Genetic Factors

A family history of ovarian cancer is the most significant known risk factor. Approximately 10% of all ovarian cancers can be associated with a familial genetic predisposition. The risk depends on the number of first- and second-degree relatives with ovarian cancer and their age at diagnosis. A woman with a single family member affected by ovarian cancer has a 4% to 5% lifetime risk of developing the disease. This risk increases to about 7% if two family members are affected3 (Table 1-4).

Approximately 7% of ovarian cancer patients have a positive family history of ovarian cancer, of whom 3% to 9% may eventually manifest certain hereditary cancer syndromes. Two clinically distinct syndromes are associated with hereditary ovarian cancer for which pedigree analysis suggests an autosomal dominant transmission with variable penetrance. Therefore, inheritance of these genetic mutations may occur from the maternal or paternal side. The hereditary breast-ovarian cancer syndrome (HBOC) is the more common of the two and is associated with germline mutations in BRCA1 and BRCA2 tumor suppressor genes. A lesser proportion is associated with the inherited form of endometrial and colorectal cancer known as hereditary non-polyposis colorectal cancer (HNPCC).

The BRCA1 gene is located on the long (q) arm of chromosome 17 at position 21 (17q21), and the BRCA2 gene is localized to the long arm of chromosome 13 (13q12). Both BRCA1 and BRCA2 gene mutations are associated with a predisposition to breast and ovarian cancer. These mutations are mainly of the frameshift or nonsense variety. BRCA1 is a tumor suppressor gene that acts as a negative regulator of tumor growth. Following the recognition of DNA damage, BRCA1 is activated, which then may be involved in the transcription-coupled repair of oxidative DNA damage. Activated BRCA1 is also likely to function as a transcription factor in regulation of complex genetic program that responds to DNA damage. Without a functional BRCA1 or BRCA2 gene, repair fails, leading to activation of p53-dependent DNA damage. A clinically significant mutation in BRCA1 confers a lifetime risk of ovarian cancer of 40% to 50% compared with 20% to 30% risk associated with a BRCA2 mutation.29 In women with a BRCA1 or BRCA2 mutation, the risk of ovarian and breast cancer may be as high as 54% and 82%, respectively.30 Most ovarian cancers associated with germline BRCA mutations are diagnosed at a younger age and are high-grade, advanced-stage serous carcinomas. Mutation rates for these genes have been reported to be as high as 8% to 10% in the general population.31,32

Women of Ashkenazi Jewish descent have been found to have an increased risk of inheriting BRCA mutations. About 40% of ovarian cancers in this population are

Table 1-3.

Associations between Unopposed Estrogen Therapy-Only Use and Ovarian Cancer among Women Enrolled in the National Institutes of Health-AARP Diet and Health Study Cohort*

Exposure

All Women (W = 97,638)

Women with Hysterectomy {N = 19,359)

Cancers Person-years

RRf (95% CI)

Cancers

Person-years

RRĀ§ (95% CI)

P Value*

No HT use

87

176,376

1.00 (referent)

14

25,030

1.00 (referent)

Only ET

49

71,815

1.33

.17

37

51,455

1.23

.43

(0.89-2.00)

(0.67-2.27)

Recency of use

Former

14

23,539

1.15

6

10,355

1.03

(0.65-2.05)

(0.40-2.70)

Current

34

47,284

1.46

.13

31

40,638

1.37

.32

(0.89-2.38)

(0.72-2.62)

Duration of use (yr)

<10

23

43,458

1.15

11

25,971

0.84

(0.72-1.82)

(0.38-1.88)

>10

26

27,501

1.89

.004

26

24,990

1.70

.06

(1.22-2.95)

(0.87-3.31)

Recency and duration

Former

14

23,539

1.16

6

10,355

1.07

(0.65-2.07)

(0.41-2.78)

Current (yr)

<10

10

22,497

1.00

7

17,481

0.83

(0.49-2.03)

(0.33-2.09)

>10

24

24,603

1.88

.06

24

22,994

1.71

.14

(1.08-3.27)

(0.87-3.35)

CD CO CD

CI, confidence inten/al; ET, unopposed estrogen therapy; HT, hormone therapy; RR, relative risk.

*Among aii women, recency of use was unknown for one woman who developed ovarian cancer and 992 person-years, duration of use was unknown for 857 person-years, and recency and duration were unknown for 1177 person-years. Among women with hysterectomy, recency of use was unknown for 462 person-years, duration of use was unknown for 494 person-years, and recency and duration were unknown for 625 person-years.

fRelative risks adjusted for continuous age (years), race (white, other/unknown}, duration of oral contraceptive use (none, <10 years, >10 years, or unknownj, body mass index (BMI) (<25, 25-29, >30 kg/m2 or unknown), and menopause and hysterectomy (natural menopause, surgical menopause, premenopause, or unknownj; models include terms for ever use of other HT fonvulatlons (ET followed by estrogen plus progestin, estrogen plus progestin only, progestin followed by estrogen plus progestin, ET and estrogen plus progestin but order unknown, other formulations, or unknownj.

P values (two-sided) were calculated using Wald chi-square tests of categorical (ever-usej or ordinal (recency of use and recency and durationj variables based on the categories and referent group shown. The P value (two-sided) for duration of use was based on an ordinal variable for total years of use at baseline (none, 1, 2, 3,.. ., 9, 10, or >10).

Ā§Relative risks adjusted for continuous age (years), race (white, other/unknown), duration of oral contraceptive use (none, <10 years, >10 years, or unknown), and BMI (<25, 25-29, >30 kg/m2 or unknown).

From Lacey JV, Brlnton LA, Leitzmann MF, et al: Menopausal hormone therapy and ovarian cancer risk In the National Institutes of Health-AARP Diet and Health Study Cohort. NCI J Natl Cancer Inst 98:1397-1405, 2006.

Table 1-4. Ovarian Cancer: Family History and Relative Risk (RR)

Relation RR Lifetime

One second degree 2.8 3.5%

One first degree 3.6 5%

Two relatives 5 7%

Two first degree 40%

From NIH Consensus Conference: Ovarian Cancer. Screening, treatment, and foiiow-up. NIH Consensus Development Panel on Ovarian Cancer. JAMA 273:491-497, 1995.

of hereditary nature. For these women, the risk of carrying a BRCA mutation is approximately 1 in 40. Three specific mutations have been carried by the Ashkenazi Jewish population: 185delAG and 5382insC on BRCA1 and 6174delT on BRCA2. The increased risk is a result of what has been defined as "founder effect" (higher rate of mutations have occurred within a defined geographic area).33 Hereditary nonpolyposis colorectal cancer (Lynch II syndrome) combines familial colon cancer with increased risk of ovarian and endometrial cancer, as well as other malignancies of the gastrointestinal and genitourinary system. It is caused by inherited mutations in DNA mismatch repair genes (MMR), hMLH1 and hMSH2 and to a lesser extent hPMS1 and hPMS2. The risk of developing ovarian cancer has been reported to be 12%. With MSH2 mutation, the risk is reported to be higher (10%) compared with MLH1, where the risk is about 3%.34

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