Genetic Modifiers of Ovarian Cancer

Inherited inactivating mutations in the BRCA1 breast and ovarian cancer susceptibility gene have been identified in more than 10% of women who develop ovarian cancer, making BRCA1 the most common ovarian cancer predisposition gene. Epidemiology studies have shown that 39% of women with mutations in the BRCA1 gene develop ovarian cancer by age 70, which is substantially higher than the frequency of ovarian cancer in the general population. While much has been learned about the contribution of BRCA1 mutations to ovarian cancer, it is not known why 61% of women with BRCA1 mutations do not develop ovarian cancer or why there is substantial variation in the age that BRCA1 mutation carriers develop ovarian cancer. Similarly, it is not currently possible to identify those mutation carriers who will develop cancer in their lifetime and those who will not.

Because these women are at greatly increased risk of developing ovarian cancer and because no effective screening strategies for the early detection of ovarian cancer exist, most women with BRCA1 mutations are counseled to consider risk-reducing prophylactic salpingo-oophorectomy (removal of the normal ovaries), preferably prior to age 40. Although prophylactic oophorectomy significantly reduces ovarian and breast cancer risk in these women, and may reduce the number of BRCA1 carriers who develop ovarian cancer or succumb to this disease, the prophylactic surgery also has significant side effects. Specifically, the removal of the ovaries leads to menopausal symptoms that can significantly affect quality of life, and also may lead to osteoporosis and premature cardiac disease over time. Thus, the 61% of women who would never develop ovarian cancer are exposed to a series of significant health issues over their lifetime in order to reduce their risk of cancer. If methods could be developed that could identify the many mutation carriers at comparatively low risk of ovarian cancer, then these women could delay or even avoid prophylactic oophorectomy. In addition, the group of BRCA1 mutation carriers at extremely high risk of developing ovarian cancer could take advantage of earlier intervention to prevent breast and/or ovarian cancer.

The absence of ovarian cancer from 61% of BRCA1 mutation carriers is strong evidence for the existence of genetic mutations that have subtle effects on genes and are common in the general population. Each so-called genetic modifier of risk probably confers only a small-to-moderate increase in the lifetime ovarian cancer risk. However, when several modifiers are inherited together, along with a BRCA1 mutation, the modifiers may have an important role in determining if and when a carrier develops ovarian cancer. As part of a large international consortium, we have recently identified several of these risk modifiers that influence the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. This is strong evidence that these modifiers exist and are important regulators of cancer. However, the results also indicate that the risk modifiers in sporadic cancer are different from the modifiers associated with BRCA1 mutation carriers. Because of this we recently undertook a genome-wide association study (GWAS) to search the entire human genome for the presence of genetic modifiers of breast cancer in BRCA1 mutation carriers using DNA samples from 11,000 BRCA1 mutation carriers collected through an international consortium of 48 groups. Once identified, these genetic modifiers will be used to predict the risk of breast cancer in BRCA1 mutation carriers.

Based on these studies, we propose to conduct a similar GWAS for ovarian cancer in BRCA1 mutation carriers. The aims are: (1) To conduct a genome-wide association scan in 1,000 BRCA1 carriers with ovarian cancer and 1,000 unaffected BRCA1 carriers. (2) To further evaluate observed associations between ovarian cancer risk and SNPs implicated in Aim 1 by genotyping 1,500 additional BRCA1 ovarian cancer cases and 1,500 unaffected BRCA1 carriers. (3) To evaluate risk modifiers from the BRCA1 breast cancer GWAS and risk factors from sporadic ovarian cancer GWAS as modifiers of ovarian cancer in BRCA1 carriers.

The international consortium has 2,400 BRCA1 carriers with ovarian cancer and we have already collected 1,400 DNA samples from these individuals for this study. In addition, we have already completed testing of 592 BRCA1 carriers with ovarian cancer, so in this study we ask for support for 408 more. We need these additional ovarian cases to generate enough statistical information to be certain of the genetic modifiers. Once a number of genetic modifiers of ovarian cancer have been identified, they will be used to improve current cancer risk assessment methods for BRCA1 mutation carriers as outlined above.