Table 1.
Summary of selected genetic alterations and clinical significance in ovarian carcinomas.
| Catalogues | Major genetic alterations | Clinical implications | Ref(s). |
|---|---|---|---|
| Detection/diagnosis | |||
| Germline mutations in BRCA1 or BRCA2 | Increased lifetime risk of developing OC; routine surveillance for early OC; indications for risk-reducing salpino-oorphorectomy | 9, 10 | |
| Germline mutations in mismatch repair genes | A 8%-10% risk of OC (Lynch syndrome); routine clinical surveillance for early OC | 13 | |
| Novel germline mutations in BARD1, BRIP1, PALB2, RAD50, RAD51C, RAD51D, TP53, ASXL1, MAP3K1, and SETD2, etc | Conferred a subset of familial OCs with high and moderate penetrance or a moderate OC susceptibility that may warrant their use in routine clinical genetic testing | 15-19 | |
| An integrated analysis of germline and somatic exome variants in OC | The candidate variants and genes have important implications for OC susceptibility and the development of screening strategies. | 20 | |
| Germline mutation in SMARCA4 (BRG1) | Improvements in genetic counseling and early detection for SSCHOT | 32-34 | |
| Mutations/loss of expression in SMARCA4 (BRG1) | Essential for precision diagnosis and potential novel treatment for SSCHOT | 35-37 | |
| Mutations of PIK3CA, RB1, and MED1 in plasma of OC patients following therapy | Applicable to monitor OC patients with high systemic tumor burden, metastasis and therapy response | 61 | |
| Risk assessment | |||
| rs7651446(3q25), rs9303542 (17q21), rs11782652 (8q21), rs1243180 (10p12), rs757210 (17q12) | Predicting OC risks | 41 | |
| rs8170 and rs2363956 at 19p13.11 | Predicting survival and genome-wide serous OC risks | 42 | |
| rs2072590 (2q31), rs2665390 (3q25), rs10088218 (8q24), rs9303542 (17q21) | Predicting OC risks | 43 | |
| rs3814113 (9p22.2) | OC risks, strongest for serous OC risks | 44 | |
| rs752590 (2q13), rs711830 (2q31.1), rs688187 (19q13.2) | Risk associations with mucinous OC | 45 | |
| Mutations in BRIP1 (c.2040_2041insTT, c.1702_1703del) | An increase in OC risks | 46 | |
| rs3814113 (9p22.2) | A reduced OC risk in BRCA1/BRCA2 mutation carriers | 49 | |
| Chemotherapy response/prognosis evaluation | |||
| Germline/somatic mutations in BRCA1, BRCA2 and other genes in the HR pathway | 1) Predictive of platinum sensitivity and longer survival in women with HGSOC; 2) Benefit from PARP inhibitors. | 3, 29-31 | |
| rs7874043 in TTC39B | The minor allele is strongly associated with PFS in patients with serous carcinoma following first-line chemotherapy. | 50 | |
| rs4910232(11p15.3), rs2549714(16q23), and rs6674079 (1q22) | The rare alleles were significantly associated with poorer outcomes in OC patients who underwent first-line treatment of cytoreductive surgery and chemotherapy. | 51 | |
| rs1649942 | Associated with PFS and OS in OC patients with carboplatin-based chemotherapy | 52 | |
| Reactivation of HR genes in platinum-resistant versus primary OCs; Increased platinum score of 13 CNAs in recurrent tumors | Treatment options should be tailored to the changing genetic profiles. All primary platinum-sensitive HGSOCs are qualified for second-line PARP inhibitor treatment. | 56 | |
| Clonal escape in chemotherapy; Novel mutations in the Golgi and ECM pathways | Target therapy towards the persistent mutations may be effective for tumor relapse while novel mutations may offer new therapeutic targets for recurrent tumors. | 57 | |
| Mutations from 8 members of the ADAMTS family | Helpful molecular markers for predicting chemotherapy response and prognosis in OC. | 58 | |
| Gains on 1q, 5q14~q23, and 13q21~q32, and losses of 8p and 9q | Clinical carboplatin resistance | 62 | |
| Gains on 1q25.2 and 1q32.2 | Clinical carboplatin resistance | 63 | |
| Loss on 13q32.1 and 8p21.1 | Predictive markers of chemoresistant serous carcinoma | 64 | |
| Gain in 3q26.2, and losses in 6q11.2-12, 9p22.3, 9p22.2-22.1, 9p22.1-21.3, Xp22.2-22.12, Xp22.11-11.3, and Xp11.23-11.1. |
Potential predictive markers of chemotherapy resistance | 65 | |
| Gains in 9p13.2-13.1, 9q21.2-21.32, 9q21.33, 9q22.2-22.31, 9q22.32-22.33 and 9q33.1-34.11 | Potential predictive markers of docetaxel/carboplatin resistance | 66 | |
| Losses of 4p, 4q31.1- qter, 5q12-q22, 8p, 16q, and X | Poor survival in stage III OC | 68 | |
| CCNE1 amplification | Poor prognosis in postoperative OCs | 4, 69 | |
| High-level amplifications at 8q24, loss of 5q | Favorable prognosis for serous OC | 70 | |
| Gain in 5p or gain in 1p and loss in 5q | A higher or significantly decrease risk of recurrence | 72 | |
| Two distinct hierarchical clusters of CNA | Patients from cluster-1 had a significantly shorter median PFS than those from cluster-2. | 73 | |
| Met amplification in ovarian clear cell carcinoma | Worse survival | 74 | |
| Target therapy/individualized therapy | |||
| Various molecular subtypes of OC signature associated with survival | They provide an opportunity to improve OC outcomes through subtype-stratified care. | 3 | |
| Few point mutations in low grade serous carcinomas and borderline tumors | Target therapeutic agents against BRAF and KRAS might be particularly effective for the recurrent inoperative cases. | 53,54 | |
| Recurrent mutations in ELF3, RNF43, GNAS, ERBB3 and KLF5 in mucinous OC | Potential novel targeted therapy for some high grade mucinous carcinomas | 55 | |
| The heterogeneity in the genome of HGSOC under the selective pressure of chemotherapy | Overcoming resistance to conventional chemotherapy will require a diversity of approaches, such as use of new inhibitors MDR1 and PARP. | 4 | |
| PPM1D amplification | A potential therapeutic target for a subgroup of ovarian clear cell carcinomas | 75 | |
| HER2 amplification | A potential therapeutic target | 76-78 | |
Abbreviations: OC=ovarian carcinoma; PFS= poor progression-free survival; HR= homologue recombinant; OS=overall survival; CNA=copy number aberration; HGSOC= high grade serous ovarian carcinoma.