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
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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
p53ER
ER p53
NONENDOMETRIOID CARCINOMA
ENDOMETRIOID CARCINOMA
ENDOMETRIAL CARCINOSARCOMA (MMMT)
UNDIFFERENTIATED ENDOMETRIAL CARCINOMA
NORMAL
EPITHELIUM
Simple Hyperplasia Atrophic endometrium
(AE)
Complex Atypical
Hyperplasia
ENDOMETRIOID
CARCINOMA
(EEC)
Endometrial
Intraepithelial Carcinoma
NON-ENDOMETRIOID
CARCINOMA
(NEEC)
PROGRESSION MODEL FOR ENDOMETRIAL CARCINOMA
Prolif Secretory
K-Ras/PTEN
ββββ-catenin/
MSI/PI3KCA/
FGFR2
P53/CIN/?
p53
hMLH1 promoter hypermethylation
NON-CODING SEQUENCES
(BAT25, BAT26,...)
CODING SEQUENCES
PTEN, BAX, hMLH6, hMSH3, TGFββββ-RII, CASP-5, BCL10
RER+ phenotype
MSI
U M
EC1
U M
EC2
U M
EC3
U M
EC4
hMLH1 hMHS2
BAT25
TNN
T
CASP-5 (A10) BCL10 (A8) RAD50 (A9)
TP53 MUTATION
CHROMOSOME INSTABILITY
ANEUPOIDY
STK15, CCNE1, CCND1, HER2
ONCOGENE AMPLIFICATION LOH TSG
CHROMOSOME INSTABILITY
CDH1
CELL CYCLE ALTERATIONS
INVASION AND METASTASIS
ALLELIC IMBALANCES
Serous endometrial carcinoma
Reduced E-cadherin
T
N
D16S496
CCNE1Cyclin E
Nature, 2013
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%
RPL22 12.6% FBXW7 5.1%
TP53 11.4% FOXA2 5.1%
FGFR2 10.9% NRAS 2.9%
ARID5B 10.9%
Gene mutations in endometrioid endometrial carcinoma
TCGA; Nature 2013
*62/136 (45.5%) tumors with PTEN mutations has > 2 mutations
GENE Grade 1 Grade 2 Grade 3
CTNNB1 47.7% 36.8% 17.9%
TP53 0 11.8 30.8%
Gene mutations in endometrioid endometrial carcinoma
CTNNB1 PTEN RAS MSI
AH (11) 1 (9%) 4 (36%) 4 (36%) 1(9%)
AHWSM (14) 7 (50%) 0 0 0
Molecular alterations in
atypical endometrial hyperplasia
Bratchel, et al.; Am J Surg Pathol 2005
GENE FREQUENCY GENE FREQUENCY
TP53 90.7% 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%
COLA11 11.6% USP36 4.6%
TAF1 (30%), EP300 (8%), TSPYL2 (6%), MAP3K4 (6%) and ABCC9 (6%).
Gene mutations in serous endometrial carcinoma
TCGA; Nature 2013
Khun et al; J Natl Cancer Inst 2012.
Le Gallo et al; Nat Genet 2012;
Zhao et al; PNAS 2013.
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 non-synonymous 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
Somatic copy number alterations (SCNA)
TCGA; Nature 2013
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%),
Somatic copy number alterations (SCNA)
TCGA; Nature 2013
GENE FREQUENCY
PIK3CA 52%
CCNE1 48%
ERBB2 44%
MYC 40%
CHD4 28%
Zhao et al; PNAS 2013
Molecular subtypes of endometrial cancer
TCGA; Nature 2013
•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.
Endometrial cancer: ultramutated group (7%)
TCGA; Nature 2013
TCGA; Nature 2013
Molecular alterations in the PI(3)K pathway
TCGA; Nature 2013
Molecular alterations in the RTK/RAS/ββββ-catenin pathway
TCGA; Nature 2013
Zhao et al; PNAS 2013
<5% of all endometrial carcinomas
Overal survival: 35%�Stage I: 50%�Estadio >II: 0-25%
Endometrial carcinosarcoma
Author p53 +De Jong et al. 2011 17/37
Keeling et al. 2011 12/12
Kanthan et al. 2010 15/23
Buza et al. 2009 18/30
Horn et al. 2009 1/1
Semczuk et al. 2008 0/1
Robinson-Bennett et al. 2006 4/5
Taylor et al. 2006 15/26
Kounelis et al. 1998 25/32
Iwasa et al. 1998 7/25
Abeln et al. 1997 3/4
Nicotina et al. 1997 4/10
Swisher et al. 1996 6/20
Mayall et al. 1994 5/17
Liu et al. 1994 17/23
This study 51/76
ALL STUDIES175/310 (56.5%)
p53 expression in endometrial carcinosarcoma
Van de Vijver e al; in preparation
p53
p16
TP53 mutations in endometrial carcinosarcoma
Author Total Jin et al. 2003 3/12
Watanabe et al. 2001 1/1
Soong et al. 1999 11/24
Kounelis et al 1998 9/9
Abeln et al. 1997 4/4Wada et al. 1997 8/25
Liu et al. 1994 17/23
ALL STUDIES53/99
(53.5%)
Van de Vijver e al; in preparation
Oncogene mutations in carcinosarcoma
Biscuola et al; Hum Pathol 2013
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%)
Oncogene mutations in carcinosarcoma
Biscuola et al; Hum Pathol 2013
OncogenAmpl. 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%)
Oncogene amplifications in carcinosarcoma
Biscuola et al; Hum Pathol 2013
HER2EGFR
EGFR
SarcomaCarcinoma
EMT inducers and miRNAs in carcinosarcoma
SNAI1
SNAI2
ZEB1
LOXL2
miR-200fmiR-203miR-205miR224miR-133
Castilla et al; J Pathol 2011
Diaz et al; in preparation
HMGA2/ECS HMGA2/ECS
*
*
let7a let7a Lin28B
HM
GA
2
HM
GA
2
Lin
28B
EEC: 3%
ESC: 45%
ECS: 54%
Romero-Pérez et al; Hum Pathol 2013
HMGA2 IN ENDOMETRIALCARCINOSARCOMA
• 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.
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 1 0 62% 7%
HMGA2 0 24% 25%
N-CDH 13% 50% 11%
Cyt. p120 0 40% 0
Undifferentiated endometrial carcinomas
Romero-Pérez et al; Mod Pathol in press
p53
ZEB1
ZEB1 overexpression is associated with down-regulation of E-cadherin and microRNA-200 expression in UEC
Romero-Pérez et al; Mod Pathol in press
•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 TP53mutations 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.
Conclusions
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