About Ovarian Cancer
Why study Ovarian Cancer?
Ovarian cancer causes around 125,000 deaths globally per year. Over the last 40 years, long term survival rates have changed very little: About 70% of women with ovarian cancer are diagnosed with advanced stage disease (stages III/IV), of whom only less than 40% will survive more than 5 years. By contrast, women diagnosed with earlier stage (stage 1) disease have a 5-year survival rate greater than 90%. The standard treatment for ovarian cancer consists of maximal cytoreductive surgery followed by administration of platinum and taxane-based chemotherapy. Most patients with advanced stage (III/IV) ovarian cancer initially respond well to primary treatment with surgery and chemotherapy, but cancer usually recurs with a drug-resistant phenotype.
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There are few clinical intervention strategies that are effective at either detecting epithelial ovarian cancer at the earliest most treatable stages, or chemo preventive strategies to reduce the burden of disease mortality. Signs and symptoms of early stage ovarian cancer are usually absent, and even when they are present in patients with late stage disease, symptoms are often subtle and may vary by ovarian cancer histotype. There are currently no effective screening approaches for detecting early stage EOC. Serum CA-125 testing is useful for differential disease diagnosis, but has not been shown to be an effective early-stage screening approach due to its low sensitivity and specificity. HE4 is another candidate ovarian cancer screening marker, although it has not been extensively tested in clinical trials. Vaginal ultrasonography can detect adnexal masses consistent with ovarian cancer, but once again this does not appear to be effective for detecting early stage ovarian cancer.
Invasive epithelial ovarian cancer represents 90% of all malignant ovarian tumors and comprises four major histological subtypes: High-grade serous, endometrioid, clear cell and mucinous ovarian cancer. Each histotype show differences in their clinical courses and survival rates. There are also two main histological subtypes of benign disease: Low grade serous and low malignant potential ovarian cancer. Different histotypes have distinct cells of origin and can be characterized by different germline and somatic genetic changes that result in the perturbation of different molecular pathways. Even within each of the different histotypes there may be significant clinical and molecular heterogeneity.
High Grade Serous Ovarian Cancer
High grade serous is the most common and the most lethal histotype of ovarian cancer. Tumors almost invariably acquire P53 mutation, DNA double strand break (DSB) repair deficiency and a genomic instability phenotype. High grade serous ovarian cancers are the predominant histotype that develops in patients carrying germline pathogenic mutations in DSB repair genes including BRCA1, BRCA2, BRIP1, RAD51C and RAD51D. Evidence indicates that high grade serous tumors originate from fallopian tube secretory epithelial cells which transform into the precursor lesion serous tubal intra-epithelial carcinomas (STICs) en route to high grade serous ovarian cancers
Mucinous Ovarian Cancer
Mucinous ovarian cancer is a rare tumor type accounting for approximately 3% of all epithelial ovarian cancers. These tumor are characteristically diagnosed at a younger age than patients diagnosed with other histotype of invasive disease. The tissues and cells of origin of mucinous ovarian cancers remain unknown, but their characteristic morphology and mutational targets in disease progression (i.e. the oncogenes RAS and BRAF) suggest they may derive from tissues with gastrointestinal lineages
Clear Cell Ovarian Cancer
Clear cell ovarian carcinomas represent 5-10% of invasive ovarian cancer with higher rates in Asian population (~11 percent) compared Europeans (~5 percent) and African Americans (~3 percent). Women dignosed with endometriosis are at a particularly increased risk of developing clear cell ovarian cancers suggesting that endometriotic lesions are a benign precursor for this histotype. Clear cell ovarian cancers have a distinct biology compared to high grade serous and mucinous tumors which may also reflects the different spectrum of gene mutations associated with cancer developed, which includes ARID1A, PIK3CA, TERT and the mismatch repair genes
Endometrioid Ovarian Cancer
Endometrioid ovarian cancers represent 2 to 4 percent of all invasive epithelial ovarian tumors. Etiologically they share many similarities with clear cell ovarian cancers: They occur more frequently in Asian populations compared to Europeans and African Americans and in women with a history of endometriosis; and they share a similar spectrum of gene mutation targets associated with cancer progression (e.g. ARID1A, PIK3CA, mismatch repair genes). High grade endometrioid and high grade serous ovarian cancers can appear pathologically similar which may reflect differences in the reporting of gene mutation frequencies and the prevalence of endometrioid ovarian cancers more generally.
Several epidemiologic studies have suggested that exposure to endogenous and exogenous hormones play an important role in ovarian cancer etiology. Oral contraceptive use and parity are both protective, with decreasing risks associated with increasing duration of oral contraceptive use and increasing parity. Younger age at menarche, breastfeeding and hysterectomy are associated with a reduction in ovarian cancer risk, while the use of menopausal hormone therapy (particularly estrogen only therapy) is associated with an increase in ovarian cancer risk. In both clinical trials and cohort studies, long-term post-menopausal hormone use is associated with increased ovarian cancer risks. A meta-analysis has indicated an approximate 20% increases of ovarian cancer risk per 5 years of postmenopausal estrogen use. Tubal ligation is another well-established risk factor which is inversely associated with ovarian cancer risk.
Some risk factors are reportedly associated with specific histotypes of ovarian cancer. Obesity may be weakly associated with an increased risk of low-grade serous invasive tumors but not invasive high-grade serous disease; and high body mass index may be associated with increased risk of borderline serous, invasive endometrioid, and invasive mucinous ovarian cancers. It is also well established that endometriosis is risk factor for clear cell and endometrioid ovarian cancer, but not for high-grade serous or mucinous histotypes. A meta-analysis has found an association between smoking and mucinous ovarian cancer, an inverse association for risks of endometrioid and clear cell ovarian cancers, and no association with high-grade and borderline serous histotypes. Menopausal hormone therapy appears to be more associated increased risks of serous and endometrioid ovarian cancers compared to other subtypes. Finally, oral contraceptive use (ever/ never) is associated with reduced risk for the serous and endometrioid subtypes, but is only weakly associate with reduced risks of mucinous and clear cell ovarian cancers.
Family history remains one of the strongest risk factors for ovarian cancer. A woman with a first-degree relative with ovarian cancer has a threefold increased risk of developing the disease compared to women with no family history. Studies of twins show that the majority of this familial risk is due to inherited genetic factors. Mutations in highly penetrant susceptibility genes are the strongest predictors of inherited risk for ovarian cancer. Mutations in the BRCA1 and BRCA2 genes confer high-penetrance susceptibility to ovarian and also breast cancer. In family studies, the cumulative risks of ovarian cancer in BRCA1 and BRCA2 mutation carriers by age 80 years are estimated to be 44% and 17% in respectively. Risk estimates in ovarian cancer cases not selected for a family history of disease can vary. In a combined analysis of 22 different studies average risks were 39% in BRCA1-mutation carriers and 11% in BRCA2-mutation carriers. The prevalence of BRCA1 and BRCA2 mutations can vary in populations of different ethnicities which may contribute to variations in risk estimates. For example mutations are substantially more prevalent in Ashkenazi Jewish populations (~ 1 in 50 subjects) compared to non-Ashkenazi Jewish European populations (~1 in 400 individuals). Germline BRCA1 and BRCA2 mutations are observed in all non-mucinous histologic subtypes of ovarian cancer, but are most commonly associated with the development of the high grade serous ovarian cancers, with around 15% patients of this histotype carrying a mutation in either gene.
The BRCA1 and BRCA2 proteins are involved in the maintenance of genome stability by regulating the expression of genes critical for the repair of DNA double-strand breaks (DNA-DSB) via homologous recombination and regulation of cell growth and division. Population based sequencing studies in ovarian cancer cases have identified other ovarian cancer susceptibility genes that interact with BRCA1 and BRCA2 in the same pathway, particularly BRIP1, RAD51C, and RAD51D. Relative risk estimates for pathogenic mutations in these genes are more modest than BRCA1/BRCA2 ranging from ~4 for RAD51C, ~7 for RAD51D and ~11 for BRIP1. DNA mismatch repair genes (MMR) are another class of genes associated with increased ovarian cancer risks. Mutations in these genes are more commonly associated with Lynch Syndrome, which mainly confers an increased risk of colorectal cancer but also some gynecological cancers, in particular endometrial cancer and the endometrioid and clear cell subtypes of ovarian cancer. There are numerous genes operating in the MMR functional complex of which germline mutations in MSH2 and MSH6 particularly show an increased prevalence in ovarian cancer population, largely in non-serous ovarian cancer cases. Other genes associated with increased risks of gynecological cancer include PMS2 and MLH1. Lifetime risks of ovarian cancer in Lynch Syndrome patients vary depending on the gene with ovarian cancer risks by age 70 estimated to be 4–20% for MLH1 mutations. 7.5-20% for MSH2 mutations and ~13.5% for MSH6 mutations.
Several common, lower risk variants for ovarian cancer have been identified using population based genome wide association studies (GWAS). Each risk variants is estimated to confer only modest increases in risk (relative risks less than 1.3 per risk allele carried). Most risk variants identified so far are associated with high grade serous and/or all invasive epithelial ovarian cancers; but a few risk alleles are specifically associated with the different subtypes have also been discovered. There is also evidence of pleiotropy, in which genetic variants in the same genomic region confer risk to two or more ovarian cancer subtypes. The vast majority of common variant risk alleles are located in the non protein-coding DNA regions suggesting that the likely functional mechanisms are through epigenomic regulation of one or more susceptibility gene targets