genomic characterization of invasive lobular breast carcinoma michael l. gatza, ph.d. tcga breast...
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Genomic Characterization of Invasive Lobular Breast Carcinoma
Michael L. Gatza, Ph.D.
TCGA Breast Cancer AWG
2
Invasive Breast Carcinoma
webmd.com
Invasive Ductal Carcinoma (IDC)50-80%
Mixed IDC.ILC4-5%
Ductal
Lobular
Invasive Lobular Carcinoma (ILC)10-15%
3
Pathology centrally re-reviewed(Andy Beck, Harvard)
817
490
127
88
112
Summary of Data Freeze
4
Identification of differentially expressed genes
Ductal Lobular
2 C
lass
SA
M F
DR
=0
N=
663
gene
s
LumA Ductal
LumA Lobular
ATM networkImmune signaling (multiple)MAPK signaling
MYC targets (multiple)E-cadherin stabilization
Normal
CDH1
Mike Gatza, UNC
Low High
mRNA Expression
5
Development of Integrated MAF
Matt Wilkerson (UNC), Lisle Mose (UNC)Giovanni Ciriello (MSKCC), Cyriac Kandoth (MSKCC)Mike McLellan (Wash U)
DNA-based MAF
Inte
grat
ed M
AF
DNA Exome sequencing
UNCeqR (mRNAseq / DNAseq)
ABRA (CDH1, TP53, GATA3, PTEN, RB1)
Integrated MAF
DNA-based MAF
Inte
grat
ed M
AF
6
Comparison of significant alterations: IDC vs. ILC
Giovanni Ciriello, MSKCC
7
Identifying IDC LumA and ILC LumA-specific alterations
Giovanni Ciriello, MSKCC
IDC ILCGATA3 (p=0.0002)
Low High
Protein Expression
8
PARADIGM analysis identifies IDC and ILC-associated signaling pathways
XBP1
MYCp53/DNA Damage Response
Immune Related
CDH1
Blue: ILC DOWN
Red: ILC UP
Christina Yau, Buck Institute
IDC ILCmRNA
IDC ILCProtein
Low High
mRNA Expression
Low High
Protein Expression
9
Development of mRNA-based ILC classes
1 2 3
Ce
ntr
oid
cla
ss
ifie
r (9
0g
en
es
)
ConsensusClusterPlus to ID 3 ILC classes
TCGA ILC LumA (n=106)
Identified samples with positive sil. width
TCGA ILC LumA (n=89)
ClaNC developed centroid predictor
TCGA ILC LumA (n=89)
Mike Gatza, UNC
10
2 Class SAM identifies differentially expressed genes in ILC classes
Mike Gatza, UNC
988
gen
es (
FD
R=
0)
Class1 C2 C3
N= 722 genesEGFRMET GLI1FGF17 WNT6 AREG KIT
KRT 14, 15, 17, 32, 81KRK 1, 6-8CLDN 8,10,11, 19 PTCH2TP63VITID4
N= 268 genesImmune-related genes: >100
LCKIFNG
Low High
mRNA Expression
11
ILC class mRNA / miRNA expression patterns correspond with IDC and Adjacent Normal
ILC IDC Norm
988
gene
s (F
DR
=0)
P<0.0001
miR
NA
(S
AM
seq
FD
R<
0.05
)
Mike Gatza, UNC Reanne Bowlby, BC Cancer Agency
Low High
miRNA Expression
Low High
mRNA Expression
ILC IDC Normal
Class 1 61 49 94
Class 2 39 167 0
Class 3 27 274 0
12
ILC Class1 corresponds with RPPA Reactive Subtype
ILC Class (n=127)
RPPA Subtype (n=70)
ReactiveNon-reactiveMissing data
Class1 Class2 Class3
Mike Gatza, UNCGordon Mills, MDACC
P<0.0001
Annexin1Caveolin1Collagen IVMyh11RMB15
RP
PA
Low High
Protein Expression
13
ILC Class1 tumors exhibit altered PDGFR/ STAT3 and FoxM1 signaling
FOXM1 sub-network
PA
RA
GIG
MR
PP
A
PDGFR
FoxM1
FoxM1
pSRC Y527pSTAT3 Y705
Christina Yau, Buck InstituteMike Gatza, UNC
Low High
Protein Expression
14
ILC class 2 defined by high immune signaling and proliferation
Mike Gatza, UNC
Low High
Signature Score
B-cellBCRB-cell (CS)CD8CD8 (CS)T-cell (CS)LCKT-cell (TNBC)NKT-cell (Teschendo)MΦ TH1 (CS)MΦ CSF1 TCR
TCGA ILC (n=127)
Class1 Class2 Class3
P=1.39e-10
Pro
life
rati
on
Sco
re (
PA
M50
)
Class 1 Class 2 Class 3
15
PARADIGM analysis identifies IFNG and FOXM1 as key pathways in ILC class 2 tumors
Christina Yau, Buck Institute
16
Summary
• Developed unique integrated MAF utilizing both DNA exome and mRNA sequencing
• ILC vs. IDC– FOXA1, CDH1 mutations associated with ILC– GATA3 mutation associated with IDC– Altered signaling: CDH1, Myc, p53/DNA damage, immune signaling– Identified differentially expressed miRNA and methylation
• ILC classes– Class 1 associated with Reactive subtype– Class 2 immune component and highly proliferative
17
TCGA Breast Cancer Analysis Working Group
Baylor College of MedicineChad CreightonXiaosong Wang
British Columbia Cancer AgencyAndy ChuElizabeth ChunAndy MungallGordon RobertsonDominik Stoll
Broad InstituteAndrew Cherniack
Greater Poland Cancer CenterMaciej Wiznerowicz
Harvard Medical SchoolTerrence WuYonghong Xiao
Institute for Systems BiologySheila ReynoldsIlya Shmulevich
Lawrence Berkeley National LaboratoryPaul Spellman
Mayo ClinicJim Ingle
The University of TexasMD Anderson Cancer CenterRoel VerhaakRehan AkbaniNancy ShihGordon Mills
Memorial Sloan-Kettering Cancer CenterGiovanni CirielloNiki SchultzEthan CeramiArthur GoldbergCaitlin ByrneAnders JacobsenTari KingChris Sander
Nationwide Children’s HospitalJay BowenJulie Gastier-Foster
National Cancer InstituteChunhua YanJohn DemchokLaura DillonMargi ShethPeter GoodJacqueline PalchikHeidi Sofia Kenna Shaw
University of California Santa CruzBuck InstituteChris BenzDavid HausslerChristina YauSam NgTed GoldsteinKyle EllrottCharlie VaskeJosh StuartJing Zhu
University of California, San FranciscoFred Waldman
University of Southern CaliforniaPeter LairdSwapna MahurkarSimeen MalikDan Weisenberger
Windber Research InstituteHai HuRichard Mural
University of North CarolinaChuck Perou (co-chair)Katie HoadleyMike GatzaJoel ParkerXiaping HeMichael IglesiaGrace SilvaWei Zhao
The Genome Instituteat Washington UniversityMatthew Ellis (co-chair)Li DingLucinda FultonDaniel KoboldtElaine Mardis