Hotspots of aberrant enhancer activity punctuate the colorectal cancer epigenome.
In addition to mutations in genes, aberrant enhancer element activity at non-coding regions of the genome is a key driver of tumorigenesis. Here, we perform epigenomic enhancer profiling of a cohort of more than forty genetically diverse human colorectal cancer (CRC) specimens. Using normal colonic crypt epithelium as a comparator, we identify enhancers with recurrently gained or lost activity across CRC specimens. Of the enhancers highly recurrently activated in CRC, most are constituents of super enhancers, are occupied by AP-1 and cohesin complex members, and originate from primed chromatin. Many activate known oncogenes, and CRC growth can be mitigated through pharmacologic inhibition or genome editing of these loci. Nearly half of all GWAS CRC risk loci co-localize to recurrently activated enhancers. These findings indicate that the CRC epigenome is defined by highly recurrent epigenetic alterations at enhancers which activate a common, aberrant transcriptional programme critical for CRC growth and survival.
Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, Ohio 44106, USA.
Andrea J
AJ
Cohen
Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, Ohio 44106, USA.
Alina
A
Saiakhova
Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, Ohio 44106, USA.|Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Olivia
O
Corradin
Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, Ohio 44106, USA.
Jennifer M
JM
Luppino
Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, Ohio 44106, USA.
Katreya
K
Lovrenert
Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, Ohio 44106, USA.
Cynthia F
CF
Bartels
Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, Ohio 44106, USA.|Department of Pathology, Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, Ohio 44106, USA.
James J
JJ
Morrow
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, Ohio 44195, USA.
Stephen C
SC
Mack
Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, Ohio 44106, USA.
Gursimran
G
Dhillon
Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Ave, Cleveland, Ohio 44106, USA.
Lydia
L
Beard
Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Ave, Cleveland, Ohio 44106, USA.
Lois
L
Myeroff
Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, Ohio 44195, USA.|Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Ave, Cleveland, Ohio 44106, USA.|Department of Colorectal Surgery, Cleveland Clinic Foundation, 9500 Euclid Ave, Cleveland, Ohio 44195, USA.
Matthew F
MF
Kalady
Department of Pathology, Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, Ohio 44106, USA.|Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Ave, Cleveland, Ohio 44106, USA.|Department of Medicine, University Hospitals Cleveland Medical Center, 11100 Euclid Ave, Cleveland, Ohio 44106, USA.
Joseph
J
Willis
Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, Massachusetts 02215, USA.|Department of Medicine, Harvard Medical School, 25 Shattuck St, Boston, Massachusetts 02115, USA.
James E
JE
Bradner
Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, Ohio 44106, USA.|Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Ave, Cleveland, Ohio 44106, USA.|Department of Pharmacology, Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, Ohio 44106, USA.
Ruth A
RA
Keri
Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, Ohio 44106, USA.|Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Ave, Cleveland, Ohio 44106, USA.|Department of Medicine, University Hospitals Cleveland Medical Center, 11100 Euclid Ave, Cleveland, Ohio 44106, USA.
Nathan A
NA
Berger
Genome Engineering and iPSC Center, Department of Genetics, Washington University, 4515 McKinley Building, St. Louis, Missouri 63110, USA.
Shondra M
SM
Pruett-Miller
Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, Ohio 44106, USA.|Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Ave, Cleveland, Ohio 44106, USA.|Department of Medicine, University Hospitals Cleveland Medical Center, 11100 Euclid Ave, Cleveland, Ohio 44106, USA.
Sanford D
SD
Markowitz
Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, 10900 Euclid Ave, Cleveland, Ohio 44106, USA.|Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, Ohio 44195, USA.|Case Comprehensive Cancer Center, Case Western Reserve University, 10900 Euclid Ave, Cleveland, Ohio 44106, USA.
Peter C
PC
Scacheri
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000601:surgery; D066264:Datasets as Topic; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D057890:Epigenomics / Q000379:methods; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci / Q000235:genetics*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D046888:Tissue Array Analysis; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D018808:Transcription Factor AP-1