some recent data and ideas - PDF document

1 Rare tumours : some recent data and ide
Rare tumours : some recent data and ideas Part two – endometriosis associated cancer David G. Huntsman BC Cancer Agency Vancouver General Hospital University of British Columbia Canada Research

2 Chair in Molecular and Genomic Pathol
Chair in Molecular and Genomic Pathology Clear cell and endometrioid ovarian carcinoma represent around 20% of cases in North America Treated as one disease despite different clinical presentation

3 and survival Clinical disease heterogene
and survival Clinical disease heterogeneity MP10 In retrospective cohorts expect up to a 20% misclassification in chart based pathology F Kommoss 2002 F Kommoss 2014 = B Gilks 2014 = • 300 cases

4 centrally reviewed in 2002 • Reviewed
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 w

5 ith outcome and biomarkers Impact of hi
ith outcome and biomarkers Impact of histotype changes Clear cell carcinoma of the ovary • 2 nd most common ovarian carcinoma subtype in NA (12%) and more frequent in Asia • Do not respond to sta

6 ndard ovarian chemotherapy • No other
ndard ovarian chemotherapy • No other treatments available • May respond to radiotherapy • Molecular basis little understood • Weird cousins of renal CCC ARID1a mutations • Common in OCCC,

7 Endometrioid of ovary and uterus and MSI
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

8 • Apart from association with PIK3Ca m
• 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 muta

9 nt cancers has been challenging ARID1A
nt cancers has been challenging ARID1A Clear cell ovarian carcinoma 2010 NEJM Wiegand K, et al.; 2010 Science Jones S, et al. Genomic perspective Clear cell ovarian carcinoma ERBB2 overexpressed and a

10 mplified Pro - oncogenic/transforming gr
mplified Pro - oncogenic/transforming growth factor receptor MET overexpressed and amplified Pro - oncogenic/transforming growth factor receptor …and more recently highlighted… 2010 GynOnc Anglesio

11 M, et al. Activated pathways in OCCC Ang
M, et al. 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

12 (Nuclear) HIF1A HIF2A (EPAS1) Nuclear H
(Nuclear) HIF1A HIF2A (EPAS1) Nuclear HIF1a in OCCC Genomic disruptions Clear cell ovarian carcinoma Anglesio 2011 Tan 2011 MET ERBB2 HNF1B Endometrioid carcinomas • Almost all are low grade yet som

13 e progress to higher grade cancers •
e 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 treatme

14 nt approaches • POLE mutations in 5% o
nt approaches • POLE mutations in 5% of cases, MSI in �20% • Beta catenin mutations in 50% of cases • Often present with synchronous uterine carcinoma Synchronous uterine and ovarian ca

15 rcinomas • Up to 50% of low grade end
rcinomas • 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 studie

16 s low resolution and interpreted as sup
s low resolution and interpreted as supporting separate primaries • Data to be shown non - validated comparisons of somatic mutations Endometriosis? Ovarian Endometrial In almost all cases the uter

17 ine and ovarian cancers share somatic
ine and ovarian cancers share somatic mutations Anglesio JNCI 2016 Copy number plots showing clonality Data and Conclusions • Clonal relationships between the endometrial and ovarian cancers seen

18 in but one of 20 cases studies so far
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

19 cancer and ovarian cancer through endo
cancer and ovarian cancer through endometriosis • Are these true metastasis? Endometriosis: the main risk factor for CCC and ENOC • First described by Sampson in 1925. Pearce et al Lancet Oncol

20 ogy 2012 • 13,226 controls, 7,919 case
ogy 2012 • 13,226 controls, 7,919 cases including 674 CCC and 1220 endometrioid Are these uterine cancers in the wrong place? Gounaris et al, J Pathology 2011 MET (HGFR) amplification and overexpr

21 ession in OCCC? Fig 1 from Yamamoto et a
ession 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 syn

22 chronous with OCCC Endometriosis Adjacen
chronous with OCCC Endometriosis Adjacent atypical endometriosis Regions of endometriosis that are synchronous to OCCC Features found in OCCC can be found in adjacent endometriosis H&E IHC CISH VOA1048

23 Adjacent Atypical Endometriosis vs. OCC
Adjacent Atypical Endometriosis vs. OCCC 21 DAH145 - VOA1048 (in some cases the adjacent atypical endometriosis is essentially cancer 22 CCC (3a) AT - E - osis (3b) E - osis (3e) E - osis (3f) Fig 3

24 A B Anglesio J Path 2015 DAH72 – VOA7
A B Anglesio J Path 2015 DAH72 – VOA734 24 ARID1A Conclusions • Adjacent atypical endometriosis can have a near complete complement of mutations - final transformation events may not be mutatio

25 ns • So far no explanation for why end
ns • 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 a

26 bout endometriosis not associated with
bout endometriosis not associated with cancer? Deep infiltrating endometriosis • Will other clinically relevant forms of endometriosis have somatic mutations as have been seen in endometriosis

27 associated with cancer ? Is endometrios
associated with cancer ? Is endometriosis a partially competent neoplasm Deep Infiltrating Endometriosis “Case 2” NTC CTRL G12V CTRL CASE2 (LCM) Normal Tissue CASE2 Endometriosis (LCM) KRAS Doub

28 le - mutation positive G12V G12A WT End
le - mutation positive G12V G12A WT Endometriosis, CCOC and ENOCa ? How do two such different cancers arise from the same precursor? How do different cancers arise from the same precursor? Do distin

29 ct mutations drive distinct oncogenic pa
ct mutations drive distinct oncogenic pathways ? ENOCA and CCC: commonly mutated genes Summary of specific genomic findings • No single feature exclusive to endometrioid or CCC discovered • No

30 feature seen exclusively in ARID1a wild
feature seen exclusively in ARID1a wild type cancers seen • KaT2. (aLL4) the most commonly mutated “new” gene of interest Landscapes: Can the genomic landscape inform our understanding of the p

31 athogenesis of these cancers • Higher
athogenesis 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 Copy number chang

32 es GCTENOCa Signatures as well as speci
es GCTENOCa Signatures as well as specific mutations track with cancer types Signatures of mutational processes in human cancers: Alexandrov et al Nature 2014 ENOCA and CCC: genomic landscapes ENOCA

33 and CCC: genomic landscapes APOBEC MMR A
and CCC: genomic landscapes APOBEC MMR AGE How do different cancers arise from the same precursor? ? Although differences no mutation is exclusive to these cancer types some landscape features are enr

34 iched Cancer associated mutations may p
iched Cancer associated mutations may precede transformation process (Anglesio) Cysteine Biosynthetic Pathway Methionine Homocysteine Cystathionine Cysteine CBS CTH Glutathione Higher in clear cell

35 CCOC ENOC HGS CTH is Highly Expressed in
CCOC ENOC HGS CTH is Highly Expressed in Clear Cell Ovarian Cancer CTH and CBS Expression in Cell Lines CTH CBS a - Tubulin A2780 IGROV1 TOV112D 2008 JHOC5 JHOC7 JHOC9 OVISE OVMANA OVTOKO RMG2 TOV21G C

36 aOV3 Hey Kuramochi CaOV3 Hey OVCAR 3 OVC
aOV3 Hey Kuramochi CaOV3 Hey OVCAR 3 OVCAR 4 OVCAR 5 OVSAYO ENOC CCC HGS Homocysteine Cystathionine Cysteine CBS CTH The Origins of Endometriosis Associated Ovarian Cancer? Cell of Origin for Endometri

37 oid Ovarian Cancer? Cell of Origin for C
oid Ovarian Cancer? Cell of Origin for Clear Cell Ovarian Cancer? CCOC and EndoCa and the ovary • Both cancers are associated with endometriosis • Although cancer associated mutations occur in e

38 ndometriosis at other sites, transformat
ndometriosis at other sites, transformation occurs almost exclusively within ovarian endometriomas • CCOC and EndoCa look similar to their endometrial counterparts and have similar mutations –

39 do these cancers arise from different c
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

40 and if so what marks each type (proteom
and if so what marks each type (proteomics screen) Thanks • My lab:, Niki Boyd ,Michelle Woo, Leah Prentice, Melissa McConechy , Winnie Yang, Sarah Mains - Bandiera , Clara Salamanca, Michael

41 Anglesio , Alicia Tone, Hector Li Chan
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 , Ga

42 vin Ha, Andrew McPherson, Gavin Ha •
vin 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 Va

43 nderhyden , A Okamoto and Sam Aparicio
nderhyden , 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,