Genomic Characterization of Invasive Lobular Breast Carcinoma Michael L. Gatza, Ph.D. TCGA Breast Cancer AWG.

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