Liang Zhiqing from Southwest Hospital of Third Military Medical University Submits IPO Prospectus Highlighting Hereditary Ovarian Cancer Syndrome Management

Hereditary Breast and Ovarian Cancer Syndrome (HBOCS) It is the most common clinical type of hereditary ovarian cancer syndrome (HOCS), accounting for 90% of HOCS cases. It refers to a family history in which two first-degree relatives, or one first-degree relative and one second-degree relative, have been diagnosed with breast or ovarian cancer, indicating a genetic predisposition. Therefore, individuals with the followingCharacteristics of patients and families requiring risk assessment:

(1) Tumors occur at an early age, mostly around 45 years old or earlier;

(2) Occurrence of bilateral breast cancer, triple-negative breast cancer, or both breast and ovarian cancers in the same woman;

(3) Two or more relatives have breast cancer and/or ovarian cancer;

(4) Male breast cancer occurs in the family.

During risk assessment, a detailed family history should be collected and presented in the form of a pedigree, which must cover at least three generations and include both affected and unaffected relatives. Subsequently, the probability of an individual or family carrying pathogenic gene mutations, as well as the risk of developing ovarian cancer, is evaluated using genetic mutation probability prediction models. If the risk assessment indicates that the probability of a gene mutation in individuals from Hereditary Breast and Ovarian Cancer Syndrome (HBOCS) families is ≥10%, genetic counseling and genetic testing are recommended.

Current research indicates that susceptibility genes associated with the pathogenesis of Hereditary Breast and Ovarian Cancer Syndrome (HBOCS) include BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2, BARD1, CHEK2, RAD50, MRE11, and NBN. These genes are all involved in the DNA damage response by repairing double-strand DNA breaks. Among these, 80%–90% of HBOCS cases harbor mutations in the BRCA1 and BRCA2 genes. BRCA genes are tumor suppressor genes whose fundamental role is to maintain chromosomal stability; they are particularly crucial in the repair of double-strand DNA breaks. Mutations in BRCA genes may initiate or promote tumorigenesis. Carriers of BRCA1 and BRCA2 gene mutations have a risk of developing ovarian cancer of 35%–60% (with a mean age at diagnosis of 50 years) and 12%–25% (with a mean age at diagnosis of 60 years), respectively.

When conducting genetic testing, it is recommended to first test for gene mutations in the known ovarian cancer patient (proband) within the family. Due to the autosomal dominant inheritance pattern of this syndrome, if a relative is found to carry an HBOCS-related mutation, other family members can undergo targeted mutation analysis. The probability of developing ovarian cancer before the age of 21 among female members of HBOCS families is very low; therefore, most experts do not recommend genetic testing for females under the age of 21 in HBOCS families.

 Hereditary Site-Specific Ovarian Cancer Syndrome (HSSOCS) is a variant of Hereditary Breast and Ovarian Cancer Syndrome (HBOCS), characterized by familial clustering of ovarian cancer without cases of breast cancer. The associated susceptibility genes are also BRCA1 and BRCA2.

Hereditary Nonpolyposis Colorectal Cancer Syndrome (HNPCCS), also known as Lynch Syndrome II (LSII), is an autosomal dominant disorder caused by systemic mutations in mismatch repair (MMR) genes. It increases the risk of early-onset cancers, primarily including colorectal cancer, endometrial cancer, ovarian cancer, small bowel cancer, gastric cancer, and urinary tract cancer. The fundamental role of MMR genes is to maintain the integrity and stability of genetic material through the recognition and repair of DNA base mismatches. Four genes (MLH1, MSH2, MSH6, and PMS2) have been confirmed to be associated with the development of ovarian cancer in patients with LSII, among which mutations in MLH1 and MSH2 are the most common.

Screening criteria for HNPCC families are as follows: At least two family members with histopathologically confirmed colorectal cancer, among whom two are in a parent-child or sibling relationship, and who meet one of the following criteria:

(1) At least one case involves a patient with multiple colorectal cancers (including adenomas);

(2) At least one case of colorectal cancer diagnosed before the age of 50;

(3) At least one individual in the family has been diagnosed with an HNPCC-associated extracolonic tumor (including gastric cancer, endometrial cancer, small bowel cancer, ureteral or renal pelvic cancer, ovarian cancer, and hepatobiliary system cancer).

The risk of ovarian cancer in women with Lynch syndrome type II (LSII) is 7%–12%, which is higher than the 1.7% incidence rate observed in the general female population. Among LSII patients whose initial tumor is ovarian cancer, the mean time interval to the development of a second primary tumor is 5 years. Recent studies have shown that the peak age of onset for LSII-associated ovarian cancer is 40–55 years, which is younger than that of sporadic cases. The risk of developing ovarian cancer varies depending on the specific mismatch repair (MMR) gene mutation; for instance, the incidence in families with MSH2 mutations is twice that of those with MLH1 mutations. Furthermore, LSII-associated ovarian cancer often occurs concurrently or sequentially with endometrial cancer, with both cancers presenting as synchronous primary tumors in 9% of cases. Endometrioid and clear cell carcinomas are the most common histological subtypes of LSII-associated ovarian cancer. Clinically, these tumors typically present at an early stage, and serous carcinoma is rare, a feature that distinguishes them from BRCA mutation-associated ovarian cancers.

For patients found to carry pathogenic mutations in HOCS susceptibility genes, Yin provides genetic counseling and appropriate clinical interventions for their family members to enhance early diagnosis of ovarian cancer, strive for early treatment, thereby reducing the incidence and mortality rates of ovarian cancer in these high-risk populations and improving prognosis.

of early diagnosis, striving for early treatment to reduce the incidence and mortality of ovarian cancer in these high-risk populations and improve prognosis

• Traditional Intervention Methods

  Historically, intensified surveillance was considered the primary intervention for high-risk women in hereditary breast and ovarian cancer syndrome (HBOCS) families who wished to preserve fertility and ovarian endocrine function. The surveillance strategy recommended that women carrying BRCA gene mutations undergo semiannual transvaginal ultrasound combined with serum CA125 testing, starting at age 25 or 5–10 years before the earliest age of ovarian cancer diagnosis in the family. Additionally, frequent breast self-examinations and annual mammography were advised. However, recent studies indicate that intensified surveillance alone does not effectively improve survival rates or reduce mortality among high-risk women. Oral contraceptives are recommended by the American Society of Clinical Oncology as a preventive medication for hereditary ovarian cancer. Literature reports suggest that using oral contraceptives for more than five years may reduce the risk of ovarian cancer by 50% in women with a family history of the disease. However, whether this simultaneously increases the risk of breast cancer remains controversial. Currently, prophylactic oophorectomy is considered the most effective method for reducing the risk of HBOCS and related gynecologic malignancies. Bilateral salpingo-oophorectomy reduces the risk of ovarian, fallopian tube, or primary peritoneal cancer by 98% and the risk of breast and ovarian cancer by 54% in BRCA mutation carriers.

• Targeted Therapy for HBOSC Gene Defects

  In patients with hereditary breast and ovarian cancer syndrome (HBOCS) harboring BRCA gene mutations, DNA double-strand break repair function is impaired, whereas the alleles in normal tissues retain intact DNA double-strand break repair capability. In this context, the DNA repair protein poly(ADP-ribose) polymerase (PARP) plays a crucial role in maintaining normal cellular homeostasis, including DNA transcription, cell cycle regulation, and DNA repair. The potent PARP inhibitor olaparib causes the accumulation of single-strand DNA breaks, which subsequently leads to double-strand DNA breaks at replication forks. This results in biallelic mutations and loss of function in tumor cells, abolishing double-strand break repair and ultimately leading to tumor cell death. Olaparib monotherapy induces tumor regression through the well-established mechanism of synthetic lethality, preventing the resolution of DNA double-strand breaks and increasing genomic instability. It has demonstrated selective inhibition of tumor cell line growth in vitro, enhancing cytotoxicity and antitumor activity against tumor cells.

  Phase I and II clinical trial reports on olaparib for the treatment of advanced epithelial ovarian cancer with BRCA1 or BRCA2 gene mutations have confirmed that its therapeutic efficacy, assessed using Response Evaluation Criteria in Solid Tumors (RECIST) and CA-125 testing, demonstrates favorable efficacy and tolerability.

  Patients with BRCA gene defects exhibit a predisposition to erroneous repair following DNA strand damage and genomic instability; consequently, cells harboring these genetic defects demonstrate increased sensitivity to DNA-damaging agents such as platinum-based drugs, including cisplatin and carboplatin. Currently, platinum-based agents, particularly carboplatin, are widely used in the clinical treatment of cancer patients with BRCA gene mutations.

• Blocking the Transmission of HOCS to Offspring

  Women with BRCA1 or BRCA2 gene mutations have a 50% chance of passing the same mutation to their offspring. Currently, there are two methods to prevent this transmission: one is to perform chorionic villus sampling in early pregnancy and terminate the pregnancy if the fetus carries the mutated gene; Another approach is fourth-generation IVF-ET, which involves preimplantation genetic diagnosis to select genetically normal zygotes for transplantation.
  

With the deepening exploration of the human genome and disease-related genes, prevention, diagnosis, and treatment at the genetic and molecular levels have become a reality for genetic disorders such as Hereditary Ovarian Cancer Syndrome (HOCS). Through pedigree analysis, genetic counseling, susceptibility gene testing, and monitoring of high-risk populations, we can improve the early diagnosis of ovarian cancer, strive for early treatment, thereby reducing the incidence and mortality rates of ovarian cancer in these high-risk groups and improving prognosis. However, there are still certain limitations to the widespread screening of HOCS. For instance, pedigree analysis is often difficult to conduct comprehensively; the mutation profiles of susceptibility genes in high-risk populations in China remain unclear; it is uncertain whether high-frequency mutation sites exist; it is challenging to identify simpler and more feasible screening methods; and the acceptance of prophylactic surgery among the Chinese population remains a question. Nevertheless, our understanding of HOCS will become increasingly comprehensive, and intervention strategies will continue to improve, indicating that the treatment of hereditary malignancies, and indeed all malignancies, has entered a new era.