Integrated genomic and epigenomic analysis of breast cancer brain metastasis.
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.
Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
Bodour
B
Salhia
Collaborative Center for Bioinformatics, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
Jeff
J
Kiefer
Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
Julianna T D
JT
Ross
Collaborative Center for Bioinformatics, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
Raghu
R
Metapally
Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
Rae Anne
RA
Martinez
Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
Kyle N
KN
Johnson
Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
Danielle M
DM
DiPerna
Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
Kimberly M
KM
Paquette
Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
Sungwon
S
Jung
Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
Sara
S
Nasser
Center for Personalized Diagnostics, Biodesign Institute, Arizona State University, Tempe, Arizona, United States of America.
Garrick
G
Wallstrom
Collaborative Center for Bioinformatics, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
Waibhav
W
Tembe
Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
Angela
A
Baker
Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
John
J
Carpten
The Van Andel Research Institute, Grand Rapids, Michigan, United States of America.
Jim
J
Resau
Iowa Spine and Brain Institute, Iowa City, Iowa, United States of America.
Timothy
T
Ryken
Department of Radiation Biology, University of Iowa, Iowa City, Iowa, United States of America.
Zita
Z
Sibenaller
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia, United States of America.
Emanuel F
EF
Petricoin
Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia, United States of America.
Lance A
LA
Liotta
Virginia G. Piper Cancer Center, Scottsdale Healthcare, Scottsdale, Arizona, United States of America.
Ramesh K
RK
Ramanathan
Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
Michael E
ME
Berens
Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
Nhan L
NL
Tran
D001932:Brain Neoplasms / Q000235:genetics* / Q000556:secondary; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D002869:Chromosome Aberrations; D019175:DNA Methylation; D057225:Data Mining; D057890:Epigenomics; D005260:Female; D018628:Gene Dosage; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D009367:Neoplasm Staging; D012189:Retrospective Studies
D009363:Neoplasm Proteins