Identifying Sequence Variants of 18 Hereditary Ovarian Cancer-Associated Genes in Chinese Epithelial Ovarian Cancer Patients

Objectives. The causes of ovarian cancer (OC) have been confirmed to be closely related to genetic factors. Identifying sequence variants of hereditary ovarian cancer (HOC) susceptibility genes can increase clinical surveillance, facilitate early detection, and provide personalized treatment for patients. This study is aimed at investigating the variation frequency of HOC susceptibility genes in the Chinese population and providing information for the etiology and genetics of OC. Methods. 118 epithelial OC patients were recruited in this clinical study. Variants of 18-gene panel were detected in blood samples by next-generation sequencing (NGS) technology. Results. Overall, 36.44% (43/118) of patients carried at least one pathogenic variant. Among these, BRCA1 pathogenic variants were detected in 31 (26.27%) patients, and 5 (4.24%) patients carried pathogenic variants of BRCA2. Moreover, 27.12% (32/118) of patients carried variants of unknown significance (VUSs). Importantly, we detected eight variants that were not reported previously. Conclusions. Our study enlarged the spectrum of HOC-associated gene sequence variants in the Chinese population and also proved the necessity of multigene testing in epithelial OC patients. The identification of patients with HOC will allow family members to undergo cascade testing where identification of unaffected carriers can facilitate early detection, risk reduction, or prevention of OC and ultimately improve long-term outcomes.

Ovarian cancer predisposition beyond BRCA1 and BRCA2 genes

Several genes associated with hereditary ovarian cancer have been discovered as a result of the work done with next generation sequencing. It is estimated that approximately 23% of ovarian carcinomas have a hereditary predisposition. The most common hereditary condition is represented by germline mutations in BRCA1 or BRCA2 genes that account for 20–25% of high grade serous ovarian cancer. A number of other hereditary ovarian cancers are associated with different genes, with a crucial role in the DNA damage response pathway, such as the mismatch repair genes in Lynch syndrome, TP53 in Li-Fraumeni syndrome, STK11 in Peutz-Jeghers syndrome, CHEK2, RAD51, BRIP1, and PALB2. The goal of this manuscript is to summarize the published data regarding the molecular pathways involved in the pathogenesis of non-BRCA related hereditary ovarian cancer and to provide a tool that might be useful in discussing risk assessment, genetic testing, prevention strategies, as well as clinical and therapeutic implications for patients with ovarian cancer.

Organizational forms and methods of early diagnosis of hereditary tumors

Background: With the development of genetic research in oncology, it has become possible to track and identify early and preclinical forms of hereditary oncological diseases, which allows timely and effective preventive and therapeutic measures in relation to relatives at risk. Aim of the study: Assessment of genetically determined neoplasms in the region and the development of organizational forms and methods for early diagnosis. Material and methods: 10,727 residents of the Belarus-Poland border region were examined. Clinical and medical history data of 2,054 patients with tumors of the breast (1406), ovaries (239), and colon (409) were analyzed. As a result of the questionnaire, three main observation groups were formed: “high risk of hereditary cancer”, “hereditary cancer suspected”, and “no risk of hereditary cancer”. Results: Register and hospital screenings were the most informative types of screening. Of the 149 HBC patients who underwent molecular genetic testing, BRCA1 gene mutations were found in 5.37%, 5382insC in all cases. Seven mutations were detected in 77 individuals with a diagnosis of HOC and in 6 cases 5382insC and in 2 - 4145delA. Signs of hereditary ovarian cancer and suspicion of it were found in 1.12%, including people who were found to have a high risk of hereditary ovarian cancer. By their effectiveness, register and hospital screenings significantly exceeded the population, p<0.01. 1.67% of women suffering from this disease met the high clinical risk criteria for hereditary ovarian cancer. A high clinical risk of hereditary tumor genesis was established in 0.73% of cases among patients with a diagnosis of colon cancer. Conclusions: The results of assessing the clinical risk of hereditary cancer according to population screening indicates that approximately 1.2% of the population has an increased clinical risk of developing hereditary breast, ovarian, and colon cancer.

The hereditary ovarian cancer: role of candidate genes in disease pathogenesis

Значительное количество злокачественных новообразований яичников являются наследственными (до 30% всех новообразований возникают в результате высокой генетической предрасположенности). Известно, по меньшей мере, 16 генов-кандидатов наследственного рака яичников (РЯ), а с внедрением и широким применением полногеномного секвенирования растет число генов и генетических вариантов, потенциально вовлеченных в патогенез семейных форм заболевания, хотя вклад этих генов в развитие наследственного РЯ еще предстоит доказать. Обнаружение специфических мутаций в ряде генов-кандидатов РЯ у здоровых женщин может оправдать не только более интенсивные и персонализированные программы наблюдения пациенток из групп риска, химиопрофилактики и/или профилактических операций, но и может дать фундаментальные знания о патогенезе развития опухолей. В статье описаны особенности клинического течения наследственного РЯ, обусловленного мутациями в ключевых генах кандидатах (BRCA1, BRCA2, TP53, BARD1, CHEK2, RAD51, PALB2). Описаны основные типы мутаций при BRCA-ассоциированном РЯ, возрастные особенности и показатели выживаемости. Показано, что большая часть (примерно 65-85%) наследственных опухолей яичников приходится на герминальные мутации в генах BRCA1 и BRCA2. Считается, что мутации в данных генах приводят прежде всего к онкогинекологическим заболеваниям в эстрогенчувствительных органах-мишенях, однако по некоторым данным имеется также вероятность возникновения рака желудка, толстой кишки, эндометрия, поджелудочной железы, меланомы кожи, опухолей мочевого пузыря, головы и шеи. Приблизительно 6% наследственного РЯ приходится на герминальные мутации в генах BARD1, BRIP1, CHEK, MRE11A, MSH6, NBN, PALB2, RAD50, RAD51C и TP53, белковые продукты которых участвуют в восстановлении гомологичной рекомбинации. Мутации в средне- и низкопенетрантных генах в отдельности обуславливают минимальный риск, но благодаря мультипликативным и/или кумулятивным эффектам могут приводить к относительно высокому риску для носителей. В статье подробно описан онкогенез РЯ, обусловленного мутациями в генах MMR (синдром Линча), которые являются второй по значимости причиной наследственного РЯ и составляют от 2% до 15% всех случаев заболевания. Описаны также другие белки, кодируемые генами RAD51, RAD50, ATM, MRE11 и PALB2, которые взаимодействуют с продуктами генов BRCA1/2 в механизме гомологичной рекомбинационной репарации. A significant number of ovarian malignancies are hereditary (up to 30% of all neoplasms result from a high genetic predisposition). At least 16 candidate genes for hereditary ovarian cancer are known, and with the introduction and widespread use of genome-wide sequencing, an increasing number of genes and genetic variants are potentially involved in the pathogenesis of familial forms of the disease, although the contribution of these genes to the development of hereditary ovarian cancer . The detection of specific mutations in a number of ovarian cancer candidate genes in healthy women can justify not only more intensive and personalized surveillance programs, chemoprophylactic approaches and / or preventive operations, but also can provide fundamental knowledge about the pathogenesis of tumor development. This article describes the clinical features of hereditary ovarian cancer due to mutations in the key candidate genes (BRCA1, BRCA2, TP53, BARD1, CHEK2, RAD51, PALB2). The main types of mutations in BRCA - associated ovarian cancer, age-related features and survival rates are described. It was shown that the majority (approximately 65-85%) of hereditary ovarian tumors account for germline mutations in the BRCA1 and BRCA2 genes. It is believed that mutations in these genes lead primarily to gynecological oncological diseases in estrogen-sensitive target organs, however, according to some reports, there is also the likelihood of cancer of the stomach, colon, endometrium, pancreas, skin melanoma, bladder, head and neck tumors. Approximately 6% of hereditary OC is accounted for by germline mutations of the BARD1, BRIP1, CHEK, MRE11A, MSH6, NBN, PALB2, RAD50, RAD51C and TP53 genes, the protein products of which are involved in the restoration of homologous recombination. Medium and low penetrant genes individually carry only minimal risk, but due to the multiplicative and / or cumulative effects, they can cause a relatively high risk for carriers. The article describes in detail the oncogenesis of ovarian cancer due to a mutation in the genes for the restoration of the mismatch MMR - Lynch syndrome, which is the second leading cause of hereditary ovarian cancer and makes up from 2% to 15% of all cases of the disease. Other proteins encoded by the RAD51, RAD50, ATM, MRE11 and PALB2 genes that interact with the products of the BRCA1 / 2 genes in the mechanism of homologous recombination repair are also described in detail