Avances en la Patología Molecular del Cáncer de Endometrio

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1 CURSO DE PATOLOGÍA GINECOLÓGICA II Actualizaciones en patología cervical y endometrial Avances en la Patología Molecular del Cáncer de Endometrio José Palacios Hospital Universitario Ramón y Cajal. Madrid

2 ENDOMETRIOID CARCINOMA p53 ER NONENDOMETRIOID CARCINOMA ER p53

3 UNDIFFERENTIATED ENDOMETRIAL CARCINOMA ENDOMETRIAL CARCINOSARCOMA (MMMT)

4 PROGRESSION MODEL FOR ENDOMETRIAL CARCINOMA Prolif NORMAL EPITHELIUM Secretory Simple Hyperplasia K-Ras/PTEN β-catenin/ MSI/PI3KCA/ FGFR2 Atrophic endometrium (AE) P53/CIN/? Complex Atypical Hyperplasia Endometrial Intraepithelial Carcinoma ENDOMETRIOID CARCINOMA (EEC) p53 NON-ENDOMETRIOID CARCINOMA (NEEC)

5 hmlh1 promoter hypermethylation EC1 U M EC2 U M EC3 U M EC4 U M hmlh1 RER+ phenotype MSI hmhs2 NON-CODING SEQUENCES (BAT25, BAT26,...) CODING SEQUENCES PTEN, BAX, hmlh6, hmsh3, TGFβ-RII, CASP-5, BCL10 N T N BAT25 T CASP-5 (A10) BCL10 (A8) RAD50 (A9)

6 TP53 MUTATION CHROMOSOME INSTABILITY ANEUPOIDY ALLELIC IMBALANCES ONCOGENE AMPLIFICATION LOH TSG STK15, CCNE1, CCND1, HER2 CDH1 CHROMOSOME INSTABILITY INVASION AND METASTASIS CELL CYCLE ALTERATIONS

7 Serous endometrial carcinoma CCNE1 Cyclin E N T D16S496 Reduced E-cadherin

8 Nature, 2013

9 Gene mutations in endometrioid endometrial carcinoma GENE FREQUENCY GENE FREQUENCY PTEN * 77.7% MLL4 9.1% PIK3CA 53.1% BCOR 8.0% PIK3R1 37.1% ATR 6.9% CTNNB1 36.6% CCND1 5.7% ARID1A 35.4% SPOP 5.7% KRAS 24.6% SIN3A 5.7% CTCF 20.6% MKI67 5.7% RPL % FBXW7 5.1% TP % FOXA2 5.1% FGFR2 10.9% NRAS 2.9% ARID5B 10.9% *62/136 (45.5%) tumors with PTEN mutations has > 2 mutations TCGA; Nature 2013

10 Gene mutations in endometrioid endometrial carcinoma GENE Grade 1 Grade 2 Grade 3 CTNNB1 47.7% 36.8% 17.9% TP %

11 Molecular alterations in atypical endometrial hyperplasia CTNNB1 PTEN RAS MSI AH (11) 1 (9%) 4 (36%) 4 (36%) 1(9%) AHWSM (14) 7 (50%) Bratchel, et al.; Am J Surg Pathol 2005

12 Gene mutations in serous endometrial carcinoma GENE FREQUENCY GENE FREQUENCY TP % PRPF18 7% PIK3CA 41.9% SPOP 7% FBXW7 30.2% CDH19 7% PPP2R1A 36.6% FGFR2 7% CHD4 16.3% ARID1A 7% CSMD3 11.6% FOXA2 4.6% COLA % USP36 4.6% TCGA; Nature 2013 TAF1 (30%), EP300 (8%), TSPYL2 (6%), MAP3K4 (6%) and ABCC9 (6%). Khun et al; J Natl Cancer Inst Le Gallo et al; Nat Genet 2012; Zhao et al; PNAS 2013.

13 Somatic copy number alterations (SCNA) Cluster 1 tumours were nearly devoid of broad SCNAs, averaging less than 0.5% genome alteration, with no significant recurrent events. Tumours also had significantly increased nonsynonymous mutation rates compared to all others. Clusters 2 and 3 consisted mainly of endometrioid tumours, distinguished by more frequent 1q amplification in cluster 3 than cluster 2 (100% of cluster 3 tumours versus 33% of cluster 2 tumours) and worse progression-free survival TCGA; Nature 2013

14 Somatic copy number alterations (SCNA) Cluster 4 included 95% serous tumours and 12% of endometrioid tumours (24% of grade 3 and 5% of grade 1 or 2). Recurrent previously reported focal amplifications of the oncogenes MYC (8q24.12), ERBB2 (17q12) and CCNE1 (19q12)13. SCNAs previously unreported in endometrial cancers: FGFR3 (4p16.3) and SOX17 (8q11.23). Frequent TP53 mutations (90%), TCGA; Nature 2013

15 GENE FREQUENCY PIK3CA 52% CCNE1 48% ERBB2 44% MYC 40% CHD4 28% Zhao et al; PNAS 2013

16 Molecular subtypes of endometrial cancer TCGA; Nature 2013

17 Endometrial cancer: ultramutated group (7%) Mutations in the exonuclease domain of POLE POLE is a catalytic subunit of DNA polymerase epsilon involved in nuclear DNA replication and repair. Hotspot mutations in POLE at Pro286Arg and Val411Leu present in 76% of ultramutated samples. Increased frequency of C to A transversion. Increased mutations in PTEN (94%), PIK3R1 (65%), PIK3CA (71%); FBXW7 (82%), KRAS (53%). Improved progression-free survival. TCGA; Nature 2013

18 TCGA; Nature 2013

20 Molecular alterations in the PI(3)K pathway TCGA; Nature 2013

21 Molecular alterations in the RTK/RAS/β-catenin pathway TCGA; Nature 2013

22 Zhao et al; PNAS 2013

23 Endometrial carcinosarcoma <5% of all endometrial carcinomas Overal survival: 35% Stage I: 50% Estadio >II: 0-25%

24 p53 expression in endometrial carcinosarcoma Author p53 + De Jong et al /37 Keeling et al /12 Kanthan et al /23 Buza et al /30 Horn et al /1 Semczuk et al /1 Robinson-Bennett et al /5 Taylor et al /26 Kounelis et al /32 Iwasa et al /25 Abeln et al /4 Nicotina et al /10 Swisher et al /20 Mayall et al /17 Liu et al /23 This study 51/76 ALL STUDIES 175/310 (56.5%) p53 p16 Van de Vijver e al; in preparation

25 TP53 mutations in endometrial carcinosarcoma Author Total Jin et al /12 Watanabe et al /1 Soong et al /24 Kounelis et al /9 Abeln et al /4 Wada et al /25 Liu et al /23 ALL STUDIES 53/99 (53.5%) Van de Vijver e al; in preparation

26 Oncogene mutations in carcinosarcoma Biscuola et al; Hum Pathol 2013

27 Oncogene mutations in carcinosarcoma Oncogen Previous studies Present series Total PI3KCA 12/49 (24.5%) 6/34 (17%) 18/83 (21.7%) AKT ND 1/34 (2.9%) 1/34 (2.9%) KRAS 15/73 (20.5%) 3/34 (8.8%) 18/104 (17.3%) NRAS 1/31 (3.2%) 2/34 (5.8%) 3/65 (4.6%) BRAF 0/18 1/34 (2.9%) 1/52 (2%) CTNNB1 1/31 (3.2%) 0/18 1/49 (2%) PDGFRA 0/25 4/34 (11.7%) 4/59 (6.8%) KIT 0/55 2/34 (5.9%) 2/89 (2.3%) MET ND 2/34 (5.9%) 2/34 (5.9%) EGFR 0/18 2/34 (5.9%) 2/52 (3.8%) Biscuola et al; Hum Pathol 2013

28 Oncogene amplifications in carcinosarcoma Oncogen Ampl. Previous studies Present series Total EGFR ND 15/76 (19%) 15/76 (19%) HER2 19/142 (13.4%) 1/76 (1.3%) 20/218 (9.2%) ALK ND 1/76 (1.3%) 1/76 (1.3%) HER2 EGFR EGFR Biscuola et al; Hum Pathol 2013

29 EMT inducers and mirnas in carcinosarcoma Carcinoma Sarcoma SNAI1 SNAI2 ZEB1 LOXL2 mir-200f mir-203 mir-205 mir224 mir-133 Castilla et al; J Pathol 2011 Diaz et al; in preparation

30 HMGA2 IN ENDOMETRIALCARCINOSARCOMA * * HMGA2/ECS HMGA2/ECS EEC: 3% ESC: 45% ECS: 54% HMGA2 Lin28B HMGA2 Romero-Pérez et al; Hum Pathol 2013 let7a let7a Lin28B

31 Undifferentiated endometrial carcinomas Tumor composed of medium or large size cells with a complete absence of glandular differentiation, and with absent or minimal (<10%) neuroendocrine differentiation. UEC represents about 9% of all ECs. Some UECs develop as undifferentiated solid areas associated with grade 1 or 2 endometrioid carcinomas (dedifferentiated carcinomas) UEC remains under-recognized and it is often classified as FIGO grade 3 endometrioid adenocarcinoma. UECs have a more aggressive phenotype than grade 3 EECs.

32 Undifferentiated endometrial carcinomas MARKER G3 EEC UEC SEC MLH1 (-) 42% 30% 4% LYNCH? 21% 10% 19% p53 27% 33% 52% E-CDH (0) 20% 66% 40% ZEB % 7% HMGA2 0 24% 25% N-CDH 13% 50% 11% Cyt. p % 0 Romero-Pérez et al; Mod Pathol in press

33 p53

34 ZEB1

35 ZEB1 overexpression is associated with down-regulation of E-cadherin and microrna-200 expression in UEC Romero-Pérez et al; Mod Pathol in press

36 Conclusions Most endometrioid carcinomas had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, KRAS and mutations in the SWI/SNF chromatin remodelling complex (ARID1A, ARID5B). Uterine serous carcinomas and 25%of high-grade endometrioid carcinomas had extensive copy number alterations and frequent TP53 mutations and cell cycle alterations. A significant proportion of serous carcinomas have mutations in chromatin-remodeling genes and ubiquitin ligase complex genes. From a molecular point of view endometrial cancer can be classified into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Carcinosarcomas and undifferentiated carcinomas are characterized by a EMT molecular phenotype.

PATOLOGIA MOLECULAR DEL CANCER GINECOLOGICO. Xavier Matias-Guiu Hospital Universitari Arnau de Vilanova, Universitat de Lleida, IRBLLEIDA.

PATOLOGIA MOLECULAR DEL CANCER GINECOLOGICO Xavier Matias-Guiu Hospital Universitari Arnau de Vilanova, Universitat de Lleida, IRBLLEIDA. Carcinoma de Endometrio Cáncer de Ovario Endometrial carcinoma