perfiles de expresión génica y nuevas dianas terapéuticas en
TRANSCRIPT
Perfiles de expresión génica y nuevas dianas terapéuticas en cáncer de endometrio
Curso Corto “Actualización en Patología Ginecológica”
David Hardisson
Departamento de Anatomía Patológica
CARCINOMA SEROSOCARCINOMA ENDOMETRIOIDE
CA. DE ENDOMETRIO TIPO 1
� PERIMENOPAUSIA
� HIPERESTRONISMO
� ENDOMETRIOIDE
� BAJO GRADO Y ESTADIO
� HIPERPLASIA
CA. DE ENDOMETRIO TIPO 2
� POSTMENOPAUSIA
� SIN HIPERESTRONISMO
� SEROSO
� ALTO GRADO Y ESTADIO
� CA. INTRAEPITELIAL
p53ER
ER p53
CARCINOMA NO ENDOMETRIOIDE
CARCINOMA ENDOMETRIOIDE
Patología molecular del carcinoma de endometrio
Matias-Guiu X & Prat J. Histopathology 2013
INITIAL GENETIC CHANGES, INCLUDING PTEN INACTIVATION AND
MICROSATELLITE INSTABILITY MAY OCCUR IN THE ABSENCE OF A CHANGE IN
HISTOMORPHOLOGY.
Hecht JL & Mutter GL. J Clin Oncol 2006
Patología molecular del carcinoma de endometrio
Matias-Guiu X & Prat J. Histopathology 2013
Molecular bases of endometrial cancer: New roles for new actors in the diagnosis and the therapy of the disease
Llauradó M et al. Mol Cell Endocrinol 2012
Guión de la presentación
� Fenotipo molecular (CEE vs CNEE).
� Dianas terapéuticas.
� Otros aspectos interesantes: miRNA,
CEE vs CEO.
• 36 carcinomas de endometrio:
- 24 endometrioides
- 11 no endometrioides
• Diferencias expresión en 66
genes.
- 31 genes sobrexpresados en
CEE (regulados hormonalmente).
- 35 genes sobreexpresados en
CNEE ( 3 relacionados con mitosis).
- STK15: aneuploidía y fenotipo
agresivo.
- Amplificado en >50% de CNEE
y en ningún CEE (p<0.001).
cDNA microarray analysis and immunohistochemistry reveal a distinct molecular
phenotype in serous endometrial cancer compared to endometrioid endometrial cancer
� A low-density cDNA microarray containing 492 genes was
designed and constructed.
� The gene expression profiles of 32 endometrioid and 5 serous
endometrial cancer tissue samples were compared.
Chen Y et al. Exp Mol Pathol 2011
I, II, III: EAIV: SC
Chen Y et al. Exp Mol Pathol 2011
EA
SC
Chen Y et al. Exp Mol Pathol 2011
Serous adenocarcinoma exhibits distinct gene expression
profiles, compared with those of endometrioid
adenocarcinoma. These differences make it feasible to
validate microarray data by immunohistochemistry, and they
will ultimately allow us to identify tumors according to their
immunohistochemical phenotype. The accuracy of
classifying endometrial tumors using a system based on their
gene expression patterns is much higher than the accuracy
of the FIGO grading system. Thus, this gene expression
pattern-based system may prove to be crucial in developing
novel treatment strategies for endometrial cancers at the
molecular level in future.
cDNA microarray analysis and immunohistochemistry reveal a
distinct molecular phenotype in serous endometrial cancer
compared to endometrioid endometrial cancer
Chen Y et al. Exp Mol Pathol 2011
Early stage
USC EAC
Early stage Late stageLate stage
USCEAC
Good progn Good progn Poor prognPoor progn
Early vs Late stage Good vs Poor prognosis
10 EAC10 USC
USC versus EAC-G1
USC EAC-G1
USC versus EAC-G3
USC EAC-G3
The number of differentially expressed genes derived from USC vs. EAC-G3 comparison is consistently less than that derived from
USC vs. EAC-G1 comparison
USC versus EAC-G1 USC versus EAC-G3
High-grade EC
� exon 20 PIK3CA-AKT/p16+
� TP53/p16+/exon 9 PIK3CA
Analysis of angiogenesis-related gene expression reveals a profile with prognostic implications in endometrioid endometrial carcinoma
� 61 patients with EAC were included in this study.
� RNAs were collected from formalin-fixed paraffin-embedded samples.
� Specific TaqMan Gene Expression assays for 82 genes were selected and gene expression was determined by qRT-PCR with TaqMan Low Density Arrays (Applied Biosystems).
We generated a predictive model based on the expression
of 5 angiogenesis-related genes (EGFR, FGFR2, GSK3B,
PDK2, PIK3C3). According to the model, patients were
divided into 2 risk groups, with 85% sensibility and 72%
specificity. In a multivariate analysis including clinical
variables the model was independently associated with
overall survival.
Hazard Ratio
0.10 0.50 2.00 6.00 14.00
EGFR - 3.598637:1.912303
FGFR2 - 1.227729:-0.0594003
GSK3B - 2.801572:1.844283
0.99 0.
9
0.7
0.8
0.95
PDK2 - 5.865487:3.376232
PIK3C3 - 4.779652:3.162732
Mendiola M et al. USCAP 2013
Personalized Health Care – Fantasy or Reality?
Here’s my tumor’s DNA sequence
Drug-Dx Co-development
Predictive biomarker: a test that can be done before treatment to predict whether a particular treatment is likely to be beneficial
�To maximize clinical benefit from our therapeutics:� Informed decision making around indication choice
� Enable patient selection
Pharmacodynamic biomarker: a test that can be done pre- and post-treatment to confirm target modulation
Phase 1 Phase 2 Phase 3Preclinical Dev’t
TargetDiscovery
Biomarker discovery
Biomarker Assay Dev’t
Clinical Validationof biomarker hypothesis
FDA filing,approval,
launch
Drug
Dx
PMA filing,approval,
launchFDA draft white paper on Drug-Dx co-development
+
�Current regulatory paradigm requires early biomarker discovery
PI3K/PTEN Pathways: multiple nodes are candidates for molecules targeting core oncogenic pathways; potential for broad application,
combinations, with strong biomarker hypotheses
PTEN
PI3K Ras
BreastOvarianHNSCC
HCCNSCLC
Endometrial
ProstateGBM
MelanomaPancreatic
BladderGastric
p110αααα oncogenic mutations in: 37% Endometrial
29% Breast
25% Colon
13% BladderPIK3CA amplified in 30% ovarian, lungPTEN mutant/lost in: breast, prostate, glioblastoma, melanoma, pancreatic, endometrial, ovarian, lung, head and neck, hepatocellular, thyroid
CRC
Matias-Guiu X & Prat J. Histopathology 2013
Ratner ES et al. Gynecol Oncol 2010
2012
Pathwork Tissue of Origin Endometrial Test
Conclusiones
� Información “masiva”.
� Nuevos biomarcadores.
� Potenciales dianas terapéuticas.
� Nuevos procedimientos basados en técnicas
moleculares: incorporación a los Servicios de
Anatomía Patológica: integración morfología y
patología molecular.
