rare tumours: some recent data and ideas part two endometriosis ... oct huntsman slides part...
TRANSCRIPT
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Rare tumours: some recent data and ideas
Part two – endometriosis associated cancer
David G. HuntsmanBC Cancer Agency Vancouver General Hospital University of British Columbia
Canada Research Chair in Molecular and Genomic Pathology
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Clear cell and endometrioid ovarian carcinoma represent around 20% of cases in North America
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Treated as one disease despite different clinical presentation and survival
Clinical disease heterogeneity
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MP10
In retrospective cohorts expect up to a 20% misclassification in chart based pathology
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F Kommoss 2002 << F Kommoss 2014 = B Gilks 2014
<<< =
• 300 cases centrally reviewed in 2002
• Reviewed again by same pathologist using 2014 WHO criteria : 54% concordance
• New histotypes showed 98% concordance with second reviewer and stronger associations with outcome and biomarkers
Impact of histotype changes
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Clear cell carcinoma of the ovary
• 2nd most common ovarian carcinoma subtype in NA (12%) and more frequent in Asia
• Do not respond to standard ovarian chemotherapy
• No other treatments available
• May respond to radiotherapy
• Molecular basis little understood
• Weird cousins of renal CCC
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ARID1a mutations• Common in OCCC, Endometrioid of ovary and uterus and MSI
positive gastric cancers
• Found in cancer types without tp53 mutations
• Occur in precancerous lesions but may not be initiating events
• Not prognostic
• Apart from association with PIK3Ca mutations no reproducible evidence that ARID1a mutant ovarian cancers are different from non mutant cases of the same type
• Specific targeting of ARID1a mutant cancers has been challenging
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ARID1AClear cell ovarian carcinoma
2010 NEJM Wiegand K, et al.; 2010 Science Jones S, et al.
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Genomic perspectiveClear cell ovarian carcinoma
ERBB2 overexpressed and amplified Pro-oncogenic/transforming growth factor receptorMET overexpressed and amplified Pro-oncogenic/transforming growth factor receptor
…and more recently highlighted…
2010 GynOnc Anglesio M, et al.
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Activated pathways in OCCC
Anglesio et al 2011. Clin Can Res
IL6 STAT3 HIF1A & HIF2A(EPAS1)(activation of hypoxia-related survival pathways)
Elevated levels:IL6(Activated) STAT3(Nuclear) HIF1AHIF2A (EPAS1)
Nuclear HIF1a in OCCC
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Genomic disruptionsClear cell ovarian carcinoma
Anglesio 2011
Tan 2011
METERBB2HNF1B
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Endometrioid carcinomas
• Almost all are low grade yet some progress to higher grade cancers
• Stage 1 low grade endometrioid carcinomas of ovary have a very good prognosis
• Higher grade endometriod carcinomas and recurrent low grade need new treatment approaches
• POLE mutations in 5% of cases, MSI in >20%
• Beta catenin mutations in 50% of cases
• Often present with synchronous uterine carcinoma
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Synchronous uterine and ovarian carcinomas
• Up to 50% of low grade endometrioid carcinomas
• Most are low grade and T1a
• Due to excellent prognosis are considered to be separate primaries
• Genomic and data molecular studies low resolution and interpreted as supporting separate primaries
• Data to be shown non-validated comparisons of somatic mutations
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SEO_VAN_65
SEO_TBG_
22
150
125
SEO_VAN_43
SEO_VAN_22
SEO_VAN_27
SEO_VAN_29
SEO_VAN_14
SEO_VAN_54
SEO_TBG_
15
SEO_VAN_58
SEO_VAN_56
SEO_VAN_60
SEO_TBG_
31
SEO_VAN_04
SEO_VAN_07
SEO_VAN_08
SEO_VAN_33
SEO_VAN_40
Endometriosis?
Ovarian
Endometrial
In almost all cases the uterine and ovarian cancers share somatic mutations
Anglesio JNCI 2016
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Copy number plots showing clonality
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Data and Conclusions • Clonal relationships between the endometrial and
ovarian cancers seen in but one of 20 cases studies so far
• Analysis of endometriosis and normal endometrium should inform whether these are metastatic cancers or whether a mutant field defect leads to both uterine cancer and ovarian cancer through endometriosis
• Are these true metastasis?
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Endometriosis: the main risk factor for CCC and ENOC
• First described by Sampson in 1925.
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Pearce et al Lancet Oncology 2012
• 13,226 controls, 7,919 cases including 674 CCC and 1220 endometrioid
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Are these uterine cancers in the wrong place?
Gounaris et al, J Pathology 2011
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MET (HGFR) amplification and overexpression in OCCC?
Fig 1 from Yamamoto et al, 2012. Mod Path
In second study by Yamamoto et al. MET overexpression and copy number changes were also correlated with atypical endometriosis that was synchronous with OCCC
Endometriosis
Adjacent atypicalendometriosis
Regions of endometriosis that are synchronous to OCCC
Features found in OCCC can be found in adjacent endometriosis
H&E IHC CISH
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VOA1048Adjacent Atypical Endometriosis vs. OCCC
21
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DAH145 - VOA1048 (in some cases the adjacent atypical endometriosis is essentially cancer
22
1:22408228:CDC42:coding:snvs:DAH145
15:100890253:AC015723.8:coding:snvs:DAH145
19:50840381:NAPSB:coding:snvs:DAH145
20:46386033:SULF2:coding:snvs:DAH145
1:6266355:C1orf188:coding:snvs:DAH145
1:29631897:PTPRU:coding:snvs:DAH145
1:46105922:GPBP1L1:coding:snvs:DAH145
1:89523838:GBP1:coding:snvs:DAH145
1:109197458:C1orf59:coding:snvs:DAH145
1:186324779:TPR:coding:snvs:DAH145
2:211085473:ACADL:coding:snvs:DAH145
2:219602546:TTLL4:coding:snvs:DAH145
3:132172461:DNAJC13:coding:snvs:DAH145
3:149700912:C1orf37:coding:snvs:DAH145
3:184580707:VPS8:coding:snvs:DAH145
4:187629068:FAT1:coding:snvs:DAH145
5:524228:SLC9A3:coding:snvs:DAH145
5:127681270:FBN2:coding:snvs:DAH145
5:140615717:PCDHB18:coding:snvs:DAH145
5:168180893:SLIT3:coding:snvs:DAH145
6:7246723:RREB1:coding:snvs:DAH145
6:74073560:OOEP:coding:snvs:DAH145
7:101944369:AC005088.3−2:coding:snvs:DAH145
8:113301714:CSMD3:coding:snvs:DAH145
9:2718192:KCNV2:coding:snvs:DAH145
9:130270400:LRSAM1:coding:snvs:DAH145
10:95069866:MYOF:coding:snvs:DAH145
10:102566211:PAX2:coding:snvs:DAH145
10:104130515:GBF1:coding:snvs:DAH145
11:45907403:CRY2:coding:snvs:DAH145
11:55135884:OR4A15:coding:snvs:DAH145
11:56143251:OR8U8:coding:snvs:DAH145
11:125853858:CDON:coding:snvs:DAH145
12:6078430:VWF:coding:snvs:DAH145
12:57586646:LRP1:coding:snvs:DAH145
12:101682807:UTP20:coding:snvs:DAH145
12:102053560:MYBPC1:coding:snvs:DAH145
13:23906156:SACS:coding:snvs:DAH145
13:73539509:PIBF1:coding:snvs:DAH145
14:92548659:ATXN3:coding:snvs:DAH145
16:4016933:ADCY9:coding:snvs:DAH145
16:22825976:HS3ST2:coding:snvs:DAH145
16:30980953:SETD1A:coding:snvs:DAH145
17:18226316:SHMT1:coding:snvs:DAH145
17:42284886:UBTF:coding:snvs:DAH145
17:68129103:KCNJ16:coding:snvs:DAH145
17:73499325:KIAA0195:coding:snvs:DAH145
18:9859309:RAB31:coding:snvs:DAH145
19:814453:PTBP1:coding:snvs:DAH145
20:25263878:PYGB:coding:snvs:DAH145
22:24829598:ADORA2A:coding:snvs:DAH145
22:37447918:7SK:coding:snvs:DAH145
22:39884587:MGAT3:coding:snvs:DAH145
X:8764386:FAM9A:coding:snvs:DAH145
X:37026831:FAM47C:coding:snvs:DAH145
X:117043429:Y:RNA:coding:snvs:DAH145
X:117540879:WDR44:coding:snvs:DAH145
X:153187162:ARHGAP4:coding:snvs:DAH145
X:153219079:HCFC1:coding:snvs:DAH145
VOA1048.A15
atypical endometriosis−adjacent
VOA1048.A6
Left Ovary CCC
VOA1048.B6
Endometrial Polyp
VOA1048.T
Left Ovary CCC
value
SOMATIC
UNDETERMINED
WILDTYPE
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CCC (3a) AT-E-osis (3b) E-osis (3e) E-osis (3f)
Fig 3
A
B
Anglesio J Path 2015
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DAH72 – VOA734
24
ARID1A
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Conclusions• Adjacent atypical endometriosis can have a near
complete complement of mutations -final transformation events may not be mutations
• So far no explanation for why endometriosis can lead to two such distinct cancers
• Are there more sensitive clonal marks for tracking relatedness
• Is there a screening window ?• What about endometriosis not associated with
cancer?
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Deep infiltrating endometriosis
• Will other clinically relevant forms of endometriosis have somatic mutations as have been seen in endometriosis associated with cancer
? Is endometriosis a partially competent neoplasm
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Deep Infiltrating Endometriosis“Case 2”
NTC CTRLG12V CTRLCASE2(LCM) NormalTissue
CASE2
Endometriosis (LCM)
KRAS Double-mutation positive
G12V
G12A
WT
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Endometriosis, CCOC and ENOCa
?
How do two such different cancers arise from the same precursor?
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How do different cancers arise from the same precursor? Do distinct mutations drive distinct oncogenic pathways
?
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ENOCA and CCC: commonly mutated genes
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Summary of specific genomic findings
• No single feature exclusive to endometrioid or CCC discovered
• No feature seen exclusively in ARID1a wild type cancers seen
• KMT2B (MLL4) the most commonly mutated “new” gene of interest
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Landscapes: Can the genomic landscape inform our understanding of the pathogenesis of these cancers
• Higher level view of cancer genome enables identification of signatures that point to mutational process
• ENOCa and CCC compared to GCT and HGSCa
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Copy number changes
GCT<<ENOCa<CCC<<HGSCa
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Signatures as well as specific mutations track with cancer types
Signatures of mutational processes in human cancers: Alexandrov et al Nature 2014
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ENOCA and CCC: genomic landscapes
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ENOCA and CCC: genomic landscapes
APOBECMMR AGE
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How do different cancers arise from the same precursor?
?
Although differences no mutation is exclusive to these cancer types some landscape features are enriched Cancer associated mutations may precede transformation process (Anglesio)
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Cysteine Biosynthetic Pathway
Methionine Homocysteine Cystathionine CysteineCBS
CTH
Glutathione
Higher in clear cell
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CCOCENOCHGS
CTH is Highly Expressed in Clear Cell Ovarian Cancer
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CTH and CBS Expression in Cell Lines
CTH
CBS
a-Tubulin
A2
78
0
IGR
OV
1
TOV
11
2D
20
08
JHO
C5
JHO
C7
JHO
C9
OV
ISE
OV
MA
NA
OV
TOKO
RM
G2
TOV
21
G
CaO
V3
Hey
Ku
ram
och
i
CaO
V3
Hey
OV
CA
R 3
OV
CA
R 4
OV
CA
R 5
OV
SAYO
ENOC CCC HGS
Homocysteine Cystathionine CysteineCBS CTH
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The Origins of Endometriosis Associated Ovarian Cancer?
Cell of Origin forEndometrioid
Ovarian Cancer?
Cell of Origin forClear Cell
Ovarian Cancer?
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CCOC and EndoCa and the ovary• Both cancers are associated with endometriosis
• Although cancer associated mutations occur in endometriosis at other sites, transformation occurs almost exclusively within ovarian endometriomas
• CCOC and EndoCa look similar to their endometrial counterparts and have similar mutations – do these cancers arise from different cells of origin?
• The IL6 pathway is dominant in OCCC, whereas ARID1A/PIK3CA mutation occurs in approximately 50% of cases
• Is OCCC more than on disease and if so what marks each type (proteomics screen)
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Thanks• My lab:, Niki Boyd ,Michelle Woo, Leah Prentice, Melissa
McConechy, Winnie Yang, Sarah Mains-Bandiera, Clara Salamanca, Michael Anglesio, Alicia Tone, Hector Li Chang, Yemin Wang, Jay Chen, Tony Karnezis,, Madlen Maassen and Janine Senz
• Sohrab Shah -- Bioinformatics: Jairhu Ding, Yikan Wang, Ali Bashashati, Gavin Ha, Andrew McPherson, Gavin Ha
• GSC: Marco Marra, Martin Hirst, Gregg Morin• Collaborators: Stefan Kommoss, M Kobel, Blaise Clarke, J
Brenton, AM Mes-Masson, D Bowtell, B Vanderhyden, A Okamoto and Sam Aparicio
• OvCaRe BC: Blake Gilks, Dianne Miller, Ken Swenerton, Paul Hoskins, YZ Wang, Nelly Auersperg, Brad Nelson, Cal Roskelly, Tom Ehlen, Anna Tinker, Jessica McAlpine