**5. Genetic predisposition to ovarian cancer**

can be produced by normal tissue as well but their levels are usually significantly elevated during a malignant process. Tumour markers are used for the early detection, to guide man-

CA125 is the most commonly used tumour marker for the detection of ovarian cancer. In 1981, Bast et al. developed OC125, a murine monoclonal antibody, which was found to react with ovarian carcinoma cells [16]. An immunoassay was then developed to detect the antigen CA125 in the serum of patients affected by non-mucinous ovarian cancer. CA125 levels were found to be elevated in 82% of women affected by non-mucinous epithelial ovarian cancer,

Elevated CA125 levels are seen in 50% of stage I and >90% of stage II–IV serous ovarian cancers [18]. However, the levels are usually not elevated with mucinous and borderline ovarian tumours. CA125 is also not very specific to ovarian cancer as the levels are increased in other malignancies such that of the gastrointestinal tract, breast and lung; and in benign gynaecological (e.g. endometriosis, fibroids, adenomyosis, benign masses and pregnancy) [18] and

A cut-off value of 35 U/ml is accepted as the upper limit of normal [17]. This cut-off value is acceptable in postmenopausal women, whereas, in premenopausal women, the cut-off value tends to be significantly higher at 50 U/ml [20]. Other factors have also been found to affect the CA125 level. A study on CA125 levels in healthy postmenopausal women observed varying levels with race (highest in Caucasian and lowest in African women), lower levels with previous hysterectomy, regular smoking and caffeine intake, and, higher levels with a previous (non-ovarian) cancer diagnosis. Age of the individual, age at menarche and menopause and previous ovarian cysts were also predictive of baseline levels in postmenopausal women [21]. The CA125 level can be elevated for up to 5 years prior to the diagnosis of ovarian cancer. This finding has been crucial for its application in screening asymptomatic women [22]. Given its low sensitivity and specificity, interpretation of CA125 level using a cut-off value has not been very useful in screening. However, sequential measurements of CA125 as a first-line test and transvaginal ultrasound as a second-line test in multimodal screening have been found to

Human epididymis protein 4 or HE4 is another tumour marker which is elevated in ovarian cancer but not with benign ovarian masses. It can therefore be used to distinguish between the two [24]. In a study using an algorithm combining both HE4 and CA125, 93.8% of epithelial ovarian cancers were accurately classified as high risk [25]. Other markers that have been tested include prolactin, transthyretin, CA72-4 and CA15-3. Combining these markers with

There are two populations of women who are at risk of developing ovarian cancer—the general population whose life time risk is around 1–2% and the high-risk population (strong family history/gene mutations) whose risk can range from 10 to 46%. Most of the ovarian cancers are

CA125 has not shown to improve its efficacy in screening for ovarian cancer [26].

non-gynaecological conditions (e.g. heart failure, pancreatitis, hepatitis) [19].

agement and to assess treatment response in cancer.

218 Ovarian Cancer - From Pathogenesis to Treatment

and it was useful in monitoring the treatment response [17].

significantly improve its sensitivity and specificity [23].

**4. Screening population**

Approximately, 5–10% of ovarian cancers are attributed to genetic mutations. Mutations in the BRCA1 and BRCA 2 genes increase the risk of developing both breast and ovarian cancer. The life time risk of developing ovarian cancer (up to the age of 70 years) is 40% (95% CI, 35–46%) for carriers of BRCA1 mutation and 18% (95% CI, 13–23%) for BRCA2 mutation carriers [27]. A strong family history of breast and ovarian cancers could be an indicator of the presence of mutations in BRCA genes given their high penetrance [28]. The age of onset of ovarian cancer tends to be younger in BRCA carriers when compared to the general population. Median age at diagnosis is 63 years in the general population [29], 51.2 years for BRCA 1 and 57.5 years for BRCA2 mutation carriers [30].

Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) is a syndrome secondary to mutations in the mismatch repair genes (MMR)—MLH1, MSH2, MSH6 and PMS2, which not only increases the risk of developing colorectal cancer but also ovarian and endometrial cancer in female carriers. The estimated cumulative risks of ovarian cancer by age 70 years for women with Lynch Syndrome is around 10% (range 6–14%) [31].

Traditionally, testing for gene mutations has been undertaken in individuals with a strong family history of ovarian cancer. Earlier studies looking at family history alone have shown that women with a first degree relative with ovarian cancer have a 4–5% life time risk of developing ovarian cancer. With two affected close relatives, the risk increases to around 10% and can become higher with even more relatives affected by ovarian cancer [32].

More recently there has been a different approach to screening for gene mutations. A randomised controlled trial looking at testing of the population regardless of family history in the Ashkenazi Jewish population reported a slightly higher incidence of BRCA mutations in the population screening group when compared with the family history group [33]. Such studies suggest that unselected testing of the population identifies 50% more carriers of genetic mutations than the traditional approach to screening based on family history alone.

Other than genetic factors, risk of ovarian cancer has also been found to increase with nulliparity, early menarche and late menopause, hormone replacement therapy and endometriosis. Factors suppressing ovulation such as use of the oral contraceptive pill, multiparity, longer periods of lactation have been associated with a decreased risk [34].
