epigenomic profiling of breast brain metastasis has provided insight into the somatic events underlying this disease, which have potential in forming the basis of future therapeutic strategies.

Original languageEnglish (US)
Article numbere85448
JournalPLoS One
Volume9
Issue number1
DOIs
StatePublished - Jan 29 2014

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Epigenomics
epigenetics
Brain Neoplasms
metastasis
breast neoplasms
Brain
Breast Neoplasms
Neoplasm Metastasis
brain
genomics
DNA Methylation
Methylation
Genes
DNA methylation
Gene expression
methylation
Breast
breasts
Aurora Kinase A
Adhesion

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Salhia, B., Kiefer, J., Ross, J. T. D., Metapally, R., Martinez, R. A., Johnson, K. N., ... Tran, N. L. (2014). Integrated genomic and epigenomic analysis of breast cancer brain metastasis. PLoS One, 9(1), [e85448]. https://doi.org/10.1371/journal.pone.0085448

Integrated genomic and epigenomic analysis of breast cancer brain metastasis. / Salhia, Bodour; Kiefer, Jeff; Ross, Julianna T D; Metapally, Raghu; Martinez, Rae Anne; Johnson, Kyle N.; DiPerna, Danielle M.; Paquette, Kimberly M.; Jung, Sungwon; Nasser, Sara; Wallstrom, Garrick; Tembe, Waibhav; Baker, Angela; Carpten, John; Resau, Jim; Ryken, Timothy; Sibenaller, Zita; Petricoin, Emanuel F.; Liotta, Lance A.; Ramanathan, Ramesh K.; Berens, Michael E.; Tran, Nhan L.

In: PLoS One, Vol. 9, No. 1, e85448, 29.01.2014.

Research output: Contribution to journalArticle

Salhia, B, Kiefer, J, Ross, JTD, Metapally, R, Martinez, RA, Johnson, KN, DiPerna, DM, Paquette, KM, Jung, S, Nasser, S, Wallstrom, G, Tembe, W, Baker, A, Carpten, J, Resau, J, Ryken, T, Sibenaller, Z, Petricoin, EF, Liotta, LA, Ramanathan, RK, Berens, ME & Tran, NL 2014, 'Integrated genomic and epigenomic analysis of breast cancer brain metastasis', PLoS One, vol. 9, no. 1, e85448. https://doi.org/10.1371/journal.pone.0085448
Salhia B, Kiefer J, Ross JTD, Metapally R, Martinez RA, Johnson KN et al. Integrated genomic and epigenomic analysis of breast cancer brain metastasis. PLoS One. 2014 Jan 29;9(1). e85448. https://doi.org/10.1371/journal.pone.0085448
Salhia, Bodour ; Kiefer, Jeff ; Ross, Julianna T D ; Metapally, Raghu ; Martinez, Rae Anne ; Johnson, Kyle N. ; DiPerna, Danielle M. ; Paquette, Kimberly M. ; Jung, Sungwon ; Nasser, Sara ; Wallstrom, Garrick ; Tembe, Waibhav ; Baker, Angela ; Carpten, John ; Resau, Jim ; Ryken, Timothy ; Sibenaller, Zita ; Petricoin, Emanuel F. ; Liotta, Lance A. ; Ramanathan, Ramesh K. ; Berens, Michael E. ; Tran, Nhan L. / Integrated genomic and epigenomic analysis of breast cancer brain metastasis. In: PLoS One. 2014 ; Vol. 9, No. 1.
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