TABLE 2.
Putative tumour suppressor genes of which function is lost in epithelial ovarian cancer
| Gene | Chromosome | Percentage of cancers in which downregulated or inactivated | Mechanisms of downregulation | Function |
|---|---|---|---|---|
| ARHI (DIRAS3) | 1p31 | 60% | Imprinting; LOH; promoter methylation; transcription downregulated by E2F1 and E2F4 | 26 kDa GTPase; inhibits proliferation and motility; induces autophagy and dormancy; upregulates P21; inhibits cyclin D1, PI3K, Ras–Mapk signalling and STAT3 |
| RASSF1A | 3p21 | 60% | Hypermethylation | Inhibits proliferation and tumorigenicity in many different cancers; interacts with Ras inhibiting and downregulating cyclin D and signalling through JNK; stabilizes microtubules; regulates spindle checkpoint; regulates CD95- and TNFα-induced apoptosis |
| DLEC1 | 3p22.3 | 73% | Promoter hypermethylation and histone hypoacetylation | 166 kDa cytoplasmic protein that inhibits anchorage-dependent growth |
| SPARC | 5q31 | 70–90% decreased expression; 9% lost expression | Transcription | 32 kDa Ca2*-binding protein; prevents adhesion |
| DAB2 (DOC2) | 5q13 | 58–85% lost expression | Transcription | 105 kDa protein binds GRB2, preventing Ras and Mapk activation; prevents FOS induction and decreases ILK activity; contributes to anoikis; inhibits proliferation; inhibits anchorage-independent growth and tumorigenicity |
| PLACL1 (LOT1) | 6q25 | 39% | Imprinting; LOH; transcription downregulated by EGF end TPA | 55 kDa nuclear zinc-finger protein; inhibits proliferation and tumorigenicity |
| RPS6KAZ | 6q27 | 64% | Monoallelic expression in ovary; LOH | 90 kDa ribosomal S6 serine threonine kinase; inhibits growth; induces apoptosis; decreases Erk phosphorylation and cyclin D1; increases p21 and p27 |
| PTEN | 10q23 | 3–8% mutated; expression lost in 27%, particularly in endometrioid and clear-cell histotypes | Promoter methylation; LOH; mutation | PI3 phosphatase; decreases proliferation, migration and survival; decreases cyclin D; increases p27 |
| OPCML | 11q25 | 56–83% | Promoter methylation; LOH; mutation | GPI-anchored IgLON family member induces aggregation; inhibits proliferation and tumorigenicity |
| BRCA2 | 13q12–13 | 3–6% | Mutation; LOH | Binds RAD51 during repair of DNA DSBs |
| ARL11 | 13q14 | 62% | Promoter methylation | ADP ribosylation factor; induces apoptosis |
| WWOX | 16q23 | 30–49%, particularly in mucinous end clear–cell histotypes | LOH; mutation | Decreases anchorage-independent growth and tumorigenicity; mouse homologue required for apoptosis |
| TP53 | 17p13.1 | 50–70% | Mutation | 53 kDa nuclear protein; induces p21 leading to cell cycle arrest and promotion of DNA stability; induces apoptosis |
| DPH1 | 17p13.3 | 37% | LOH | 50 kDa protein; decreases proliferation and clonogenicity; decreases cyclin Dl |
| BRCA1 | 17q21 | 6–8% | Mutation; LOH | E3 ubiquitin ligase that participates directly in repair of DNA DSBs through homologous recombination; regulates ABL1; induces p53, androgen receptor, oestrogen receptor and MYC |
| PEG3 | 19q13 | 75% | Imprinting; LOH; promoter methylation; transcription | Induces p53-dependent apoptosis |
Table adapted from REF. 11 ARL11. ADP-ribosylation factor-like 11; DAB2. disabled homologue 2; DLEC1. deleted in lung and esophageal cancer 1; DSB. double strand break; EGR, epidermal growth factor; CPI, glycosylphosphatidylinositol; GRB2. growth factor receptor-bound 2; ILK, integrin-linked kinase; JNK. JUN N-terminal kinase; LOH, loss of heterozygosity; OPCML, opioid-binding protein/cell adhesion molecule-Like; PEG3, paternally expressed 3; PLAGL1, pleiomorphic adenoma gene-like 1; RPS6KA2 ribosomal protein S6 kinase 2; SPARC. secreted protein, acidic, cysteine-rich; STAT3, signal transducer and activator of transcription 3; TNFα, tumour necrosis factor-α; TPA, tissue plasminogen activator.