Atlas of Genetics and Cytogenetics in Oncology and Haematology
Ovary: Epithelial tumors
| Identity |
| Note | Ovarian epithelial tumours are thought to arise from the simple cuboidal surface epithelium of the ovary, and account for 75% of all ovarian tumours, and 90-95% of ovarian malignancies. |
| Classification |
| Note | Ovarian epithelial tumours are classified according to the following histological subtypes: Usually each subtype can be classified as benign, borderline (low malignant potential, LMP), or malignant (invasive). |
| Serous tumours are further subdivided into the following: Mucinous tumours are further classified as: |
| Clinics and Pathology |
| Etiology | Epidemiology studies have provided data showing increased risk for ovarian cancer with greater numbers of ovulation cycles. Multiple pregnancies and use of oral contraceptives are thought to have a protective effect because of decreased ovulation and hormonal influences. There are two theories explaining for the association of decreased risk with decreased number of ovulation cycles: Epithelial ovarian carcinoma develops sporadically in about 90-95% of patients. Environmental and dietary factors are thought to have a role. These include use of talc on the perineum and vulva, asbestos, pelvic irradiation, viruses (particularly mumps), high-fat diet, and lactose consumption. Other factors are associated with an increased number of ovulation cycles: low parity, delayed childbearing, early menarche and late menopause. However, genetic factors are the most important risk factor for ovarian epithelial carcinoma (See Genetics section of this review for further details). Factors that decrease the risk for ovarian cancer predominantly reduce the number of ovulation cycles a women encounters-such as the use of oral contraceptives, breast-feeding and multiparity. Long-term use of oral contraceptives has reduced the risk of ovarian cancer by more than 50% in unselected women. Decreased risk of ovarian cancer has also been associated with tubal ligation and hysterectomy. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
| Epidemiology | Epithelial ovarian cancer is the sixth most common cancer in women and is the second most common female genital tract malignancy after endometrial cancer. They are usually found in postmenopausal women and are the commonest cause of death among women with gynaecologic malignancies in the USA, accounting for approximately 15,000 deaths annually. The annual lifetime risk for ovarian cancer is 1.4 per 100 women in the USA. Epithelial ovarian cancer can occur in females as young as 15, however the mean presentation age is 56 years. The age-specific incidence gradually rises and peaks at 70 years of age (55 per 100,000 Caucasians), whereas it affects only 3 women per 100,000 before 30 years of age. The median age for ovarian adenocarcinoma (which accounts for 85-90% of all malignant tumours) is between 60-65 years. The LMP ovarian tumours present at a younger age; the mean age of diagnosis is 48 years, and no large peak of incidence is observed. Brenner tumours are diagnosed in peri- or postmenopausal women. The incidence of ovarian epithelial tumours varies globally, with highest rates being observed in Scandinavia, Israel and North America, whereas the lowest rates are found in developing countries and Japan. A racial predisposition to ovarian epithelial tumours is apparent, with lower risks for black women. Clear cell adenocarcinoma is more prevalent in Japanese than western countries. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinics | Most early ovarian carcinomas and the serous and mucinous cystadenomas are asymptomatic. Two-thirds of patients present with extensive intra-abdominal metastases. Patients with advanced carcinomas usually present with vague abdominal swelling or discomfort, abdominal bloating, dyspepsia and early satiety, lack of appetite, malaise, urinary frequency and weight change (either gain or loss). Pelvic examination revealing firmness, fixation, nodularity, lack of tenderness, ascites, or cul-de-sac nodules are indicative of malignancy. 50% of all ovarian carcinomas are bilateral. Malignant serous tumours constitute over 40% of invasive epithelial carcinomas. Both borderline and malignant serous tumours are often bilateral. Mucinous carcinomas are diagnosed at stage I in approximately half of patients, whereas serous tumours are usually diagnosed at advanced stages. Brenner tumours are virtually always benign, and the exceptional malignant cases resemble transitional cell carcinoma of the bladder. As with the other types of ovarian neoplasm, it is usually asymptomatic until it has grown to a large size. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
| Pathology | Serous Histological analysis of borderline serous tumours reveals papillary cystic pattern, stratification, tufting, increased mitotic figures and cytologic atypia. H and E histology of borderline serous tumour can be viewed at:
Histological review of malignant serous tumours indicates significant stromal invasion. Calcifications (Psammoma bodies) are present in one-third of patients. Characteristic microscopic features include finger-like papillae with fibrovascular core, covered by multilayered cuboidal or columnar epithelium, hyperchromatic nuclei, prominent nucleoli, frequent mitoses, Psammoma bodies and desmoplasia (invasion of stroma with fibrosis). Examples can be viewed at: Mucinous
Their microscopic appearance resembles intestinal adenocarcinoma. Multiple glands comprising mucin-containing cells are present, demonstrating nuclear atypia, hyperchromasia with prominent nuclei and desmoplasia. Borderline/LMP Approximately 25% of borderline tumours show cell proliferations on the outer surface only. Of these, 90% develop peritoneal implants, which can be invasive or non-invasive. Both have a similar appearance, glandular or papillary proliferations with cell detachments, sometimes Psammoma bodies, cellular atypia and desmoplastic fibrosis. However, epithelial cells infiltrate the stroma in the invasive implants. Brenner tumours Clear Cell Carcinoma Endometrioid Carcinoma Mixed Mesodermal They are usually large variegated lesions with necrotic and haemorrhagic regions, and may have adhesions. Microscopic examination reveals serous or endometrioid epithelial component displaying squamous differentiation. Stroma may comprise spindle cell or soft tissue differentiation including cartilage, skeletal muscle or smooth muscle. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
| Treatment | The primary treatment of epithelial ovarian cancer is aggressive surgical tumour debulking, including total abdominal hysterectomy and bilateral salpingo-oophorectomy. Most women with ovarian epithelial tumours, except some stage Ia patients, receive chemotherapy. Postoperative treatment usually involves taxane-platinum combination chemotherapy; cisplatin or carboplatin with paclitaxel is the usual first-line treatment. High response rates, about 80%, are obtained, however most patients relapse, and other combination therapies fail. The mean disease-free interval for patients with stage III and IV disease is about 18 months. Only 20-30% of stage III and IV cases are long-term survivors. Postoperative intraperitoneal chemotherapy or external radiation therapy are used to treat patients with minimal residual disease. Clear cell adenocarcinoma is usually resistant to platinum-based chemotherapy. A strong association exists between ovarian mucinous tumours and appendiceal mucinous neoplasms. Consequently the appendix should be removed in patients with mucinous neoplasms. Repeat laparotomy or peritoneal lavage is required to remove gelatinous material in the persistent recurrences of Pseudomyxoma peritonei . Brenner tumours are cured with surgical resection. Prophylactic oophorectomy at an early age has significantly reduced the risk of coelomic epithelial cancer. Oral contraceptives have a protective effect against ovarian cancer in carriers of BRCA1 or BRCA2 mutations. | ||||||||||||||||||||||||||||||||||||||||||||||||||||
| Evolution | Epithelial ovarian cancer initially spreads by direct seeding of the peritoneal surfaces, and is found on the underside of the diaphragm, paracolic gutters, bladder, cul-de-sac, surface of liver, mesentery and serosa of large and small bowel, omentum, uterus and paraaortic and pelvic lymph nodes. The tumour cells may remain confined to the surface of the coated abdominal viscera without penetrating it. They may also spread to the pleural cavity, lungs and groin lymph nodes. Mucinous tumours tend to form large masses, whereas serous tumours tend to distribute more diffusely, and are more often bilateral. Endometrioid and clear cell tumours usually invade locally and retroperitoneally. Sometimes mucus-secreting ovarian carcinomas fill the peritoneal cavity with a gelatinous neoplastic mass, referred to as pseudomyxoma peritonei . | ||||||||||||||||||||||||||||||||||||||||||||||||||||
| Prognosis | The most important determinant for a favourable prognosis is diagnosis of ovarian carcinoma at an early stage. The prognosis of invasive epithelial ovarian cancer is poor, and relates to stage (see Tables 1 and 2), tumour grade and residual disease after surgery. The prognosis or early-stage ovarian invasive cancers and borderline tumours of all stages is significantly better. 5-year survival rates for patients with stage I disease are more than 90%, but less than 25% for advanced stage cancers. Patients with borderline tumours have an excellent prognosis. Age at diagnosis and the presence of invasive peritoneal implants are associated with a poorer prognosis in borderline tumours. The recurrence rate is 20%, with a mean time from diagnosis to relapse is 3.1 years in women with borderline serous tumours with non-invasive implants. However, borderline serous tumours with invasive implants have much higher recurrence rates of 32-45%, which occur much earlier (median time 24 months). Clear cell adenocarcinoma has a worse prognosis that the other histological subtypes as it is resistant to platinum-based chemotherapy. Some data suggests familial ovarian cancers have prolonged survival in comparison to the nonfamilial cases. In one study, patients with familial ovarian cancer exhibited a 67% 5-year survival, in comparison with a 17% 5-year survival in the nonfamilial ovarian cancer cases.
Table 1 Definitions of the FIGO classification scheme for Staging Primary Ovarian Carcinoma (taken from Jones, 2000)
Table 2 Survival Rates of Ovarian Carcinoma according to Disease Stage (adapted table from Jones, 2000) |
| Genetics |
| Note | INHERITED PREDISPOSITION As mentioned in the Aetiology section, genetic factors are the most important risk factor for ovarian epithelial carcinoma. Having 1 or 2 first-degree relatives with ovarian cancer increases the lifetime risk to 3-5% and 39% respectively. Three hereditary syndromes in which familial aggregation of ovarian carcinoma occurs have been described: All 3 patterns of familial ovarian cancer are consistent with autosomal-dominant transmission of one or more genes responsible for the development of >1 cancers, with incomplete penetrance and variable expression. The age of diagnosis of hereditary epithelial ovarian cancer is approximately 10 years earlier than its sporadic counterpart. Breast-Ovarian Syndrome The variable penetrance of BRCA1 suggests that other genetic and non-genetic factors contribute to the pathogenesis in these individuals. One such modifier is a VNTR polymorphism, 1-kb downstream of HRAS. BRCA1 carriers with rare alleles of the VNTR had an 2.11 increased risk of developing ovarian cancer compared with the common alleles (p=0.015). about 50% of familial ovarian cancers are not associated with germline BRCA1 or BRCA2 mutations. Linkage and LOH analysis has suggested a susceptibility gene for familial ovarian cancer at 3p22-p25. LOH of 3p33-p25 is higher (52%) in non-BRCA1/BRCA2 familial ovarian cancers than in the BRCA1 (29.7%) group. HNPCC Site-Specific Ovarian Cancer Syndrome Early onset ovarian carcinoma (<30 years age) Other familial cases |
| Cytogenetics |
| Cytogenetics Morphological | There is far more cytogenetic data available on ovarian carcinomas than for the other subtypes of ovarian tumours (germ cell tumours, sex-cord stromal tumours). At present, there are over 400 published karyotypes of ovarian carcinomas. The cytogenetic aberrations are non-random and complex. However, no pathognomonic rearrangements have been identified thus far. The karyotypes often show severe aneuploidy, with hypodiploid or near-triploid stemline chromosome numbers. The different subtypes of ovarian carcinoma show no marked cytogenetic differences, except seropapillary tumours more frequently display chromosome aberrations than the other subtypes. Complex chromosomal aberrations are present in invasive carcinomas, but not in benign or LMP tumours. The complexity of the karyotypes obtained from advanced tumours have obscured the initiating events in the pathogenesis of these tumours. Often normal karyotypes or simple cytogenetic aberrations were found in low-grade tumours. However, a correlation exists between karyotypic complexity and tumour grade. Simple chromosome changes (numerical changes only or a single structural rearrangement) were found in well-differentiated carcinomas, whereas complex karyotypes were found in poorly differentiated tumours. Patients with aberrant tumour karyotypes, particularly complex ones, were associated with short survival. Approximately 10-20% of ovarian carcinomas display homogeneously staining regions (hsr), although the loci they contain are unknown. However dmin are rarely observed. The most prevalent numerical changes are gains of chromosomes 1, 2, 3, 6, 7, 9, 12 and 20 losses of chromosomes 4, 8, 11, 13, 14, 15, 17 and 22. Structural rearrangements primarily involve deletions and unbalanced translocations involving 1p, 1q, 3p, 3q, 6q, 7p, 10q, 11p, 11q and 12q. In the review of 244 primary ovarian adenocarcinomas 201/244 tumours displayed clonal chromosomal abnormalities and hsr were identified in 20 cases. Using log-rank and proportional hazards regression analysis, it has been found that the presence of a chromosome breakpoint in any of 21 nonrandomly involved regions and breaks in 9 distinct regions (1p1, 1q2, 1p3, 3p1, 6p2, 11p1, 11q1, 12q2, and 13p1) were associated with reduced patient survival rate and time. Furthermore, only breakpoints within 1p1 and 3p1 retained independent, deleterious effects on survival and clinical variables associated with survival. In one review, 37% of serous LMP tumours displayed chromosomal anomalies, commonly trisomies of 7, 8 and 12. A much higher proportion, 91%, of invasive serous carcinomas of low-grade malignancy display clonal chromosomal abnormalities. A combination of karyotyping and microsatellite analyses identified a small deletion of 6q27, between D6S149 and D6S193, in both benign and advanced ovarian epithelial tumours, suggesting the presence of a putative tumour suppressor gene which is involved in the early events of the genesis of this tumour. Invasive serous and undifferentiated ovarian carcinomas have complex cytogenetic rearrangements, including amplification of oncogenes. Complex chromosomal anomalies are rarely found in mucinous and endometrioid carcinomas (mainly in advanced stages), and are never found in serous LMP tumours. Epithelial ovarian tumours are characterised by gains at 3q, 8q and 20q, often with high level amplification. Thus the cytogenetic profiles of ovarian carcinomas differ from that of ovarian granulosa cell tumours, trisomy 14 and monsomy 22 are rarely found in ovarian carcinomas. Chromosome 1 and 3 abnormalities are the commonest aberrations found in ovarian metastatic tumours. Cytogenetic investigation of 11 individuals with bilateral ovarian carcinoma showed identical baseline karyotypes, suggesting both tumours arise from the same transformed cell, rather than the tumours arising independently. 46/52 ovarian carcinomas had complex karyotypes, often with a stemline chromosome number that was approaching near-triploid or hypodiploid. Chromosome losses of X, 22, 17, 13, 14 and 8, (lost in <20 tumours) were most frequent (compared to the nearest euploid level). Chromosomal gains were less prevalent, trisomy 20 was found in 10 tumours. The most common structural rearrangements are deletions and unbalanced translocations, which frequently involved 19p13 (n=26), 19q13 (n=14), 1p36 (n=13), 11p13 (n=13), 3p12-13 (n=12), 1q23 (n=11), and 6q21 (n=10). In a study, 26/36 ovarian carcinomas displayed aberrant karyotypes. Chromosomal gains of 1, 2, 3, 6, 7, 9 and 12 were common, as were losses of chromosomes X, 4, 8, 11, 13, 15, 17 and 22. Structural rearrangements frequently involved 1p, 1q, 3p, 3q, 7p, 9q, 11q, 17q, 19p and 19q. In a cohort of 54 tumours, the breakpoints of structural anomalies preferentially involved 1p35, 1p11-q21, 3p11-23, 7p, 11p, 11q, 12p13-q12 and 12q24. Loss of the X chromosome and trisomy 7 were the most common numerical changes. A third of all ovarian carcinomas have deletions of distal 11p. The frequent occurrence and variability of the deletions of chromosome 1, both the distal half of 1q and 1p34-36, and the frequent observations of similar entities in other tumour types suggest that they are secondary, non-specific changes. Deletions and unbalanced translocations resulting in loss of 3p, particularly of 3p13-21 are recurrently found in ovarian carcinomas, but not as sole anomalies. The cytogenetic findings of 370 cases of ovarian adenocarcinoma can be found listed on the Mitelman Database of Chromosome Aberrations in Cancer (http://cgap.nci.nih.gov/Chromosomes/Mitelman). The imbalances arising from the cytogenetic rearrangements listed in the database are summarised in Table 3. Of the cases listed, 36% had polyploid karyotypes (with chromosome numbers ranging between 58 and 127), 28% had hyperdiploid karyotypes (with 48-57 chromosomes), 22% had hypodiploid karyotypes (<45 chromosomes), and only 14% were peridiploid (45-47).
Table 3 A summary of the frequency of imbalances in ovarian carcinomas (table from Hoglund et al., 2003, data from Mitelman Database of Chromosome Aberrations in Cancer) Very little is known about the sequence of cytogenetic and genetic events accompanying the progression of disease from early to advanced disease. This question has been addressed by analysing the cytogenetic data in the Mitelman Database of Chromosome Aberrations in Cancer and proposed that ovarian carcinomas undergo >3 modes of karyotypic evolution: Their analyses hypothesised that the temporal order of imbalances were as follows: 1q-, 6q-, +7 and +8q occurred early, -4, -8, +1q, +12 and +20 were intermediate imbalances, and the remaining imbalances were late events. It has been concluded that karyotypic evolution in ovarian carcinomas followed at least 2 cytogenetic pathways. The first pathway involved chromosomal gains of +7/+8q/+12 and was associated with low-stage and low-grade tumours. The second pathway involved chromosomal losses of 6q- and 1q- was found in tumours of moderate stage and grade. The early stages of karyotypic evolution result from the step-wise acquisition of changes resulting in Phase I tumours. Chromosome instability resulted in the transition to Phase II tumours, possibly as a result of extensive telomere crisis and breakage fusion breakage cycles, which is linked to imbalances characteristic of the 6q-/1q- pathway. Consequently, low-grade and borderline tumours cannot progress unless they have mixed-pathway features. The 6q-/1q- pathway was associated with triploidization. The 6q-/1q- pathway is instrumental in the progression of ovarian carcinomas. The proposed pathway of karyotypic evolution in ovarian carcinomas is summarised in Figure 1. A cohort of 114 ovarian neoplasms was analysed, including benign, borderline and invasive carcinomas by conventional and molecular cytogenetics. The chromosome abnormalities were categorised as follows: The presence of cytogenetic aberrations common to all subtypes suggests these tumours develop by progression. The main conclusions from cytogenetic investigations of ovarian epithelial tumours are as follows: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Figure 1 Summary of karyotypic evolution in Ovarian carcinomas (taken from Hoglund et al., 2003) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cytogenetics Molecular | Interphase cytogenetics demonstrated a high frequency of gain of copy number of 20q13.2 (70%) and cyclin D1 (CCND1 at 11q13, 72%) which were associated with poor prognosis. Another study addressing amplification of 20q12-q13.2 using a series of FISH probes in 24 sporadic and 7 hereditary ovarian carcinomas found amplification of at least one of the regions in 54% of sporadic cases and all of the hereditary cases, and amplification of AIB1 (20q12), a steroid receptor coactivator correlated with poor survival. Online access to summaries of the recurrent DNA copy number amplifications and losses identified by CGH in ovarian epithelial neoplasms (and other tumour entities) can be viewed at http://www.helsinki.fi/cmg/cgh_data.html, and undergo regular updates. The criteria for recurrent losses and gains employed were as follows. For losses, 10% of the cases should have the loss, and there must be at least 3 aberrant cases. Highly frequent aberrations which do not meet the criteria of 10% of cases or 3 cases are indicated by parentheses-such as 1p21-p31. Recurrent amplicons were defined as at least 3 cases and >5% frequency display the amplicon. The recurrent losses and gains are summarised in Table 4.
Table 4 Recurrent amplifications and losses in epithelial ovarian tumours, including hereditary neoplasms (data taken from http://www.helsinki.fi/cmg/cgh_data.html) Other studies have identified gain of chromosome 8 in 1/10 ovarian carcinomas. A study of 31 primary ovarian carcinomas in Chinese women by CGH identified several non-random changes in copy number including gains of 3q (17 cases, 55%) with a minimum region of gain of 3q25-q26, 8q (16 cases, 52%), 19q (12 cases, 39%), Xq (11 cases, 35%), 1q (10 cases, 32%), 12p12-q13 (10 cases, 32%), 17q (10 cases, 32%) with a minimum region of gain at 17q21, and 20q (9 cases, 29%); together with losses of 16q (9 cases, 29%), 1p (7 cases, 23%), 18q (7 cases, 23%) and 22 (7 cases, 23%). High copy number amplifications were observed at 3q25-q26 (4 cases), 8q24 (3 cases) and 12p11.2-q12 (3 cases). The commonest imbalances detected by CGH of epithelial neoplasms were gain of 3q25-26, gain of 8q24, loss of 16q, and loss of 17pter-q21. 12p gains were seen in 8/44 cases, which has been reported previously in both ovarian and testicular germ cell tumours. Another study by Hauptmann et al., 2002 using CGH to analyse ovarian carcinomas identified frequent gains of 3q, 6p, 7, 8q and 20, together with losses of 4q, 6q, 12q, 13q and 16q, which have supported the available cytogenetic data. CGH was used to screen a mucinous ovarian carcinoma and a Brenner tumour coexisting in different ovaries of the same female. Amplification of 12q14-q21 was identified in both tumours, in the presence of other copy number changes, 4 such changes in the Brenner tumour and 6 in the mucinous carcinoma. Correlation of CGH data with Clinical data In a large study of 106 primary ovarian carcinomas, the CGH findings were correlated with clinical parameters such as tumour grade of differentiation. 103 tumours displayed imbalances. Amplifications of 8q, 1q, 20q, 3q and 19p were frequent findings present in 69-53% of the tumours. Underrepresentations of 13q, 4q and 18q were also common, present in 54-50% of cases. Underrepresentation of 11p and 13q and overrepresentation of 8q and 7q correlated with undifferentiated ovarian carcinoma, whereas 12p underrepresentation and 18p overrepresentation were more commonly associated with well-differentiated and moderately differentiated tumours. These findings corroborate other CGH studies including. A CGH study of a cohort of 12 ovarian clear cell carcinomas revealed similarities to the data of other subtypes of epithelial neoplasms, such as gains of 8q and 17q and losses of 19p. They also correlated their findings with disease status (i.e. disease free, recurrent disease, or death from disease). DNA copy number changes present in over 20% of cases included overrepresentation of 8q11-q13, 8q21-q22, 8q23, 8q24-qter, 17q25-qter, 20q13-qter and 21q22; and underrepresentation of 19p. Overrepresentation of 8q11-q13, 8q21-q22, 8q23, 8q24-qter was more common in disease-free patients than in those with recurrent disease or who had died. Conversely, overrepresentation of 17q25-qter, 20q13-qter was more frequent in patients with recurrent disease or non-survivors, than in disease-free patients. This data suggests ovarian clear cell carcinoma develop along 2 cytogenetic pathways. In a study correlating CGH genomic imbalances with clinical endpoints in 60 ovarian carcinomas, the following associations were found: CGH findings of Sporadic and Hereditary Ovarian Carcinoma CGH profiles were compared from sporadic and hereditary (3 BRCA1 and 1 BRCA2 mutation carriers) ovarian cancers. The commonest imbalance included amplification of 8q22.1-qter (66.6%), 1q22-32.1 (41.1%), 3q (75%) and 10p (33.2 %), and deletion of 9q (41.6%) and 16q21-q24 (33.3%). Deletions of 9q were found in all 3 BRCA1 carriers and 2/8 sporadic tumours, and deletions of 19 were found in 2/3 BRCA1 carriers and none of the sporadic cases. These findings suggest preferential somatic losses of chromosome 9 and 19 in BRCA1 mutation carriers. In contrast, another study identified extensive similarity by CGH between sporadic and hereditary ovarian carcinomas, except for 2q24-q32. CGH analysis of a further 36 hereditary tumours found the majority of imbalances to be similar to that of sporadic tumours (Gains: 8q23-qter, 3q26.3-qter, 11q22, 2q31-32; losses: 8p21-pter, 16q22-qter, 22q13, 12q24, 15q11-15, 17p12-13, Xp21-22, 20q13, 15q24-25, 18q21). However some imbalances were identified that were specific to hereditary tumours, including deletions of 15q11-15, 15q24-25, 8p21-pter, 22q13 and 12q24, and gains of 11q22, 13q22 and 17q23-35. Deletions of 15q11-15 and 15q24-25 were found in 16/36 and 12/36 cases respectively which implicated hRAD51 and other tumour suppressor genes in these loci in the genesis of hereditary ovarian cancer. |
| Genes involved and Proteins |
| Note | In addition to involvement of germline mutations of BRCA1, BRCA2 and the mismatch repair genes in the predisposition of ovarian epithelial tumours (see Genetics: Inherited Predisposition section), many studies have investigated somatic changes at specific loci. The somatic aberrations are summarised below according to whether the studies involved allelotyping or analysing specific genes (which is further subdivided into oncogenes and tumour suppressor genes). Allelotyping/LOH/MSI The pattern of allelic loss differs according to the histological subtypes of epithelial ovarian cancer. Clear cell adenocarcinoma predominantly demonstrates LOH of 1p, 19p and 11q. Serous adenocarcinoma demonstrates allelic losses in >50% of cases of 1p, 4p, 5q, 6p, 8p, 9q, 12q, 13q, 15q, 16p, 17p, 17q, 18p, 18q, 19p, 20p and Xp. Endometrioid adenocarcinoma frequently demonstrated LOH of 7p, and mucinous adenocarcinoma demonstrated recurrent LOH at 17p13.1. LOH analysis using RFLP markers in 6q24-q27 demonstrated allelic loss at a few or all loci in 17/33 ovarian serous tumours, 1/15 ovarian mucinous tumours, and 2/12 ovarian clear cell tumours. Allelic loss of 1p31 has been found in about 40% of ovarian carcinomas, where the maternally imprinted tumour suppressor gene ARH1(NOEY2) resides. Approximately 1/3 of epithelial ovarian tumours of all stages demonstrate LOH of 9p. 69% of 78 ovarian epithelial tumours displayed LOH of 17p13.1 where TP53 is located. Allelic loss at 10q23.3 flanking PTEN and within PTGN have been found in 45% of ovarian epithelial cancers (n=68). Loss of PTEN expression was associated with elevated phosphorylated AKT levels. No microsatellite instability (MSI) was apparent among the 23 benign cystadenomas and 31 LMP ovarian tumours examined using 69 microsatellite markers. Thus these findings suggest MSI is not a pathogenic mechanism in the development of LMP tumours, and abnormalities of the DNA mismatch repair mechanisms are not involved. In contrast, about one-third of endometrioid carcinomas and up to 40% of serous LMP tumours display MSI, although in serous LMP tumours the MSI is low level. LOH of 3p14.2, 11p15.5, 11q23.3, 11q24, 16q24.3 and 17p13.1 are more frequent in advanced than lower stage tumours. LOH of 3p14.2 correlated with tumour metastasis, whereas LOH at 11p15.5 and 11q23.3 were associated with reduced survival. LOH of 11q22.3 was associated with reduced survival and a serous histology, meanwhile LOH of 11q24-25 correlated with a higher tumour stage, serous histology, presence of residual tumour, but not with survival. LOH of 1p36 is associated with poor histological grade. Tumour Suppressor Genes
Allelic deletions of 17p or P53 mutations occur frequently in ovarian carcinoma. P53 mutations are found in about 50-80% of tumours when analysed by complete gene sequencing. LOH of P53 is also a frequent finding in ovarian carcinomas, ranging from 30% to 80%. P53 mutations have been found in ovarian carcinoma and borderline ovarian tumours. Invasive serous and undifferentiated ovarian carcinomas are characterised by P53 mutations with protein accumulation, extensive allelic loss of chromosome 17 and complex cytogenetic aberrations. Functional wild-type P53 is required for chemo- and radio-sensitivity due to its role in apoptosis. Thus mutation of P53 followed by loss of the wild-type results in resistance to therapy. Of the ovarian neoplasms that express nuclear P53, 90% of them have mutations of P53 which increases the half-life of the P53 protein. 50% of advanced ovarian carcinomas have overexpressed or mutant P53 which correlates with high grade and poor survival, but not with chemoresponsiveness. However, P53 does not appear to be involved in the pathogenesis of clear cell adenocarcinoma.
Homozygous deletions or intragenic mutations of CDKN2A (p16INK4A) are also found in ovarian epithelial tumours. CDKN2A encodes an inhibitory protein of cyclin-dependent kinase 4. The CDKN2A complex blocks phosphorylation of the Retinoblastoma (RB) protein. Phosphorylation of the RB protein is a prerequisite for cells to enter the S phase of the cell cycle. Thus CDKN2A is a negative regulator of the cell cycle.
Abnormalities of the RB gene in epithelial ovarian cancers have been found by immunohistochemical analysis and molecular approaches, however they are thought to affect a minority of tumours and are possibly a late event in tumourigenesis.
No expression of GATA4, a transcription factor gene located at 8p23.1, was found in the majority of serous carcinomas, whereas it is expressed in most mucinous carcinomas, suggesting that these tumour types develop along discrete pathogenic pathways.
Reduced expression of RNASET2 (RNASE6PL), located at 6q27, was found in 30% of ovarian cancers. Transfection of RNASET2 cDNA into ovarian cancer cell lines suppressed tumourigenicity, suggesting it to be a candidate tumour suppressor gene.
Somatic mutations of BRCA1 and BRCA2 have not been found in sporadic ovarian neoplasms, however allelic losses including 17q21, were BRCA1 is located, were common. This suggests that additional tumour suppressor genes are required in the molecular aetiology of sporadic tumours, one proximal to BRCA1, the other on 17p. Oncogenes
KRAS mutations are found in 30% of ovarian carcinomas, and are frequently observed in mucinous adenoma and thus may be an early event in the pathogenesis of ovarian mucinous tumours. KRAS mutations are present in 40-50% of mucinous LMP tumours and mucinous carcinomas, and also in one-third of serous LMP tumours. Amplification of KRAS has been reported in 3-5% of ovarian cancers. In one study, KRAS2 amplification occurred in 2/53 of ovarian epithelial tumours, (6 borderline serous, 2 low grade serous, 31 high grade serous; 4 low grade mucinous; 2 low grade endometrioid, 8 high grade endometrioid), and only in the aggressive types (2 high grade serous tumours). A mutation in codon 12 of KRAS has been identified in small cell carcinoma. HRAS acquires transforming activity either as a result of substitution mutations or by increased expression of the normal gene. Mutated HRAS lack GTPase activity, resulting in dysregulation of cell growth.
Abnormal cell signalling mediated by protein kinases can result from alterations of the growth factor receptors in ovarian epithelial neoplasms. These include:
Amplification of MYC oncogene, 8q24, occurs in 10-20 % of ovarian cancers, and in about one-third of advanced ovarian carcinomas. MYC amplification is more frequently found in the serous subtypes than the mucinous subtypes. MYC encodes a DNA-binding nuclear-associated protein that regulates cell proliferation. Dividing cells have increased amounts of nuclear c-myc, whereas quiescent cells express negligible quantities. MYC amplification is often indicative of biologically aggressive tumours. MYC amplification was not associated with prognosis or survival. Significantly higher levels of p62c-myc were found in serous papillary ovarian carcinoma. LMP tumours expressed MYC at values intermediate between that of normal ovary tissue and carcinoma.
Amplification, altered expression, and malfunction of several protein kinases and phosphatases are involved in the pathogenesis of ovarian epithelial neoplasms, in particular the phosphatidylinositol 3-kinase (PI3K) pathway. Increased PI3K activity is important in the growth and dissemination of ovarian cancer cells. The PIK3CA gene which encodes the catalytic subunit of PI3K, and its downstream effector AKT2 are amplified in primary ovarian tumours. Overexpression of AKT2 is found in high-grade and late-stage tumours. Mutation and/or down-regulation of the PI3K phosphatase PTEN/MMAC1 are frequently observed in ovarian endometrioid carcinomas. AKT2 mediates some of the transforming signals of RAS and SRC which are mutated and overexpressed/activated respectively in late-stage tumours. Downregulation of the cGMP-dependent protein kinase PKG and upregulation of MAP2K6 (MEK6) were significantly correlated with the genesis of ovarian cancer. Amplification of AKT2 has been reported in 3-5% of ovarian cancers.
Amplification of other oncogenes such as FGF3 (formerly INT2) and MDM2 have been reported in 3-5% of ovarian cancers. As mentioned in the Molecular Cytogenetics section, high level amplification of 20q12-q13.2 is a frequent finding in ovarian carcinomas, and a gene located at 20q11.2-12, TGIF2, was amplified and over-expressed in 14 ovarian cancer cell lines. EIF5A2 is a candidate oncogene for the 3q25-q26 amplification in ovarian carcinomas. Overexpression of the Kallikrein gene, KLK4, located at 19q13.4, has been found in 69/147 ovarian tumours and is indicative of a poor prognosis. NME1 is thought to have a role in ovarian neoplastic process. Elevated levels of inhibin are found in most postmenopausal women with mucinous ovarian cancers.
Overexpression of BCL2 is present in about 90% of endometrioid carcinomas, and MSI is present in about one-third of cases, as has been described in endometrioid endometrial carcinomas. Overexpression of P53, EGFR, ERBB2 and ERBB3 was also detected in ovarian endometrioid carcinoma. Expression Profiling Several other expression profiling studies have been undertaken which identified differentially expressed genes between serous and mucinous carcinomas; and also identified differences in gene expression during progression of ovarian carcinoma. |
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