Part two endometriosis associated cancer David G. Huntsman BC - PowerPoint PPT Presentation

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 Chair in Molecular and Genomic Pathology

Clear cell and endometrioid ovarian carcinoma represent around 20% of cases in North America

Clinical disease heterogeneity Treated as one disease despite different clinical presentation and survival

MP10 In retrospective cohorts expect up to a 20% misclassification in chart based pathology

Impact of histotype changes • 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 <<< = F Kommoss 2002 << F Kommoss 2014 = B Gilks 2014

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 standard ovarian chemotherapy • No other treatments available • May respond to radiotherapy • Molecular basis little understood • Weird cousins of renal CCC

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

ARID1A Clear cell ovarian carcinoma 2010 NEJM Wiegand K, et al.; 2010 Science Jones S, et al.

Genomic perspective Clear cell ovarian carcinoma …and more recently highlighted… ERBB2 overexpressed and amplified Pro-oncogenic/transforming growth factor receptor MET overexpressed and amplified Pro-oncogenic/transforming growth factor receptor 2010 GynOnc Anglesio M, et al.

Activated pathways in OCCC IL6  STAT3  HIF1A & HIF2A(EPAS1) (activation of hypoxia-related survival pathways) Elevated levels: IL6 (Activated) STAT3 (Nuclear) HIF1A HIF2A (EPAS1) Nuclear HIF1a in OCCC Anglesio et al 2011. Clin Can Res

Genomic disruptions Clear cell ovarian carcinoma ERBB2 MET HNF1B Anglesio 2011 Tan 2011

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

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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Copy number plots showing clonality

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?

Endometriosis: the main risk factor for CCC and ENOC • First described by Sampson in 1925.

Pearce et al Lancet Oncology 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

Features found in OCCC can be found in adjacent endometriosis MET (HGFR) amplification and overexpression in OCCC? Regions of endometriosis that are synchronous to OCCC H&E IHC CISH Endometriosis Adjacent atypical endometriosis 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

VOA1048 Adjacent Atypical Endometriosis vs. OCCC 21

DAH145 - VOA1048 (in some cases the adjacent atypical endometriosis is essentially cancer X:153219079:HCFC1:coding:snvs:DAH145 X:153187162:ARHGAP4:coding:snvs:DAH145 X:117540879:WDR44:coding:snvs:DAH145 X:117043429:Y:RNA:coding:snvs:DAH145 X:37026831:FAM47C:coding:snvs:DAH145 X:8764386:FAM9A:coding:snvs:DAH145 22:39884587:MGAT3:coding:snvs:DAH145 22:37447918:7SK:coding:snvs:DAH145 22:24829598:ADORA2A:coding:snvs:DAH145 20:25263878:PYGB:coding:snvs:DAH145 19:814453:PTBP1:coding:snvs:DAH145 18:9859309:RAB31:coding:snvs:DAH145 17:73499325:KIAA0195:coding:snvs:DAH145 17:68129103:KCNJ16:coding:snvs:DAH145 17:42284886:UBTF:coding:snvs:DAH145 17:18226316:SHMT1:coding:snvs:DAH145 16:30980953:SETD1A:coding:snvs:DAH145 16:22825976:HS3ST2:coding:snvs:DAH145 16:4016933:ADCY9:coding:snvs:DAH145 14:92548659:ATXN3:coding:snvs:DAH145 13:73539509:PIBF1:coding:snvs:DAH145 13:23906156:SACS:coding:snvs:DAH145 12:102053560:MYBPC1:coding:snvs:DAH145 12:101682807:UTP20:coding:snvs:DAH145 12:57586646:LRP1:coding:snvs:DAH145 12:6078430:VWF:coding:snvs:DAH145 11:125853858:CDON:coding:snvs:DAH145 value 11:56143251:OR8U8:coding:snvs:DAH145 11:55135884:OR4A15:coding:snvs:DAH145 SOMATIC 11:45907403:CRY2:coding:snvs:DAH145 UNDETERMINED 10:104130515:GBF1:coding:snvs:DAH145 WILDTYPE 10:102566211:PAX2:coding:snvs:DAH145 10:95069866:MYOF:coding:snvs:DAH145 9:130270400:LRSAM1:coding:snvs:DAH145 9:2718192:KCNV2:coding:snvs:DAH145 8:113301714:CSMD3:coding:snvs:DAH145 7:101944369:A C005088.3−2:coding:sn vs:DAH145 6:74073560:OOEP:coding:snvs:DAH145 6:7246723:RREB1:coding:snvs:DAH145 5:168180893:SLIT3:coding:snvs:DAH145 5:140615717:PCDHB18:coding:snvs:DAH145 5:127681270:FBN2:coding:snvs:DAH145 5:524228:SLC9A3:coding:snvs:DAH145 4:187629068:FAT1:coding:snvs:DAH145 3:184580707:VPS8:coding:snvs:DAH145 3:149700912:C1orf37:coding:snvs:DAH145 3:132172461:DNAJC13:coding:snvs:DAH145 2:219602546:TTLL4:coding:snvs:DAH145 2:211085473:ACADL:coding:snvs:DAH145 1:186324779:TPR:coding:snvs:DAH145 1:109197458:C1orf59:coding:snvs:DAH145 1:89523838:GBP1:coding:snvs:DAH145 1:46105922:GPBP1L1:coding:snvs:DAH145 1:29631897:PTPRU:coding:snvs:DAH145 1:6266355:C1orf188:coding:snvs:DAH145 20:46386033:SULF2:coding:snvs:DAH145 19:50840381:NAPSB:coding:snvs:DAH145 15:100890253:AC015723.8:coding:snvs:DAH145 1:22408228:CDC42:coding:snvs:DAH145 V V V V O O O O A A A A a L E L 1 1 1 1 t y 0 e 0 n 0 e 0 p 4 f 4 d 4 f 4 t t i c 8 O 8 o 8 O 8 . . m . . a A v A B v T l 1 a 6 e 6 a e r t r 5 y r y n i a d C C o l C P C m C o C e l t y r p i o s i s 22 − a d j a c e n t

Fig 3 A B CCC (3a) AT-E-osis (3b) E-osis (3e) E-osis (3f) Anglesio J Path 2015

DAH72 – VOA734 ARID1A 24

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?

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

Deep Infiltrating Endometriosis “Case 2” KRAS WT Double-mutation positive G12A G12V CASE2 Endometriosis (LCM) CASE2 G12V CTRL NTC CTRL (LCM) Normal Tissue

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 distinct 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 feature seen exclusively in ARID1a wild type cancers seen • KMT2B (MLL4) the most commonly mutated “new” gene of interest

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

Copy number changes GCT<<ENOCa<CCC<<HGSCa

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