Are gynecologic malignancies hereditary? In daily clinical work, we often encounter patients asking such a question. Tumor occurrence is the result of the joint action of genetic factors and environmental factors. Years of research on tumor etiology have shown that genetic factors play an indispensable role in the occurrence of malignant tumors. However, it is generally believed that more than 80% of human malignant tumors are caused by various environmental factors, and only some relatively rare tumors are congenital or hereditary. Hereditary, as it is usually called, does not mean that the tumor will be directly inherited from the parent to the offspring; what is inherited is the susceptibility and predisposition to the causative factors. Individuals with a family history of cancer have a greater risk of developing cancer than the general population. The genetic mechanisms of tumorigenesis are primarily chromosomal and genetic alterations. Tumor chromosomal abnormalities include abnormalities in chromosome number and structure. The most common chromosome number abnormality is aneuploidy, i.e., one or several chromosomes more or less than diploid; chromosome structure abnormality includes chromosome deletion, breakage, inversion, duplication and translocation. Genetic changes include activation of proto-oncogenes and inactivation of oncogenes. Proto-oncogenes are a class of genes that control cell growth and differentiation and are mutated under the action of viral transformation or oncogenic factors. The mechanisms by which proto-oncogenes are activated into oncogenes include DNA methylation, gene amplification and point mutations. The development of many hereditary tumors involves aberrant alterations in genomic methylation. These include hypermethylation of tumor suppressor genes leading to gene silencing, and demethylation of proto-oncogenes leading to gene activation. Common oncogenes include myc, ras, C-erbB-2, sis, etc. Oncogenes are specific cellular genes that express cancer-suppressing proteins and act against anticancer genes, and mutation or deletion of oncogenes may lead to tumorigenesis. Common oncogenes include RB gene, P53 gene, BRCA gene, PTEN gene, p16 gene and so on. It has been found that deletion and mutation of RB gene can cause the development of many malignant tumors, including retinoblastoma, osteosarcoma, breast cancer, and lung cancer, etc. Mutation of P53 gene reaches 20%~30% in breast and endometrial cancer; BRCA gene is involved in the repair of DNA damage and is associated with familial breast cancer, which is the most important genetic defective gene known for ovarian cancer. inactivation of PTEN gene and mutations are common in endometrial cancer. Hereditary-phase tumors usually have the following characteristics: early age of onset, bilateral organs easily involved at the same time, prone to multi-organ primary tumors, and morphologically indistinguishable from their hereditary counterparts. I. Genetic correlation of gynecologic tumors Are all gynecologic malignant tumors related to heredity? The relationship between various types of gynecological malignant tumors and heredity is discussed below. Breast cancer is the first major malignant tumor threatening women’s health. The average risk of breast cancer in a woman’s life is 9%, and its incidence factors are not only related to estrogen, age, diet, obesity and other factors, but also related to heredity, especially in the women who have less estrogen, and the role of hereditary factors is more obvious. Research confirms that about 5% of breast cancer is related to heredity, characterized by early onset and bilateral development. The incidence of breast cancer in mothers or sisters is three times higher than in women in general. The occurrence of breast cancer is a combination of innate susceptibility and environmental factors. BRCAl and BRCA2 genes are proven genetic susceptibility genes for breast cancer, which are closely related to hereditary breast cancer. Ovarian Cancer Ovarian cancer is the gynecological malignant tumor with the highest mortality rate, and most of the ovarian malignant tumors are originated from ovarian epithelial cells, and its pathogenesis is unknown. 10-15% of ovarian malignant tumors occur in the form of family aggregation, and this family aggregation phenomenon may be a result of the genetic predisposition combined with the role of environmental factors. Recent studies have found that genetic factors are the most important risk factors for the development of ovarian cancer, and 5-10% of patients are related to heredity, among which hereditary breast-ovarian cancer syndrome and Lynch syndrome type II caused by BRCA1 and BRCA2 gene mutations account for the majority. Hereditary breast-ovarian cancer syndrome, which is caused by mutations in the BRCA1 or BRCA2 genes, can occur in breast cancer, ovarian cancer or both. A family with a predisposition to hereditary breast cancer and the occurrence of breast cancer or two or more ovarian cancers in a first-degree relative is generally categorized as hereditary breast ovarian cancer syndrome. Demographic investigations testing genetic relationships of the breast, ovary, and endometrium have shown that the relative risk of breast and ovarian cancer is higher in families of breast cancer patients, with a doubling of the incidence of ovarian cancer in patients with breast cancer, and a 2- to 3-fold increase in the risk of breast cancer in patients with ovarian cancer, whereas the risk of endometrial cancer is not as high, thus suggesting the presence of the hereditary breast-ovarian cancer syndrome, with a high incidence of breast and ovarian cancer susceptibility may have some overlap. Lynch syndrome, hereditary nonpolypoid colorectal cancer syndrome (HNPCC), is an autosomal dominant disorder caused by mutations in DNA mismatch repair genes. According to the existence of extracolorectal tumors, HNPCC is divided into type I and type II. Type I manifests itself as colorectal cancer, and type II manifests itself as a diversity of extracolorectal tumors in addition to colorectal cancer, commonly endometrial cancer, ovarian cancer, and other malignant tumors occurring in the family members of certain patients with Lynch syndrome II, such as urological and other digestive systems and thyroid cancers, brain tumors, and skin cancers. Endometrial cancer accounts for 20%~30% of the malignant tumors in female reproductive tract, and the incidence rate has been on the rise in recent years. Increasing age, obesity, anovulatory infertility, infertility, diabetes mellitus, hypertension, gynecological diseases related to the increase of estrogen and family history of tumor are all regarded as high risk factors. Approximately 10% of endometrial cancers are genetically linked, with the most closely related genetic syndrome being Lynch syndrome, caused by mutations in mismatch repair genes, which is associated with the development of endometrial cancer in young women. Endometrial cancer is the most common extraintestinal malignancy in Lynch syndrome type II, and the risk of endometrial cancer in patients with hereditary nonpolypoid colorectal cancer is 40% to 60%. There are two types of endometrial cancer: type I estrogen-dependent type, which is caused by the prolonged action of estrogen without progesterone antagonism, leading to endometrial hyperplasia and then carcinoma formation. Its mechanism is mainly related to molecular events such as PTEN gene inactivation and microsatellite instability. type II non-estrogen-dependent endometrial cancer, which has no clear relationship with estrogen, is most common in old and thin women, and its endometrium tends to be atrophic, and its mechanism is mainly related to the mutation of the P53 gene and the overexpression of the HER2 gene. In addition, 80% of endometrial cancer patients have chromosomal misalignment, and chromosomal trisomy is often reported. The allelic deletion of chromosome 10q, 17p and p53 mutations are related to endometrial cancer. Cervical cancer Cervical cancer is the most common malignant tumor of female reproductive system. The occurrence of cervical cancer is mainly due to HPV virus infection, but also related to early sexual life, multiple sexual partners, smoking, sexually transmitted diseases and immunosuppression. Familial tendency of cervical cancer has been found in clinic, about 1.7%-7% of cervical cancer patients have family history. The famous actress Anita Mui died of cervical cancer, and her sister and mother also suffered from cervical cancer. A study showed that the incidence of cervical cancer in mothers of cervical cancer patients was 7.9%, which was significantly higher than the incidence of mothers in the control group. However, the incidence rate of fallopian tube cancer is lower than that of fallopian tube cancer. The causes of fallopian tube cancer are thought to be related to chronic inflammation of fallopian tube, and the mutation of tumor suppressor gene and BCRA may be related to the occurrence of fallopian tube cancer. Currently, it is believed that fallopian tube cancer and ovarian epithelial carcinoma both originate from the epithelium of Miller’s canal, have similar etiologic basis and gene mutations and genetic abnormalities, such as c-erb, p53 and K-ras mutations, and are associated with mutations in BCRA1 and BCRA2 genes. P53 gene mutations have been reported to be detected in more than half of the cases of tubal intraepithelial carcinoma. About 16% of primary fallopian tube cancers are carriers of BRCA gene mutation. Gestational trophoblastic tumors Gestational trophoblastic tumors refer to a group of diseases related to pregnancy and characterized by trophoblastic hyperplasia and malignant tendency of different degrees. Including invasive hyperemesis gravidarum, choriocarcinoma and placental trophoblastic tumor. The aetiology of these diseases is complex, epidemiological and genetic studies have revealed the importance of host factors in the etiology of the disease, and at least some of the patients are associated with hereditary factors; the most striking feature of these tumors is the chromosomal imbalance of the parental chromosomes, and abnormalities of the chromosomal karyotypes are considered to be the main factor. Paternal genetic origin is the main cause of trophoblastic hyperplasia and is associated with disorders of genomic imprinting. Partial gravidarians are mostly triploid, and excess paternal chromosomes are the main cause of trophoblast hyperplasia, while complete gravidarians have diploid chromosome karyotypes, all of which are derived from the paternal lineage and lack maternal chromosomes. Second, the prevention of hereditary gynecological sex tumors The occurrence of gynecological sex tumors comes from the joint action of genetic factors and environmental factors. Genetic factors are only the internal causes of malignant tumors, while external environmental factors play a major role, malignant tumors can be prevented to a large extent. For example, reduce cancer-causing exposures, change poor lifestyle and living habits, and have regular gynecological examinations for early detection and treatment. It is also important to learn self-monitoring. When breast lumps, abdominal masses, abnormal vaginal bleeding, postmenopausal vaginal bleeding and abnormal vaginal discharge, abdominal pain, and changes in bowel movements and body weight occur, one should consult a doctor promptly. For women with a family history of tumors and genetic predisposition to tumors, what can be done to prevent and detect malignant tumors early? First of all, there is no need to panic and worry, but to raise the awareness of cancer prevention, pay attention to environmental and behavioral factors, and perform regular preventive examinations. Clinically, special monitoring and management should be carried out for high-risk groups, and genetic counseling should be provided for high-risk groups with family genetic predisposition to tumors. Starting from systematic personal and family history, complete genealogical investigation and hereditary risk assessment should be carried out for the whole family. Appropriate preventive measures should be taken as early as possible for those who have been confirmed as carriers of the BRCA gene mutation by genetic testing. Currently, the main preventive measures that can be taken include close observation, oral medication, and prophylactic surgery. Some scholars advocate risk-reducing surgery for women with high genetic risk to prevent tumor occurrence and improve long-term survival rate. Prevention of hereditary breast cancer includes prophylactic mastectomy and prophylactic oophorectomy. Studies have shown that unilateral subcutaneous mastectomy of the contralateral breast in women with breast cancer can reduce the recurrence rate of breast cancer in patients. Some scholars have observed that prophylactic surgical removal of both breasts in women at intermediate and high risk of breast cancer can reduce the expected incidence of breast cancer by more than 90%. Most breast cancer patients who carry the BRCAl mutation gene are estrogen receptor negative. Prophylactic oophorectomy reduces the risk of both ovarian and breast cancer in carriers of BRCA-1 and BRCA-2 mutations. A study confirmed that the incidence of breast cancer in women with BRCA mutation genes who underwent bilateral oophorectomy was significantly lower than that in those who did not, and the risk of breast cancer gradually decreased with the increase in the number of years of post-operative follow-up. Prevention of Hereditary Ovarian Cancer The prognosis of ovarian cancer is related to early diagnosis, and the early 5-year survival rate can reach more than 73%, but there is still a lack of effective means of early screening for ovarian cancer. After menopause, the ovaries no longer play a role, but there is a potential risk of malignancy. It is estimated that the removal of both ovaries during hysterectomy for benign uterine lesions in women who are close to or over menopausal age can prevent 9%~18% of ovarian cancer. Therefore, removal of both ovaries at the same time as hysterectomy is advocated for postmenopausal women. Currently, annual or biannual serum CA125 combined with vaginal ultrasound examination is considered to be the best test for high-risk women with BRCA gene mutations, and this test should preferably be started at the age of 25-35 years. Prophylactic oophorectomy may be considered if the risk of hereditary ovarian cancer is estimated to be 50% and there are no fertility requirements, but there is no standard for the optimal age for prophylactic oophorectomy. Premature removal of ovaries may lead to cardiovascular disease and osteoporosis, etc. After ovariectomy, hormone supplementation therapy is feasible to minimize the impact on cardiovascular and bone metabolism. For high-risk young gorillas can we get a bull’s eye to incite palpitations and or fermium planted in Shilaje to fatigue the inquisition in the general population, oral contraceptives can reduce the incidence of epithelial carcinoma of the ovary by 40%. Some studies have found that oral contraceptives can reduce the incidence of ovarian cancer in patients with BRCA gene mutations by more than 3 consecutive months, and even by 60% in 6 years of use. Oral contraceptives have been recognized as significantly reducing the incidence of ovarian cancer in the general population. However, whether oral contraceptive use in patients with BRCA gene mutations increases the risk of breast cancer remains to be further investigated. Many early-stage ovarian cancers are diagnosed during prophylactic removal of both adnexa in patients with hereditary breast-ovarian cancer syndrome. The National Institutes of Health suggests that, given the high risk of ovarian cancer in women with hereditary ovarian cancer syndrome families, it is recommended that these women undergo prophylactic oophorectomy at the age of 35 or after childbirth. This approach reduces the risk of ovarian and fallopian tube cancer by 85 to 96 percent, and the risk factor for breast cancer by 50 to 70 percent. However, after prophylactic oophorectomy, there is still a 2% to 4% chance of occult cancer. At present, there is a lack of long-term prospective study on the preventive effect of prophylactic gynecological surgery on women with high risk of hereditary cancer syndrome, but retrospective analysis of cumulative data of hereditary ovarian cancer shows that prophylactic ovariectomy can reduce the number of ovarian cancer patients in cancer families. 3.Prevention of hereditary endometrial cancer Hereditary non-polypoid colorectal cancer syndrome in the family of women with primary endometrial cancer and ovarian cancer. Some scholars suggest that women with a family history of endometrial cancer and hereditary HNPCC mutations should be screened from the age of 25-30 years, and the commonly used methods are vaginal ultrasound, endometrial biopsy and serum CAl25 measurement. However, the usefulness of screening has not been proven, and some people oppose such screening because of the good prognosis of early-onset endometrial cancer. family members of patients with Lynch syndrome often carry DNA mismatch repair genes, and it has been suggested that prophylactic total hysterectomy plus double adnexectomy can be beneficial in preventing adenocarcinomas in the uterus after they have completed childbearing. Concurrent prophylactic hysterectomy may be considered for women with patient NPCC undergoing bowel surgery. Although there is insufficient evidence to suggest an increased incidence of endometrial cancer in individuals with BRCA mutations, hysterectomy in conjunction with prophylactic salpingo-oophorectomy has been recommended. Patients treated with triamcinolone acetonide have an increased incidence of uterine cancer (primarily endometrial cancer, but also uterine sarcoma), so prophylactic salpingo-oophorectomy with hysterectomy may be selectively applied to triamcinolone-treated patients. Tubal ligation also reduces the risk of ovarian cancer in BRCA carriers, although it is less effective than prophylactic oophorectomy. Therefore, tubal ligation may be considered in patients who have completed their reproductive function but do not wish to undergo prophylactic oophorectomy. In conclusion, gynecological malignant tumors have a certain correlation with heredity, but external environmental factors still play a major role. By controlling environmental and man-made factors, the occurrence of gynecological tumors can be prevented, and gynecological checkups should be done regularly for early detection and early treatment. For women with family history of tumors, it is necessary to raise the awareness of cancer prevention and conduct regular preventive examinations. Relevant genetic tests can be conducted if possible, and risk-reducing preventive surgeries can be performed on mutation gene carriers and those with indications for preventive surgeries, so as to reduce the incidence of malignant tumors and improve the survival rate. However, due to the influence of various factors such as ethical, legal, psychological, economic and social factors, prophylactic surgery cannot be accepted as a routine method to prevent hereditary tumors.