Small genomic insertions form enhancers that misregulate oncogenes.
The non-coding regions of tumour cell genomes harbour a considerable fraction of total DNA sequence variation, but the functional contribution of these variants to tumorigenesis is ill-defined. Among these non-coding variants, somatic insertions are among the least well characterized due to challenges with interpreting short-read DNA sequences. Here, using a combination of Chip-seq to enrich enhancer DNA and a computational approach with multiple DNA alignment procedures, we identify enhancer-associated small insertion variants. Among the 102 tumour cell genomes we analyse, small insertions are frequently observed in enhancer DNA sequences near known oncogenes. Further study of one insertion, somatically acquired in primary leukaemia tumour genomes, reveals that it nucleates formation of an active enhancer that drives expression of the LMO2 oncogene. The approach described here to identify enhancer-associated small insertion variants provides a foundation for further study of these abnormalities across human cancers.
Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, Massachusetts 02142, USA.
Brian J
BJ
Abraham
Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, Massachusetts 02142, USA.
Denes
D
Hnisz
Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, Massachusetts 02142, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Abraham S
AS
Weintraub
Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, Massachusetts 02142, USA.
Nicholas
N
Kwiatkowski
Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, Massachusetts 02142, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Charles H
CH
Li
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.|Division of Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02115, USA.
Zhaodong
Z
Li
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.|Division of Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02115, USA.
Nina
N
Weichert-Leahey
Department of Haematology, UCL Cancer Institute, University College London, London WC1E 6DD, UK.
Sunniyat
S
Rahman
Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Yu
0000-0001-8928-2558
Y
Liu
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.|Division of Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02115, USA.
Julia
J
Etchin
Key Laboratory of Pediatric Hematology &Oncology Ministry of Health, Department of Hematology &Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.|Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
Benshang
B
Li
Key Laboratory of Pediatric Hematology &Oncology Ministry of Health, Department of Hematology &Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.|Pediatric Translational Medicine Institute, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
Shuhong
S
Shen
Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, Massachusetts 02142, USA.
Tong Ihn
TI
Lee
Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Jinghui
J
Zhang
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA.|Division of Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02115, USA.
A Thomas
AT
Look
Department of Haematology, UCL Cancer Institute, University College London, London WC1E 6DD, UK.
Marc R
MR
Mansour
Whitehead Institute for Biomedical Research, 455 Main Street, Cambridge, Massachusetts 02142, USA.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Richard A
0000-0001-8855-8647
RA
Young
D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D004742:Enhancer Elements, Genetic; D015973:Gene Expression Regulation, Leukemic; D015894:Genome, Human; D006801:Humans; D007223:Infant; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics; D016254:Mutagenesis, Insertional / Q000235:genetics*; D009857:Oncogenes; D015203:Reproducibility of Results; D055815:Young Adult