Ovarian cancer, the leading cause of death from gynecologic malignancy, is characterized by advanced presentation with loco-regional dissemination in the peritoneal cavity and the rare incidence of visceral metastases (Chi et al., 2001). These typical features relate to ... Ovarian cancer, the leading cause of death from gynecologic malignancy, is characterized by advanced presentation with loco-regional dissemination in the peritoneal cavity and the rare incidence of visceral metastases (Chi et al., 2001). These typical features relate to the biology of the disease, which is a principal determinant of outcome (Auersperg et al., 2001). Epithelial ovarian cancer is the most common form and encompasses 5 major histologic subtypes: papillary serous, endometrioid, mucinous, clear cell, and transitional cell. Epithelial ovarian cancer arises as a result of genetic alterations sustained by the ovarian surface epithelium (Stany et al., 2008; Soslow, 2008).
Grindedal et al. (2010) performed a retrospective survival study of 144 women with ovarian cancer due to MMR mutations. Fifty-one (35.4%) had a mutation in MLH1, 78 (54.2%) had a mutation in MSH2, and 15 (10.4%) had a ... Grindedal et al. (2010) performed a retrospective survival study of 144 women with ovarian cancer due to MMR mutations. Fifty-one (35.4%) had a mutation in MLH1, 78 (54.2%) had a mutation in MSH2, and 15 (10.4%) had a mutation in MSH6. The mean age of onset was 44.7 years, compared to 51.2 years in carriers of BRCA1 (113705) mutations with ovarian cancer and 57.5 in carriers of BRCA2 (600185) mutations with ovarian cancer (Risch et al., 2001). Most (81.5%) women with MMR mutations were diagnosed at stage 1 or 2. Twenty-nine (20.1%) of 144 woman with MMR-related ovarian cancer died of their ovarian cancer. The 5-, 10-, 20- and 30-year survival specific for deaths due to ovarian cancers were 82.7%, 80.6%, 78.0% and 71.5%, respectively. About 50% of the women developed another cancer in the HNPCC/Lynch syndrome tumor spectrum. The 5-, 10-, 20-, and 30-year survival specific for deaths due to HNPCC/Lynch syndrome-associated cancers were 79.2%, 75.7%, 68.4% and 47.3%, respectively. Overall, the survival for women with ovarian cancer due to MMR mutations was better than for those with ovarian cancer due to BRCA1/2 mutations, which is less than 40% at 10 years. The lifetime risk of ovarian cancer in MMR mutation carriers was about 10% and the risk of dying from ovarian cancer was 20%, yielding an overall risk of dying from ovarian cancer of about 2% in MMR mutation carriers. Grindedal et al. (2010) suggested that mutations in the MMR and BRCA1/2 genes may predispose to biologically different types of tumors.
Stratton et al. (1999) conducted a population-based study to determine the contribution of germline mutations in known candidate genes to epithelial ovarian cancer diagnosed before the age of 30 years. Two of 101 ... - Germline Mutations Stratton et al. (1999) conducted a population-based study to determine the contribution of germline mutations in known candidate genes to epithelial ovarian cancer diagnosed before the age of 30 years. Two of 101 women with invasive ovarian cancer had germline mutations in the MLH1 gene (120436), which is involved in hereditary nonpolyposis colorectal cancer-2 (HNPCC2; 609310). In addition to colon cancer, ovarian cancer may be a manifestation of this syndrome. No germline mutations were identified in any of the other genes analyzed, including BRCA1, the 'ovarian cancer-cluster region' (nucleotides 3139-7069) of BRCA2, and MSH2. There were no striking pedigrees suggestive of families with either breast/ovarian cancer or HNPCC. There was a significantly increased incidence of all cancers in first-degree relatives of women with invasive disease (relative risk = 1.6, P = 0.01), but not in second-degree relatives or in relatives of women with borderline cases. First-degree relatives of women with invasive disease had an increased risk of ovarian cancer, myeloma, and non-Hodgkin lymphoma. The data indicated that germline mutations in BRCA1, BRCA2, MSH2, and MLH1 contribute to only a minority of cases of early-onset epithelial ovarian cancer. Liede et al. (1998) raised the question of the existence of hereditary site-specific ovarian cancer as a genetic entity distinct from hereditary breast-ovarian cancer syndrome. They identified a large Ashkenazi Jewish kindred with 8 cases of ovarian carcinoma and no cases of breast cancer. However, in all but 1 of the ovarian cancer cases, the 185delAG mutation in the BRCA1 gene (113705.0003) segregated with the cancer. Liede et al. (1998) concluded that site-specific ovarian cancer families probably represent a variant of the breast-ovarian cancer syndrome, attributable to mutation in either BRCA1 or BRCA2. - Somatic Mutations Cesari et al. (2003) identified the complete PARK2 gene (602544) within an LOH region on chromosome 6q25-q27. LOH analysis of 40 malignant breast and ovarian tumors identified a common minimal region of loss, including the markers D6S305 (50%) and D6S1599 (32%), both of which are located within the PARK2 gene. Expression of the PARK2 gene appeared to be downregulated or absent in the tumor biopsies and tumor cell lines examined. In addition, Cesari et al. (2003) found 2 somatic truncating deletions in the PARK2 gene (see, e.g., 602544.0016) in 3 of 20 ovarian cancers. The data suggested that PARK2 may act as a tumor suppressor gene. Because PARK2 maps to FRA6E, one of the most active common fragile sites in the human genome (Smith et al., 1998), it may represent another example of a large tumor suppressor gene, like FHIT (601153) and WWOX (605131), located at a common fragile site. Denison et al. (2003) found that 4 (66.7%) ovarian cancer cell lines and 4 (18.2%) primary ovarian tumors were heterozygous for the duplication or deletion of 1 or more exons in the PARK2 gene. Additionally, 3 of 23 (13%) nonovarian tumor-derived cell lines were found to have a duplication or deletion of 1 or more parkin exons. Diminished or absent parkin expression was observed in most of the ovarian cancer cell lines when studies with antibodies were performed. Denison et al. (2003) suggested that parkin may represent a tumor suppressor gene. Sellar et al. (2003) determined that D11S4085 on 11q25 is located in the second intron of the OPCML gene (600632). OPCML was frequently somatically inactivated in epithelial ovarian cancer tissue by allele loss and by CpG island methylation. OPCML has functional characteristics consistent with tumor suppressor gene properties both in vitro and in vivo. A somatic missense mutation from an individual with epithelial ovarian cancer showed clear evidence of loss of function (600632.0001). These findings suggested that OPCML was an excellent candidate for an ovarian cancer tumor suppressor gene located on 11q25. By examining DNA copy number of 283 known miRNA genes, Zhang et al. (2006) found a high proportion of copy number abnormalities in 227 human ovarian cancer, breast cancer, and melanoma specimens. Changes in miRNA copy number correlated with miRNA expression. They also found a high frequency of copy number abnormalities of DICER1 (606241), AGO2 (EIF2C2; 606229), and other miRNA-associated genes in these cancers. Zhang et al. (2006) concluded that copy number alterations of miRNAs and their regulatory genes are highly prevalent in cancer and may account partly for the frequent miRNA gene deregulation reported in several tumor types. Kan et al. (2010) reported the identification of 2,576 somatic mutations across approximately 1,800 megabases of DNA representing 1,507 coding genes from 441 tumors comprising breast, lung, ovarian, and prostate cancer types and subtypes. Kan et al. (2010) found that mutation rates and the sets of mutated genes varied substantially across tumor types and subtypes. Statistical analysis identified 77 significantly mutated genes including protein kinases, G protein-coupled receptors such as GRM8 (601116), BAI3 (602684), AGTRL1 (600052), and LPHN3, and other druggable targets. Integrated analysis of somatic mutations and copy number alterations identified another 35 significantly altered genes including GNAS (see 139320), indicating an expanded role for G-alpha subunits in multiple cancer types. Experimental analyses demonstrated the functional roles of mutant GNAO1 (139311) and mutant MAP2K4 (601335) in oncogenesis. The Cancer Genome Atlas Research Network (2011) reported that high-grade serous ovarian cancer is characterized by TP53 (191170) mutations in almost all tumors (96% of 489 high-grade serous ovarian adenocarcinomas); low prevalence but statistically recurrent somatic mutations in 9 further genes including NF1 (613113), BRCA1 (113705), BRCA2 (600185), RB1 (614041), and CDK12 (615514); 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated 4 ovarian cancer transcriptional subtypes, 3 microRNA subtypes, 4 promoter methylation subtypes, and a transcriptional signature associated with survival duration, and shed new light on the impact that tumors with BRCA1/2 and CCNE1 (123837) aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumors analyzed, and that NOTCH (190198) and FOXM1 (602341) signaling are involved in serous ovarian cancer pathophysiology. - Modifier Genes Quaye et al. (2009) used microcell-mediated chromosome transfer approach and expression microarray analysis to identify candidate genes that were associated with neoplastic suppression in ovarian cancer cell lines. In over 1,600 ovarian cancer patients from 3 European population-based studies, they genotyped 68 tagging SNPs from 9 candidate genes and found a significant association between survival and 2 tagging SNPs in the RBBP8 gene (604124), dbSNP rs4474794 (hazard ratio, 0.85; 95% CI, 0.75-0.95; p = 0.007) and dbSNP rs9304261 (hazard ratio, 0.83; 95% CI, 0.71-0.95; p = 0.009). Loss of heterozygosity (LOH) analysis of tagging SNPs in 314 ovarian tumors identified associations between somatic gene deletions and survival. Thirty-five percent of tumors in 101 informative cases showed LOH for the RBBP8 gene, which was associated with a significantly worse prognosis (hazard ratio, 2.19; 95% CI, 1.36-3.54; p = 0.001). Quaye et al. (2009) concluded that germline genetic variation and somatic alterations of the RBBP8 gene in tumors are associated with survival in ovarian cancer patients.