Many studies have shown that some cases of ovarian cancer are transmitted familially (familial or hereditary ovariancancer syndrome (FOCS or HOCS)). Women belonging to these families have a high risk of ovarian cancer, and their screening, diagnosis, counseling and preventive management are among the most important concerns in the field of gynecologic oncology today.
1. Definition
A large number of case-control studies and clinical reports have shown that family history of ovarian cancer is the most important risk factor for the development of ovarian cancer. Detailed genealogical analysis has demonstrated that ovarian cancer is vertically transmitted in families in a manner consistent with autosomal dominant inheritance.Watson et al. defined 3 definite FOCS:
(1) hereditary breast-ovarian cancersyndrome (HBOC ), which refers to a family with at least 3 cases of early-onset (age < 60 years) breast or ovarian cancers, including at least 1 ovarian cancer.
(2) hereditary site-specific ovarian cancer syndrome (HBOC), which refers to a family with at least 3 cases of ovarian epithelial cancer (at any age), but no cases of breast cancer before the age of 50.
(3) hereditary nonpolyposis colorectal cancer (HNPCC), mainly manifested as colorectal cancer, may be combined with endometrial cancer and ovarian cancer, but ovarian cancer is less likely to appear than other types of cancer, its diagnosis refers to Amsterdam/Bethesda criteria.
2. Epidemiology
Familial ovarian cancer is heterogeneous, with more than 5% of all ovarian cancer cases belonging to some form of FOCS. Ponde et al. reported a prevalence of up to 50% in women with two or more first-degree relatives with ovarian cancer, and stratified this risk as 10% in women aged 40 years, 20% at age 50, rising to 30% at age 60, and 40% at age 70. The risk of the disease is 10% at age 40, 20% at age 50, 30% at age 60 and 40% at age 70. For confirmed carriers of the gene, such as women whose mother or daughter has ovarian cancer and who already have breast or colon cancer themselves, the lifetime risk is theoretically nearly 100%.
The relative risk of ovarian cancer in the relatives of 391 patients was 4.5 in total, 7.4 if the pre-determined person was under 55 years of age, and 3.7 in first-degree relatives if the pre-determined person was over 55 years of age. The risk increases with the number of first-degree relatives, the total number of patients in the family, the number of patients per generation and the number of younger patients.
3. Molecular biology basis
In recent years, molecular biology studies have provided a reliable basis for the diagnosis of FOCS, and several relevant susceptibility genes have been identified. The BRCA gene, located at 17g12-21, is the most studied FOCS-related gene, which was localized and named by Hall et al. in 1990. Subsequently, Miki et al. completed the cloning of BRCA in 1994, which has 24 exons, 22 of which are coding exons, and occupies more than l00 kb of genomic DNA.
Its encoded protein product contains 1863 amino acids and acts in the nucleus to exert tumor suppressive effects by regulating the cell cycle, participating in DNA damage repair, controlling DNA damage response nodes, regulating a series of specific transcriptional pathways, and inducing apoptosis, among other activities, for which no identical protein has been identified to date. To date, over 300 mutations have been identified to occur in the BRCA,gene, most of which result in the production of short, nonfunctional protein products.
It is now believed that in the FOCS family, the BRCA, gene is inherited in an autosomal dominant manner, i.e., mutations in one allele at the gamete level cause an individual to be susceptible to tumors, but in somatic cells this defective gene is negative, while the loss or inactivation of the other normal allele completes the transition to malignancy. The risk of breast cancer by age 70 is over 80% and the risk of ovarian cancer is over 40%.
However, some specific BRCA mutations, such as the 185delAG and 5383insC mutations that occur in German Jews, can reduce the risk of breast and ovarian cancer in this population. Therefore, further studies on the association of BRCA, mutations with FOCS are needed.BR CA :gene localized to 13gl2-13 is another gene that is highly associated with FOCS. The wild-type allele deletion was found to be the characteristic alteration in the BRCA: related family, thus suggesting that BRCA: functions as a tumor suppressor gene. the BRCA: gene has 27 coding exons and encodes a 390ku nuclear protein, almost twice the size of the BRCA, gene protein, and the BRCA,gene mutations are all generating relatively short protein products.
Wooster et al. found that although families associated with the BRCA: gene had a higher incidence of breast cancer, their odds of developing ovarian cancer were substantially lower than those of families associated with the BRCA, gene. The hM SH 2, hMSH6, hMLH1, hPMS1, and hPMS2 are the genes associated with HNPCC, and they are the “housekeeping genes” that oversee the DNA mismatch repair process.
The most common mutated genes in HNPCC are hMLHI and hMSH2, which are characterized by DNA double-stranded mismatches caused by microsatellite instability, manifested as poly(C A),0-3, and other simple repetitive sequence insertions or deletions. hNPCC affected individuals usually have inactivation of a mismatch gene and deletion of the corresponding wild-type allele in tumor cells ( The “second strike” theory), leading to tumorigenesis. However, there are many other HNPCC and HNPCC-like families that are not associated with any of the above five genes, suggesting the presence of other unknown susceptibility genes, including gene mutations and gene polymorphisms. p53 gene, as a representative of oncogenes, has been positively associated with ovarian cancer. It was found that mutations in the Lu3 gene at the gamete level were found in families with Li-Fraumeni cancer syndrome; the odds of mutations in the p53 gene at the gamete level were also as high as 40% in susceptible families with non-Li-Fraumeni syndrome; less than 2% in sarcoma patients without family history, and almost none in the control general population. It is reasonable to speculate that the Lu3 gene plays a role in FOCS, but there have been only isolated reports to date, and whether there is an etiologic link remains to be explored.
4. Clinical features and pathology
Detailed genealogical analysis is the most basic means to diagnose FOCS. Considering the genetic heterogeneity, a complete record of the family line should include the age of onset and pathological reports of malignant tumors such as breast cancer, ovarian cancer, colorectal cancer, endometrial cancer, etc. However, at present, due to factors such as too small families, insignificant changes in epizootic rates, and missing relatives additionally, early age of onset is an important feature of FOCS. Studies by the National Cancer Society have shown that the median age of ovarian cancer onset in the general population is 56 years, while in FOCS families it is advanced to 47 years, with about 17% of patients being diagnosed with ovarian cancer when they are less than 40 years old. This has important clinical implications for screening for disease, for conducting family planning, and for the timing of preventive surgery.
In 1996, the Gil daR adner Familial Ovarian Cancer Registry in the United States analyzed its collection of 1000 familial ovarian cancer histologic types and compared them with data from the National Association for the Epidemiologic Detection of Cancer and found that the former had a preponderance of plasmacytic adenocarcinoma (40% vs. 25%) and a lesser number of burrowing carcinomas (3% vs. 12%) 0 200() years later, the center conducted another study of 126 families with In 200(), the center analyzed the pathological types of 200 ovarian cancer patients combined with BRCA gene mutation types and found that there were no exclusionary fluid ovarian cancer and junctional tumors in 65 patients from BRCA:positive families, while 12 patients with fluid cancer and 10 junctional tumors in 135 patients from BRCA:negative families. This suggests that the histopathological types of familial ovarian cancer may not include fluid-bearing adenocarcinoma and junctional tumors.
5. Management of high-risk groups
Early surveillance is necessary for members of FOCS families. Annual pelvic examination, serum CA, test, transvaginal ultrasound, and color Doppler ultrasound are performed to observe ovarian blood flow changes. Studies have shown that the sensitivity of vaginal ultrasound in detecting ovarian cancer is 78%-100%, the specificity is 98%-99.4%, the positive predictive value is 11%-87.5%, and the negative predictive value is 98.8%-100%. The use of color Doppler flowmetry can improve the positive predictive value of vaginal ultrasound and reduce the false-positive rate.
The specificity of CA,, in the diagnosis of ovarian cancer is 97%, with a positive predictive value of 44% and a negative predictive value of 97%. However, CA,, is also elevated in other benign gynecologic conditions such as endometriosis, pelvic inflammatory disease, and fibromatous ovarian cystadenoma, thus limiting its use in ovarian cancer screening. Women with a family history suggestive of HBOC should undergo breast self-examination and annual mammography, and members of HNPCC families should also undergo annual colonoscopy and endometrial biopsy.
Prophylactic oophorectomy has been recommended when women have had children or after 35-40 years of age, in most cases with total hysterectomy and bilateral adnexal resection, to avoid endometrial hyperplasia from hormone replacement therapy after oophorectomy or endometrial cancer in HNPCC. However, there is still controversy regarding prophylactic oophorectomy.
On the one hand, it is considered to be the only effective means of preventing ovarian cancer, reducing the risk of ovarian cancer to near 0.
On the other hand, there is still some risk after ovariectomy. For example, the risk of primary peritoneal plasmacytic papillary carcinoma in women of FOCS family still exists, and the clinical mortality rate of this cancer is high, with a prognosis of the same period of ovarian cancer; in addition, there is the emotional stress of loss of ovaries leading to menopause, the risk of surgery and the need for long-term hormone replacement therapy.
In addition to prophylactic oophorectomy, oral contraceptives are also a method of preventing ovarian cancer. Studies have shown that taking the pill for 3-6 months can reduce the risk of ovarian cancer by 40%, and taking it for 10 years or more can reduce the risk by 80%, and the preventive effect lasts for 10-15 years after stopping the pill. Therefore, oral contraceptives are also an option for women at high risk who do not want to undergo prophylactic oophorectomy. The screening, diagnosis, counseling and preventive management of women with a high risk of ovarian cancer is one of the most important concerns in the field of gynecologic oncology today.