Michael L Gatza PhD TCGA Breast Cancer AWG Invasive Breast Carcinoma webmdcom Invasive Ductal Carcinoma IDC 5080 Mixed IDCILC 45 Ductal Lobular Invasive Lobular Carcinoma ILC ID: 811736
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Slide1
Genomic Characterization of Invasive Lobular Breast Carcinoma
Michael L. Gatza, Ph.D.
TCGA Breast Cancer AWG
Slide2Invasive Breast Carcinoma
webmd.com
Invasive Ductal Carcinoma (IDC)
50-80%
Mixed IDC.ILC
4-5%
Ductal
Lobular
Invasive Lobular Carcinoma (ILC)
10-15%
Slide3P
athology centrally re-reviewed
(Andy Beck, Harvard)
817
490
127
88
112
Summary of Data Freeze
Slide4Identification of differentially expressed genes
Ductal
Lobular
2 Class SAM FDR=0
N=663 genes
LumA
Ductal
LumA
Lobular
ATM network
Immune signaling (multiple)
MAPK signaling
MYC targets (multiple)
E-cadherin stabilization
Normal
CDH1
Mike Gatza, UNC
Low High
mRNA Expression
Slide5Development of Integrated MAF
Matt Wilkerson (UNC), Lisle
Mose (UNC)Giovanni Ciriello (MSKCC), Cyriac Kandoth
(MSKCC)Mike McLellan (Wash U)
DNA-based MAF
Integrated MAF
DNA Exome sequencing
UNCeqR
(
mRNAseq
/ DNAseq)ABRA (CDH1, TP53, GATA3, PTEN, RB1)Integrated MAF
DNA-based MAF
Integrated MAF
Slide6Comparison of significant alterations: IDC vs. ILC
Giovanni Ciriello, MSKCC
Slide7Identifying IDC
LumA
and ILC
LumA-specific alterations
Giovanni Ciriello, MSKCC
IDC ILC
GATA3 (p=0.0002)
Low High
Protein Expression
Slide8PARADIGM analysis identifies IDC and ILC-associated signaling pathways
XBP1
MYC
p
53/DNA Damage Response
Immune Related
CDH1
Blue: ILC DOWN
Red: ILC UP
Christina Yau, Buck Institute
IDC ILC
mRNA
IDC ILC
Protein
Low High
mRNA Expression
Low High
Protein Expression
Slide9Development of mRNA-based ILC classes
1 2 3
Centroid classifier (90genes)
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
Slide102 Class SAM identifies differentially expressed genes in ILC classes
Mike Gatza, UNC
988 genes (FDR=0)
Class1 C2 C3
N= 722 genes
EGFR
MET
GLI1
FGF17
WNT6
AREG
KITKRT 14, 15, 17, 32, 81KRK 1, 6-8
CLDN 8,10,11, 19 PTCH2TP63VIT
ID4
N= 268 genes
Immune-related genes: >100
LCKIFNG
Low High
mRNA Expression
Slide11ILC class mRNA /
miRNA expression patterns correspond with IDC and Adjacent Normal
ILC
IDC
Norm
988 genes (FDR=0)
P<0.0001
miRNA
(
SAMseq
FDR<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
Slide12ILC Class1 corresponds with RPPA Reactive Subtype
ILC Class (n=127)
RPPA Subtype (n=70)
Reactive
Non-reactive
Missing data
Class1 Class2 Class3
Mike Gatza, UNC
Gordon Mills, MDACC
P<0.0001
Annexin1
Caveolin1
Collagen IV
Myh11
RMB15
RPPA
Low High
Protein Expression
Slide13ILC
Class1 tumors exhibit altered PDGFR/ STAT3 and FoxM1 signaling
FOXM1 sub-network
PARAGIGM
RPPA
PDGFR
FoxM1
FoxM1
pSRC
Y527
pSTAT3 Y705
Christina Yau, Buck Institute
Mike
Gatza, UNC
Low High
Protein Expression
Slide14ILC class 2 defined by high immune signaling and proliferation
Mike Gatza, UNC
Low High
Signature Score
B-cell
BCR
B-cell (CS)
CD8
CD8 (CS)
T-cell (CS)
LCK
T-cell (TNBC)
NKT-cell (Teschendo
)MΦ TH1 (CS)
MΦ CSF1
TCR
TCGA ILC (n=127)
Class1 Class2 Class3
P=1.39e-10
Proliferation Score (PAM50)
Class 1 Class 2 Class 3
Slide15PARADIGM analysis identifies IFNG and FOXM1 as key pathways in ILC class 2 tumors
Christina Yau, Buck Institute
Slide16Summary
Developed unique integrated MAF utilizing both DNA exome and mRNA sequencing
ILC vs. IDCFOXA1, CDH1 mutations associated with ILCGATA3 mutation associated with IDCAltered signaling: CDH1, Myc
, p53/DNA damage, immune signalingIdentified differentially expressed miRNA and methylationILC classesClass 1 associated with Reactive subtype
Class 2 immune component and highly proliferative
Slide17TCGA Breast Cancer Analysis Working Group
Baylor College of Medicine
Chad Creighton
Xiaosong Wang
British Columbia Cancer AgencyAndy Chu
Elizabeth ChunAndy Mungall
Gordon RobertsonDominik Stoll
Broad Institute
Andrew Cherniack
Greater Poland Cancer CenterMaciej
WiznerowiczHarvard Medical School
Terrence WuYonghong Xiao
Institute for Systems BiologySheila ReynoldsIlya
ShmulevichLawrence Berkeley National Laboratory
Paul SpellmanMayo Clinic
Jim Ingle
The University of Texas
MD Anderson Cancer CenterRoel Verhaak
Rehan Akbani
Nancy ShihGordon Mills
Memorial Sloan-Kettering Cancer CenterGiovanni Ciriello
Niki Schultz
Ethan CeramiArthur Goldberg
Caitlin ByrneAnders JacobsenTari
KingChris Sander
Nationwide Children’s HospitalJay BowenJulie
Gastier-Foster
National Cancer InstituteChunhua
YanJohn DemchokLaura Dillon
Margi
Sheth
Peter Good
Jacqueline
Palchik
Heidi Sofia
Kenna Shaw
University of California Santa Cruz
Buck Institute
Chris Benz
David Haussler
Christina
Yau
Sam Ng
Ted Goldstein
Kyle
Ellrott
Charlie
Vaske
Josh Stuart
Jing Zhu
University of California,
San Francisco
Fred Waldman
University of Southern California
Peter Laird
Swapna
Mahurkar
Simeen Malik
Dan
Weisenberger
Windber Research Institute
Hai
Hu
Richard Mural
University of North Carolina
Chuck Perou (co-chair)
Katie Hoadley
Mike Gatza
Joel Parker
Xiaping He
Michael Iglesia
Grace Silva
Wei Zhao
The Genome Institute
at Washington University
Matthew Ellis (co-chair)
Li Ding
Lucinda Fulton
Daniel Koboldt
Elaine Mardis