Assessing Pelvic Epithelial Cancer Risk and Intercepting Early Malignancy

Genetic Ovarian Cancer Syndromes

There are three well-recognized genetic syndromes that account for the vast majority of familial ovarian cancer and approximately 10% of all ovarian cancers. These are breast ovarian cancer syndrome (BOCS), site-specific ovarian cancer syndrome (SSOCS), and hereditary nonpolyposis colorectal cancer (HNPCC) syndrome (or Lynch syndrome). Both BOCS and SSOCS are caused by inherited mutations in the BRCA-1 and BRCA-2 genes. In fact, although often described as separate entities, these two syndromes are most likely phenotypic variants of the same genetic mutations. BRCA-1 and BRCA-2 function as classic tumor suppressor genes and are inherited in an autosomal dominant fashion. Lynch syndrome is caused by mutations in DNA mismatch repair genes responsible for repairing errors in DNA replication. Inactivation of these genes result in a high incidence of right-sided colon cancer, endometrial cancer, and ovarian cancer. Hereditary ovarian cancers associated with BRCA-1 and BRCA-2 mutations will be discussed first, followed by Lynch syndrome–related ovarian cancer.

Breast Ovarian Cancer Syndrome and Site-Specific Ovarian Cancer Syndrome

Germline mutations in the BRCA-1 and BRCA-2 tumor suppressor genes account for approximately 90% of cases of hereditary ovarian epithelial cancers and confer a risk of ovarian carcinoma by age 70 of 40% to 50% and 10% to 20%, respectively. BRCA-1 and BRCA-2 are located on chromosomes 17q21 and 13q12-13, respectively, and are inherited in an autosomal dominant fashion. They encode nuclear proteins that are functionally similar. Both proteins participate in the repair of double-stranded DNA damage, as well as the regulation of gene expression at a transcriptional level. Loss of BRCA protein function leads to failure to repair DNA damage, resulting in the activation of p53, with subsequent initiation of cell cycle arrest or apoptosis. In the absence of functional p53, however, the cell continues to proliferate, DNA damage accumulates, and the likelihood of ensuing malignancy increases.

The lifetime risk of developing ovarian cancer in the United States is about 1.4%, but among women with BRCA-1 and BRCA-2 mutations, the risk has been estimated to be about 40% and 20%, respectively. These genes also impart a significant lifetime risk of breast cancer in women and, in the case of BRCA-2, in men as well. Less than 0.3% of those in the general population are carriers of BRCA-1 or BRCA-2 mutations; however, the carrier rate is dependent on ethnic background.

Founder mutations have been identified among multiple unrelated families in Iceland, the Netherlands, Sweden, and among Jews of Central or Eastern European (Ashkenazi) descent. The best-described founder mutations are the 185delAG and 5382insC mutations in BRCA-1 and the 6174delT mutation in BRCA-2, occurring in Ashkenazi Jews at a carrier rate of 2%. Although women of Ashkenazi Jewish descent do not have an overall increased rate of ovarian cancer, if an Ashkenazi Jewish woman develops ovarian cancer, it is far more likely to be genetic rather than sporadic. Consequently, if a woman of Ashkenazi Jewish descent develops ovarian cancer, there is a 40% chance she carries a mutation in one of these two genes. The implications for her first-degree relatives (mother, sisters, daughters) are that they have a 20% risk for being gene carriers (given autosomal dominant transmission). Therefore, a woman of Ashkenazi Jewish heritage needs only one first-degree relative with ovarian cancer to be considered for further genetic counseling. Routine screening of Ashkenazi women has been proposed given the high likelihood missing carriers based on family history alone.

In contrast to hereditary breast cancers, in which BRCA-1 and BRCA-2 mutations are found with equal frequency, BRCA-1 mutations are found more commonly than BRCA-2 mutations in patients with familial ovarian carcinoma. The mean age of developing ovarian cancer in the setting of a BRCA-1 mutation is younger than in the women without a mutation (53 vs. 63 in the latter group). Although BRCA-1 carriers have a 2% to 3% risk of ovarian carcinoma by age 40, for BRCA-2 carriers, this risk is not until age 50. Mutations in BRCA genes are rare in the setting of sporadic ovarian tumors, but loss of function of their encoded proteins may play a role in tumor development. Inactivation of BRCA-1 in sporadic ovarian tumors has been attributed to promoter hypermethylation.

The Society of Gynecologic Oncologists (SGO) has issued recommended criteria for referral of women to genetic counselors and consideration for genetic testing for BRCA-1 and BRCA-2 genes. These risk variables are summarized in Box 24.1 . Because women with high-grade serous carcinoma probably have a higher rate of underlying germline mutations in BRCA (16% to 20%) than other ovarian tumors, testing should be considered for all women with this type of tumor. Some have argued for population-based testing, independent of history, given the feasibility of such testing, risk associated with missing carriers, and variability in assessment of family history and referral to genetic counselors. In addition, it is currently far more common to obtain expanded panel testing to include other lower penetrance genes.

Most ovarian malignancies diagnosed in women with BRCA mutations are high-grade serous carcinomas of advanced stage. These tumors tend to have morphologic features known as SET, referring to more than 50% solid, pseudoendometrioid, or transitional. Other histologic types have less frequently been described in patients with BRCA-1 mutations, including endometrioid, clear cell, transitional, and undifferentiated carcinomas; carcinosarcoma; and dysgerminoma. Borderline tumors and mucinous tumors do not appear to be associated with BRCA mutations. The overwhelming majority of malignancies identified in the fallopian tube in women with BRCA mutations are also high-grade serous carcinomas.

Lynch Syndrome

Mutations in mismatch repair genes (Lynch syndrome) account for only a small percentage of hereditary ovarian cancer; these women have a lifetime risk of up to 12% for ovarian cancer. Mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) most frequently lead to loss of function and, therefore, to microsatellite instability (MSI). Mismatch repair proteins function to DNA base-pair mismatches. Microsatellites are repetitive DNA sequences that are prone to replication errors, such as base-pair mismatches. Loss of mismatch repair protein function results in an inability to repair these mismatches with resultant MSI. MSI is characterized by these repetitive DNA areas retracting or expanding and causing frameshift mutations. Tumors presumably form when the frameshift mutations occur within the coding region of genes involved in tumor development. Not all mismatch repair gene mutations bear an equivalent risk for ovarian cancer; mutations in PMS2 are associated with the lowest overall risk.

Most ovarian cancers in Lynch syndrome are non-serous histology, specifically endometrioid, clear cell, or undifferentiated carcinomas. Up to 10% of ovarian carcinomas in patients less than or equal to 50 years old are associated with Lynch syndrome. There is a strong association between Lynch syndrome and clear cell carcinoma of the ovary, with mismatch repair protein mutations in 14% or 17% of clear cell carcinomas.

Guidelines for Lynch syndrome in ovarian cancer are not well defined. The Amsterdam and Bethesda criteria primarily focus on colorectal carcinoma, but the SGO has also outlined guidelines for gynecologic tumors. In general, testing for Lynch syndrome should be considered in woman with non-serous ovarian epithelial carcinoma. Because most women with Lynch syndrome who present with ovarian cancer are younger than 50 years old, many age-based algorithms must take this into account. Molecular analysis of the DNA mismatch repair genes is the gold standard for definitive diagnosis of Lynch syndrome, but it is not routinely employed as a screening method due to cost and is used mostly for confirmation. Various algorithms for using mismatch repair protein immunohistochemistry, MSI analysis, and MLH1 methylation studies have been employed. In our institution, we screen all non-serous ovarian epithelial carcinomas by mismatch repair protein immunohistochemistry, with reflex to MLH1 methylation studies in cases where MLH1 expression is lost. This information is directly forwarded to our genetic counseling department to determine the need for further assessment and potential germline testing. Parenthetically, all women with ovarian cancers at the Dana Farber Cancer Institute/Brigham and Women's Hospital are referred for genetic counseling and undergo expanded panel testing if consenting. We no longer use family history to guide us.

Hereditary Predisposition to Ovarian Cancer: Beyond BRCA and Mismatch Repair Genes

Given that there are still families with strong histories of ovarian cancer with no identifiable mutations in BRCA-1, BRCA-2, or mismatch repair genes, current efforts are focused on identification of other inherited genetic mutations, which might account for the increased risk. Analysis of the large genomic library of single nucleotide repeats in large populations of cases and controls has been performed with the intent to identify loci that segregate with malignancy. This has been successful to a degree, identifying potentially predictive genomic markers for ovarian cancer. The downside has been the relatively low overall risk imposed by individual changes (less than twofold), which are too small to justify their use in a clinical setting, but combined risk models are emerging. Multigene panel testing for cancer risk has become available to patients complicating management recommendations and further stressing the invaluable role of genetic counselors in the process. The risk associated with the genes is highly variable with about 20% of mutations considered to be variants of uncertain significance.

Although BRCA-1, BRCA-2, and mismatch repair genes are certainly the most well-known and studied genes associated with a hereditary disposition to ovarian cancer, recent advances have identified other genes associated with potential increased risk. Mutations in BRIP1, RAD51C, and RAD51D confer a lifetime risk of 10% to 15%. A multi-gene profile (BROCA) is also in use. PALB2 gene mutations have been identified in some families with strong breast and ovarian cancer histories, but the actual risk of ovarian cancer with this gene is currently unknown. Some recently identified mutations are associated with particular types of ovarian tumors. For example, DICER1 mutations are associated with increased risk for the development of Sertoli-Leydig cell tumors, and SMARCA4 gene mutations confer risk for ovarian small cell carcinoma.

Demographic Risk Factors for Ovarian Cancer

Endometriosis

Endometriosis increased ovarian cancer risk with a RR of 1.3 to 1.8. Such cancers are more often low stage and of low-grade endometrioid and clear cell histology. The risk is higher with increasing age and cyst complexity on ultrasound.