Next Generation Sequencing and Molecular Biomarkers in Ovarian Cancer—An Opportunity for Targeted Therapy
Abstract
:1. Introduction
2. Next Generation Sequencing
Testing Modalities
3. Genomic Alterations and Targetable Therapeutics in Ovarian Cancer
3.1. Molecular Pathogenesis of Ovarian Cancers
3.2. Homologous Recombination Repair, PARP Inhibitors, and Role of BRCA1/2
3.2.1. Homologous Recombination Repair and Deficiency
3.2.2. HRD Incidence in HGSOC
3.2.3. PARP Inhibitors Targeted Therapy for HRD
3.3. Microsatellite Instability (MSI) and Mismatch Repair (MMR) as Indications for Immunotherapy
3.3.1. MSI and MMR Function
3.3.2. MSI-MMR Incidence
3.3.3. Use of Immunotherapy in dMMR/MSI-H Ovarian Cancer
3.4. Tumor Mutation Burden (TMB) as Biomarker for Immunotherapy
3.4.1. Tumor Mutation Burden as Biomarker
3.4.2. TMB-H Incidence
3.4.3. Use of Immunotherapy in TMB-H Ovarian Cancer
3.5. Programmed Death Ligand 1 (PD-L1) Expression as Biomarker for Immunotherapy
3.5.1. PD-L1 Expression and Function
3.5.2. PD-L1 Expression Incidence in Ovarian Cancer
3.5.3. Use of Immunotherapy in PD-L1 Positive Ovarian Cancer
3.6. NTRK Mutations
3.6.1. NTRK Gene Function
3.6.2. NTRK Gene Fusion Incidence
3.6.3. Targetable NTRK Mutations
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Histologic Subtype | Frequent Molecular Alterations | Available Targeted Therapies |
---|---|---|
Epithelial Tumors | ||
High grade serous carcinoma | TP53, BRCA1, BRCA2, HRR deficiency | PARP inhibitors (1) |
Low grade serous carcioma | KRAS, BRAF, NRAS, PIK3CA, ERBB2, PTEN, CTNNB1, ER/PR positive | MEK inhibitors (2) Fulvestrant (2) Hormonal therapy (2) |
Clear cell carcinoma | PIK3CA, ARID1A | None |
Endometrioid carcinoma | CTNNB1, ARID1A, PIK3CA | None |
Mucinous carcinoma | KRAS, ERBB2 | None |
Germ Cell Tumors | Karyotypic abnormalities | |
Dysgerminoma | KIT, DICER1, TP53, KRAS | None |
Yolk sac tumor | KRAS, PIK3CA | None |
Sex-Cord Stromal Tumors | DICER1 | None |
Granulosa cell tumors | FOXL2, ER/PR positive | Aromatase inhibitors (2) Leuprolide (2) |
Histology Agnostic | ||
TMB-H | Pembrolizumab (1) | |
MSI-H dMMR | Pembrolizumab (2) Dostarlimab (2) | |
NTRK fusions | Larotrectinib (2) Entrectinib (2) |
Testing Platform | Tissue Type | Genes Assessed | HRD | MSI | TMB | PD-L1 | FDA Approval |
---|---|---|---|---|---|---|---|
FoundationOne® CDx | FFPE | 324 | X | X | X | X + | Yes |
CARIS® MI Profile | FFPE | 592 * | X | X | X | X | Partial |
Tempus xT | FFPE plus blood or saliva | 648 ** | X + | X | X | X | No |
FoundationOne® Liquid CDx | Peripheral whole blood | 324 | X | X | X + | Yes | |
Guardant360® | Peripheral whole blood | 83 | X | X | No | ||
Tempus xF | Peripheral whole blood | 105 | X | X | No |
HRR Gene | Mutations per Number of Cases (%) | Number of Unique Mutations | Consequence of Mutation (Frequency/Total # Mut) |
---|---|---|---|
ATM | 15/437 (3.43%) | 16 | Missense (13/16) Stop gained (1/16) Splice donor deletion (1/16) Intron (1/16) |
BRIP1 | 6/436 (1.38%) | 6 | Missense (4/6) Frameshift (1/6) Intron (1/6) |
CHEK2 | 6/436 (1.38%) | 7 | Missense (4/7) Synonymous (2/7) Splice acceptor (1/7) |
NBN | 4/436 (0.92%) | 4 | Missense (1/4) Frameshift (1/4) Synonymous (2/4) |
PALB2 | 11/437 (2.52%) | 12 | Missense (7/12) Stop gained (2/12) 3′ UTR (1/12) Splice region substitution (1/12) Protein altering insertion (1/12) |
RAD51B | 3/436 (0.69%) | 2 | Frameshift (1/2) Intron (1/2) |
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Harbin, L.M.; Gallion, H.H.; Allison, D.B.; Kolesar, J.M. Next Generation Sequencing and Molecular Biomarkers in Ovarian Cancer—An Opportunity for Targeted Therapy. Diagnostics 2022, 12, 842. https://doi.org/10.3390/diagnostics12040842
Harbin LM, Gallion HH, Allison DB, Kolesar JM. Next Generation Sequencing and Molecular Biomarkers in Ovarian Cancer—An Opportunity for Targeted Therapy. Diagnostics. 2022; 12(4):842. https://doi.org/10.3390/diagnostics12040842
Chicago/Turabian StyleHarbin, Laura M., Holly H. Gallion, Derek B. Allison, and Jill M. Kolesar. 2022. "Next Generation Sequencing and Molecular Biomarkers in Ovarian Cancer—An Opportunity for Targeted Therapy" Diagnostics 12, no. 4: 842. https://doi.org/10.3390/diagnostics12040842