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Cis-regulatory somatic mutations andgene-expression alteration in B-cell lymphomas
A. Mathelier, C. Lefebvre, A.W. Zhang, D.J. Arenilas, J. Ding,W.W. Wasserman, and S.P. Shah
Genome Biology, 2015, 16:84
2015 June 8th
anthony.mathelier@gmail.com @AMathelier
1
A cancer gene discovery gap
M.S. Lawrence et al.,Nature, 2013.
I Highly mutated cancer genes revealed through The CancerGenome Atlas project.
I Still a discovery gap in the search of new cancer genes.I We assert this gap can be partially filled through the analysis
of the non-coding genome.2
Cis-regulatory mutations may impact gene expression
Variation
TF
..GATCC.. ..GAACC..
TF
TFBS
adapted from W. Shi’s figure
One needs to accurately locate TFBSs to identify and characterizethe regulatory sequences controlling specific genes transcription.
3
Cis-regulatory mutations may impact gene expression
Variation
TF
..GATCC.. ..GAACC..
TF
TFBS
adapted from W. Shi’s figure
One needs to accurately locate TFBSs to identify and characterizethe regulatory sequences controlling specific genes transcription.
3
Predicting cis-regulatory elements genome wide
...gctaaGTAACAATgcgca......cttaaGTAAACATcgctc...
...ccaatGTAAACAAacgga...
MANTA
Adapted from Szalkowski and Schmid.Briefings in Bioinfomatics, 2010
Mathelier et al.,Nucleic Acids Research, 2014.
4
TFBSs defined as cis-regulatory elements
I 477 ChIP-seq data from ENCODE and literature
I 103 TFs with a JASPAR2014 TF binding profiles
I 76,160,599bp in TFBSs predicted in ChIP-seq peaks(∼2% of the human genome)
5
Somatic cis-regulatory mutations in B-cell lymphomas
I Whole genome sequence for 84 B-cell lymphoma patientsamples with matched control samples :
I cohort 1 : 40 diffuse large B-cell lymphomas (DLBCL)I cohort 2 : 44 of mixed histology – 14 Burkitt lymphomas, 15
DLBCLs, 1 primary mediastinal B-cell lymphoma (PMBCL),and 14 follicular lymphomas (FL)
I 406,611 SNVs and 15,739 indels in samples from cohort 1
I 282,636 SNVs and 8,080 indels in samples from cohort 2
I RNA-seq for the cancer samples
Richter et al., Nat. Genetics, 2012 ; Morin et al., Blood, 2013
6
Promoters are frequent targets of cis-regulatory mutationsA BCohort1 Cohort2
1
2
3
4
5
6
7
89
10
11
12
13
14
15
16
17
18
19
20
21
22
x
y
HIST1H1B
ST6GAL1
TMSB
4X
ZFP36L1
NEDD9
BCL7A
RHOH
BIRC3
CIITA
IGLL5
BTG
2
SGK1
CD74
BCL2
BCL6
1
2
3
4
5
6
7
89
10
11
12
13
14
15
16
17
18
19
20
21
22
x
y
HIST1H1C
HIST1H1E
TMSB
4X
ZFP36L1
BCL2L11
BZRAP1
DNMT1
ZNF860
NCOA3
FOXO
1
BACH2
CXCR4
DUSP2
RFTN1
TCL1A
BCL7A
SOCS1
SEPT9
P2RX5
S1PR2
RHOH
EPS15
BIRC3
CIITA
DTX1
IGLL5
BTG
2
BTG1 SGK1
CD74CD83
BCL2
BCL6
PIM1
MYC
B2M
IRF1IRF4
LTB
ID3
p = 1.16 x 10-75 p = 3.28 x 10-156
I 12 genes targeted in both cohorts independentlyI Additional 13 genes from combined cohorts not previously
described as hypermutated−→ 6 of them exclusively mutated in their promoters
7
Promoters are frequent targets of cis-regulatory mutationsA BCohort1 Cohort2
1
2
3
4
5
6
7
89
10
11
12
13
14
15
16
17
18
19
20
21
22
x
y
HIST1H1B
ST6GAL1
TMSB
4X
ZFP36L1
NEDD9
BCL7A
RHOH
BIRC3
CIITA
IGLL5
BTG
2
SGK1
CD74
BCL2
BCL6
1
2
3
4
5
6
7
89
10
11
12
13
14
15
16
17
18
19
20
21
22
x
y
HIST1H1C
HIST1H1E
TMSB
4X
ZFP36L1
BCL2L11
BZRAP1
DNMT1
ZNF860
NCOA3
FOXO
1
BACH2
CXCR4
DUSP2
RFTN1
TCL1A
BCL7A
SOCS1
SEPT9
P2RX5
S1PR2
RHOH
EPS15
BIRC3
CIITA
DTX1
IGLL5
BTG
2
BTG1 SGK1
CD74CD83
BCL2
BCL6
PIM1
MYC
B2M
IRF1IRF4
LTB
ID3
p = 1.16 x 10-75 p = 3.28 x 10-156
I 12 genes targeted in both cohorts independentlyI Additional 13 genes from combined cohorts not previously
described as hypermutated−→ 6 of them exclusively mutated in their promoters
7
Promoters of apoptic, B-cell, and cancer pathway genesare frequent targets of cis-regulatory mutations
Cohort1
lymphoma
small cell lung cancer
apoptosis
in apoptotic signaling
role of mitochondria
hiv-1 nef: negative
effector of fas and tnf
keratinocyte differentiation
ceramide signaling pathway
regulation of B cell
proliferation
positive regulation of B
cell proliferation
lymphocyte differentiation negative
regulation of lymphocyte apoptotic process
leukocyte activation
negative regulation of B cell apoptotic
process
regulation of B cell activation
leukocyte differentiation
positive regulation of lymphocyte proliferation
regulation of cell growth
lymphocyte activation
T cell differentiation
positive regulation of B cell activation
negative regulation of intracellular
signal transduction
positive regulation of leukocyte
proliferation
regulation of type 2 immune
response
regulation of B cell apoptotic
process
negative regulation of T
cell differentiation
positive regulation of mononuclear
cell proliferation
GO BiologicalProcess OMIM
KEGGPathway BioCarta
FDR < 0.05
8
Landscape of mutations and altered gene expression
mutationTFBSProtein-coding exon
TSS
A
B
C
xseq input
PC and disrupting TFBS
Protein coding (PC)
PC and TFBSDisrupting TFBS
TFBS
MYCEYS
TP53PTPRD
SMARCA4BCL6RYR2ITPKBWWC1
FCGBPSGK1
TBL1XR1ID3
CSMD3SIN3A
VPS13CUNC5D
NBASMTOR
PPP1R16BUSP25ASCC3GPHN
DHX35PEX2
XRCC4PXDNJRKL
WHSC1L1FBXW11
SRP72CRIM1FOXO1DGKDPHIP
PYGLUSP15BRD2
C2CD3LMO4FMN2
SRFBP1N4BP2CCNG1RHOA
DUSP2TGFBR2ARRDC3CADPS2
PIM1STIM2
GNA13
SA32
1012
SA32
0920
SA32
0824
SA32
0932
SA32
1004
SA32
0860
SA32
0992
SA32
0830
SA32
1030
SA32
0914
SA32
0842
SA32
0818
SA32
0980
SA32
0998
SA32
0848
SA32
0866
SA32
1106
SA32
0872
SA32
1119
SA32
0968
SA32
0962
SA32
0944
SA32
1050
SA32
1048
SA32
0956
SA32
1021
SA32
1103
SA32
0836
SA32
0902
SA32
1128
SA32
0974 0 2 4 6 8 10 12
0
5
10
15
20Cohort2
Ding et al., submitted.
9
Landscape of mutations and altered gene expression
mutationTFBSProtein-coding exon
TSS
A
B
C
xseq input PC and disrupting TFBS
Protein coding (PC)
PC and TFBSDisrupting TFBS
TFBS
MYCEYS
TP53PTPRD
SMARCA4BCL6RYR2ITPKBWWC1
FCGBPSGK1
TBL1XR1ID3
CSMD3SIN3A
VPS13CUNC5D
NBASMTOR
PPP1R16BUSP25ASCC3GPHN
DHX35PEX2
XRCC4PXDNJRKL
WHSC1L1FBXW11
SRP72CRIM1FOXO1DGKDPHIP
PYGLUSP15BRD2
C2CD3LMO4FMN2
SRFBP1N4BP2CCNG1RHOA
DUSP2TGFBR2ARRDC3CADPS2
PIM1STIM2
GNA13
SA32
1012
SA32
0920
SA32
0824
SA32
0932
SA32
1004
SA32
0860
SA32
0992
SA32
0830
SA32
1030
SA32
0914
SA32
0842
SA32
0818
SA32
0980
SA32
0998
SA32
0848
SA32
0866
SA32
1106
SA32
0872
SA32
1119
SA32
0968
SA32
0962
SA32
0944
SA32
1050
SA32
1048
SA32
0956
SA32
1021
SA32
1103
SA32
0836
SA32
0902
SA32
1128
SA32
0974 0 2 4 6 8 10 12
0
5
10
15
20Cohort2
9
Predicted genes and their deregulated interactors areenriched for pathways related to cancer
Cohort2
phosphatidylinositol signaling system
chronic myeloid leukemia
gliomahuntingtons disease
focal adhesion pancreatic cancer
small cell lung cancer
endometrial cancer
non small cell lung cancer
colorectal cancer
cell cycle
prostate cancer
calcium signaling pathway
inositol phosphate metabolism
erbb signaling pathway
mapk signaling pathway
vegf signaling pathway
long term potentiation
fc epsilon ri signaling pathway
gnrh signaling pathway
Cohort1
chronic myeloid
leukemia
erbb signaling pathway
acute myeloid leukemia
pancreatic cancer
prostate cancer
endometrial cancer glioma
ecm receptor interaction
focal adhesionepithelial cell signaling in helicobacter
pylori infection
renal cell carcinoma
small cell lung cancer
oxidative phosphorylation
colorectal cancer
WikiPathways
FDR < 0.05
10
Cis-regulatory mutation and associated gene with alteredexpression
Scor
e di
ffere
nce
−20
24
68
bits
1
2
1 2 3 4 5 6 7 8 9 10 11
ATATCTGTGGATTGATAAGAGTCAGAATCACATATCTGTGGATTGATACGAGTCAGAATCAC
ref.alt.
GATA3
ReferenceAlternative
GNA13
Expression
Den
sity
0 50 100 150 200 2500.00
00.
002
0.00
40.
006
Expression in sampleharbouring mutation
SOS1
F2RL3
CTNNA1ARHGEF2
AGTR1
ARHGAP4
ADRA1D
PLEKHG5ARHGEF1
RASGRF2
TBXA2R
FGD1
ESR1
PIK3CA
ECT2
PIK3R2
SOS2
GNG2
ARHGEF6
TIAM1
RAC2
PIK3R1
VAV1
GNA13
ARHGEF18ARHGEF9
RGS22 RHOB
CTNNB1S1PR4
11
Summary
I We analyzed ∼ 700, 000 somatic mutations from 84 B-celllymphoma samples
I We characterized a set of cis-regulatory elements fromChIP-seq
I Cis-regulatory mutations are enriched in promoter regions ofgenes involved in apoptosis or growth/proliferation
I We combined gene expression and mutation data from thecoding and non-coding spaces
I We highlight candidate regulatory-disrupting variationsdysregulating the gene expression program in cancer pathways
12
Acknowledgements
Wasserman lab :I Wyeth WassermanI David ArenillasI Allen ZhangI all the Wasserman lab members
Shah lab :I Sohrab ShahI Calvin LefebvreI Jiarui Ding
Funding :
Centre for Molecular Medicine and Therapeutics
13
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