Epidemiology of Ovarian Cancer

A population-based series of 649 unselected incident cases of ovarian cancer diagnosed in Ontario, Canada, during 1995-96 was screened for germline mutations in BRCA1 and BRCA2. We specifically tested for 11 of the most commonly reported mutations in the two genes. Then, cases were assessed with the protein-truncation test (PTT) for exon 11 of BRCA1, with denaturing gradient gel electrophoresis for the remainder of BRCA1, and with PTT for exons 10 and 11 of BRCA2. No mutations were found in all 134 women with tumors of borderline histology. Among the 515 women with invasive cancers, we identified 60 mutations, 39 in BRCA1 and 21 in BRCA2. The total mutation frequency among women with invasive cancers, 11.7% (95% confidence interval [95%CI] 9.2%-14.8%), is higher than previous estimates. Hereditary ovarian cancers diagnosed at age 60 years were due to BRCA2. Mutations were found in 19% of women reporting first-degree relatives with breast or ovarian cancer and in 6.5% of women with no affected first-degree relatives. Risks of ovarian, breast, and stomach cancers and leukemias/lymphomas were increased nine-, five-, six- and threefold, respectively, among first-degree relatives of cases carrying BRCA1 mutations, compared with relatives of noncarriers, and risk of colorectal cancer was increased threefold for relatives of cases carrying BRCA2 mutations. For carriers of BRCA1 mutations, the estimated penetrance by age 80 years was 36% for ovarian cancer and 68% for breast cancer. In breast-cancer risk for first-degree relatives, there was a strong trend according to mutation location along the coding sequence of BRCA1, with little evidence of increased risk for mutations in the 5' fifth, but 8.8-fold increased risk for mutations in the 3' fifth (95%CI 3.6-22.0), corresponding to a carrier penetrance of essentially 100%. Ovarian, colorectal, stomach, pancreatic, and prostate cancer occurred among first-degree relatives of carriers of BRCA2 mutations only when mutations were in the ovarian cancer-cluster region (OCCR) of exon 11, whereas an excess of breast cancer was seen when mutations were outside the OCCR. For cancers of all sites combined, the estimated penetrance of BRCA2 mutations was greater for males than for females, 53% versus 38%. Past studies may have underestimated the contribution of BRCA2 to ovarian cancer, because mutations in this gene cause predominantly late-onset cancer, and previous work has focused more on early-onset disease. If confirmed in future studies, the trend in breast-cancer penetrance, according to mutation location along the BRCA1 coding sequence, may have significant impact on treatment decisions for carriers of BRCA1-mutations. As well, BRCA2 mutations may prove to be a greater cause of cancer in male carriers than previously has been thought.

The estimation of cancer burden is valuable to set up priorities for disease control. The comprehensive global cancer statistics from the International Agency for Research on Cancer indicate that gynaecological cancers accounted for 19% of the 5.1 million estimated new cancer cases, 2.9 million cancer deaths and 13 million 5-year prevalent cancer cases among women in the world in 2002. Cervical cancer accounted for 493 000 new cases and 273 000 deaths; uterine body cancer for 199 000 new cases and 50 000 deaths; ovarian cancer for 204 000 new cases and 125 000 deaths; cancers of the vagina, vulva and choriocarcinoma together constituted 45 900 cases. More than 80% of the cervical cancer cases occurred in developing countries and two-thirds of corpus uteri cases occurred in the developed world. Political will and advocacy to invest in healthcare infrastructure and human resources to improve service delivery and accessibility are vital to reduce the current burden in low- and medium-resource countries.

In the United States, ovarian cancer is the fourth most frequent cause of cancer death among women, following lung, breast, and colorectal cancers. Each year, approximately 26,000 women are diagnosed with ovarian cancer and 14,000 die of it. Germline mutations in BRCA1, BRCA2, or other genes have been implicated in a small fraction of cases. However, it has been suggested that, for the great majority of patients, the risk of epithelial ovarian cancer could be related to "incessant ovulation" (i.e., to the chronically repeated formation of stromal epithelial clefts and inclusion cysts following ovulation) or to some type of hormonal stimulation of ovarian epithelial cells, either on the surface of the ovary or within ovarian inclusion cysts, possibly mediated through excessive gonadotropin secretion. From the evidence to date, the relative importance of these two hypotheses--incessant ovulation and gonadotropin stimulation--cannot be distinguished. While either or both may play a role in the development of ovarian cancer, it appears that an additional major factor must also be involved. The purpose of this review is to evaluate evidence for and against the incessant ovulation and gonadotropin hypotheses, as well as to consider the possibility that risk of ovarian cancer may be increased by factors associated with excess androgenic stimulation of ovarian epithelial cells and may be decreased by factors related to greater progesterone stimulation. Many features of the evidence bearing on the pathophysiology of ovarian cancer appear to support a connection with androgens and progesterone.