Endometrial Cancer Molecular Characterization: The Key to Identifying High-Risk Patients and Defining Guidelines for Clinical Decision-Making?
Abstract
:Simple Summary
Abstract
1. Introduction
1.1. Incidence and Symptoms
1.2. Classification
1.3. Current Treatment Options
2. The Cancer Genome Atlas (TCGA) Molecular Classification for Endometrial Cancer
3. Post TCGA Molecular Classification and Prognostic Significance in Endometrial Cancer
3.1. Prognostic Impact of Histology and Grade
3.2. Prognostic Impact within High-Risk EC (HR-EC)
4. Treatment Benefit in HR-ECs under the Influence of TCGA Molecular Subtypes
5. Potential Clinico-Molecular Guided Risk Stratification and Treatment Benefit in HR-ECs
6. Potential of Molecular Targeted Therapies in HR ECs
7. Characterization of EC Patient-Derived Preclinical Models
8. Conclusions and Future Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
Akt | Protein kinase B |
APC | Adenomatous polyposis coli |
ARID1A | AT-rich interaction domain 1A |
ARID5B | AT-rich interaction domain 5B |
CDH1 | Cadherin-1 |
CTCF | CCCTC-binding factor |
CSS | Cancer specific survival |
CTNNB1 | Catenin beta 1 |
CCNE1 | Cyclin E1 |
CDK4,6 | Cyclin-dependent kinase 4,6 |
CHD4 | Chromodomain helicase DNA-binding protein 4 |
COL1A1 | Collagen Type I Alpha 1 Chain |
CNH | Copy number high |
CNL | Copy number low |
CR | |
CSMD3 | CUB and Sushi multiple domains 3 |
DNA-PK | DNA-dependent protein kinase |
EC | Endometrial cancer |
EEC | Endometrioid endometrial cancer |
EZH2 | Enhancer of zeste homolog 2 |
ER/PR | Estrogen/progesterone receptor |
EGFR | Epidermal growth factor receptor |
E-cadherin | Epithelial cadherin |
EBRT | External beam radiotherapy |
ENITEC | European Network for Individualized Treatment of Endometrial Cancer |
ESGO | European Society of Gynaecological Oncology |
ESMO | European Society for Medical Oncology |
ESTRO | European SocieTy for Radiotherapy & Oncology |
FANCD2 | Fanconi Anemia, Complementation Group D2 |
FBXW7 | F-box and WD repeat domain containing protein 7 |
FGFR2 | Fibroblast growth factor receptor 2 |
GOG | Gynecologic Oncology Group |
δ-H2AX | H2A histone family member X |
HER2 | Human epidermal growth factor receptor 2 |
HIR | High–intermediate risk |
HRD | Homologous recombination deficiency |
HR-ECs | High-risk endometrial cancer |
IMRT | Intensity-modulated radiation therapy |
FIGO | International Federation of Gynecology and Obstetrics |
KRAS | KRAS proto-oncogene, GTPase |
L1CAM | L1 cell adhesion molecule |
KMT2B | Lysine Methyltransferase-2B |
LVSI | Lymphovascular space invasion |
mTOR | Mammalian target of rapamycin |
MSI | Microsatellite instability |
MSI-H | Microsatellite instability-high |
MMR | Mismatch repair |
SMAD4 | Mothers against decapentaplegic homolog 4 |
MLH | MutL homolog 1 |
MYC | MYC Proto-Oncogene |
NRAS | Neuroblastoma RAS viral oncogene homolog |
OS | Overall survival |
ORR | Overall response rate |
PADI2 | Peptidyl arginine deiminase 2 |
PARP1 | PARP Poly (ADP-ribose) polymerase 1 |
PD-1 | Programmed cell death protein 1 |
PD-L1/2 | Programmed cell death protein ligand ½ |
PI3K | Phosphoinositide 3-kinase |
PIK3CA | Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha |
PIK3R1 | Phosphoinositide-3-kinase regulatory subunit 1 |
PDX | Patient-derived xenograft |
POLE | Polymerase ɛ |
POLE-mt | Polymerase mutant |
PORTEC3 | Postoperative Radiation Therapy in Endometrial Cancer 3 |
PFS | Progression free survival |
ProMisE | Proactive Molecular Risk Classifier for Endometrial Cancer |
PPP2R1A | Protein Phosphatase 2 scaffold subunit A alpha |
PgR | Progesterone receptor |
PR | Partial response |
PTEN | Phosphatase and tensin homolog |
RAD51 | RAD51 recombinase |
RFS | Recurrence-free survival |
RPL22 | Ribosomal protein L22 |
SOX17 | SRY-related HMG-box 17 |
p53 | TP53 Tumor protein |
TCGA | The Cancer Genome Atlas |
TGF-β1 | Transforming growth factor beta 1 |
VBT | Vaginal brachytherapy |
VEGFR | Vascular endothelial growth factor receptor |
Wnt | Wingless/integration-1 |
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Genetic Alteration | Type I (%) | Type II (%) | Reference |
---|---|---|---|
PTEN mutation | 30–93.7 | 2–55 | [13,14,15,16,17,18] |
PTEN loss | 80 | 5 | [13,14,15,16,17,18] |
MSI mutation | 33–44 | 2–14 | [13,14] |
TP53 mutation | 3–35 | 28–93 | [13,15,16,17] |
POLE mutation | 11–20 | 2–7 | [13] |
PIK3CA mutation | 22–90 | 10–50 | [13,14,15,16,17] |
PIK3R1 mutation | 9–43 | 5–20 | [13,17] |
CTNNB1 mutation | 19–52 | 2.7–4.8 | [13,15] |
ARID1A mutation | 39–68.7 | 7–24 | [6,10,18] |
KRAS mutation | 7–43 | 2–17 | [13,14,15,16] |
FGFR2 mutation | 2–18 | 1–8 | [13,16] |
FBXW7 mutation | 10–15 | 7.9–39 | [13,15] |
PPP2R1A mutation | 2.5–13 | 7–43.2 | [13,15,17] |
KMT2B mutation | 43.7 | 0 | [17] |
CTCF mutation | 20.6 | 0 | [17] |
CHD4 mutation | 0 | 16.3 | [17] |
RPL22 mutation | 12 | 0 | [18] |
ARID5B mutation | 11 | 0 | [18] |
CSMD3 mutation | 0 | 11.6 | [18] |
COL1A1 mutation | 0 | 11.6 | [18] |
HER2 overexpression | 3–10 | 18–80 | [14,16] |
HER2 amplification | 1–4 | 9–44 | [13,16] |
ER and PgR overexpression | 70–73 | 19–24 | [14] |
E-cadherin loss | 5–50 | 60–90 | [16] |
EGFR overexpression | 46 | 34 | [16] |
Molecular Subgroup | Characteristics | Mutations | Somatic Mutation Rate | Prognosis |
---|---|---|---|---|
POLE-mt | EEC grade 3 tumors POLE exonuclease domain mutations, with V411L and P286R being the most common hotspot mutations in POLE | PTEN (94%), PIK3CA (71%), PIK3R1 (65%), FBXW7(82%), ARID1A (76%), KRAS (53), ARID5B (47%) | Very high (232 × 106 mutations/Mb) | Excellent prognosis even in high grade tumors |
MSI | EEC with high histological grade Most result of epigenetic silencing of MLH1 by promoter hypermethylation coupled with low PTEN levels and high phospho-AKT levels. | PTEN(88%), RPL22 (33%), KRAS (35%), PIK3CA (54%), PIK3R1 (40%), ARID 1A (37%) | High (18 × 106 mutations/Mb) | Intermediate prognosis |
CNH | Mainly serous endometrial tumors (94%) and mixed EC (62%), with fraction of EEC (12%), and about 25% of high-grade EEC. High copy number alterations. | TP53 (92%), PPP2R1A (22%), PIK3CA (47%) Recurrent amplifications in MYC, HER2, CCNE1, FGFR3 and SOX17 | Low (2.3 × 106 mutations/Mb) | Poor prognosis with significantly worse progression-free survival |
CNL | Microsatellite stable tumors EEC (grades 1, 2 and 3) low somatic copy number alterations p53-wild-type (p53-wt) or few TP53 mutations | PTEN (77%), PIK3CA (53%), PIK3R1 (33%), ARID1A (42%), CTNNB1 (52%) | Low (2.9 × 106 mutations/Mb) | Good-to-intermediate prognosis Significant prognostic impact Mutations in exon 3 of CTNNB1, L1CAM and ER/PR expression Amplification of chromosome 1q1q32.1 |
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Baiden-Amissah, R.E.M.; Annibali, D.; Tuyaerts, S.; Amant, F. Endometrial Cancer Molecular Characterization: The Key to Identifying High-Risk Patients and Defining Guidelines for Clinical Decision-Making? Cancers 2021, 13, 3988. https://doi.org/10.3390/cancers13163988
Baiden-Amissah REM, Annibali D, Tuyaerts S, Amant F. Endometrial Cancer Molecular Characterization: The Key to Identifying High-Risk Patients and Defining Guidelines for Clinical Decision-Making? Cancers. 2021; 13(16):3988. https://doi.org/10.3390/cancers13163988
Chicago/Turabian StyleBaiden-Amissah, Regina Esi Mensimah, Daniela Annibali, Sandra Tuyaerts, and Frederic Amant. 2021. "Endometrial Cancer Molecular Characterization: The Key to Identifying High-Risk Patients and Defining Guidelines for Clinical Decision-Making?" Cancers 13, no. 16: 3988. https://doi.org/10.3390/cancers13163988