Особенности определения мутаций генов BRCA1 и BRCA2 при серозном раке яичников

Демидова И.А. Особенности определения мутаций генов BRCA1 и BRCA2 при серозном раке яичников. Современная Онкология. 2017; 19 (1): 30–33.

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Demidova I.A.The characteristics of determination of BRCA1 and BRCA2 mutations in serous ovarian cancer. Journal of Modern Oncology. 2017; 19 (1): 30–33.

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Аннотация

Мутации в генах BRCA1/BRCA2 встречаются в 15–20% случаев рака яичников (РЯ) и ассоциируются с высокой чувствительностью к терапии препаратами платины и новыми таргетными препаратами, ингибирующими белки семейства PARP. Появление новой терапевтической опции в лечении пациенток с РЯ, ассоциированном с мутациями генов BRCA1/BRCA2, привело к существенным изменениям в международных и национальных клинических рекомендациях и разработке новых подходов к определению мутаций в Российской Федерации. Первые результаты Программы Российского общества клинической онкологии, направленной на совершенствование молекулярно-генетической диагностики в РФ с целью повышения эффективности противоопухолевого лечения (www.cancergenome.ru) показали релевантность нового двухэтапного алгоритма тестирования, включающего секвенирование следующего поколения для определенных групп больных. Были исследованы образцы 1385 пациенток с платиночувствительным рецидивом РЯ. Мутации BRCA1/BRCA2 обнаружены у 22% больных.
В 93,5% случаев выявлялись мутации в гене BRCA1, в 6,5% случаев – в гене BRCA2. Метод секвенирования нового поколения позволил дополнительно выявить 47 мутаций, встречавшихся с частотой 0,03–2,3%. Мутации достоверно чаще встречались у больных с классическими признаками семейного рака и у пациенток до 50 лет. Продолжение работы Программы позволит полностью охарактеризовать группу пациенток с мутациями BRCA1/BRCA2, как кандидатов для получения нового высокоэффективного вида терапии.

Ключевые слова: рак яичников, мутации BRCA1/BRCA2, ингибиторы PARP, секвенирование следующего поколения.

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Mutations of the BRCA1/BRCA2 genes occur in 15–20% cases of ovarian cancer (OC) and are associated with increased sensitivity to platinum drugs and new target drugs that inhibit proteins of poly(ADP-ribose) polymerase family. The discovery of new therapeutic options in the treatment of patients with OC associated with mutations of the BRCA1/BRCA2 genes is resulted in significant changes in national and international clinical guidelines and in the development of new approaches for identification of mutations in the Russian Federation. The first results of the project of Russian Society of Clinical Oncology aimed at improvement of molecular genetic testing in the Russian Federation and associated with enhancing the effectiveness of antitumor treatment (www.cancergenome.ru), have showed the relevance of new two-stage testing algorithm including next-generation sequencing in special groups of patients. 1385 patients with platinum-sensitive relapsed OC were examined. BRCA1 and BRCA2 mutations were found in 22% of patients. BRCA1 gene mutations were found in 93.5% of cases and in 6.5% of cases – BRCA2 mutations. Next-generation sequencing helped to identify another 47 mutations and to determine mutations frequency – 0.03–2.3%. Statistically significant mutations were determined in patients with classical signs of familial cancer and in patients under 50 years of age. Continuation of this project would fully describe the characteristics of group of patients with mutations of the BRCA1/BRCA2 genes as the candidates for new and highly efficient therapy.

Key words: ovarian cancer, BRCA1/BRCA2 mutations, PARP inhibitors, next-generation sequencing.

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1. Ashworth A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers defıcient in DNA double-strand break repair. J Clin Oncol 2008; 26: 3785–90.
2. Lee JM, Ledermann JA, Kohn EC. PARP Inhibitors for BRCA1/2 mutation-associated and BRCA-like malignancies. Ann Oncol 2014; 25: 32–40.
3. Jazaeri AA. Molecular profıles of hereditary epithelial ovarian cancers and their implications for the biology of this disease. Mol Oncol 2009; 3: 151–6.
4. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011; 474: 609–15.
5. Alsop K, Fereday S, Meldrum C et al. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group. J Clin Oncol 2012; 30: 2654–63.
6. Lord CJ, Ashworth A. PARP inhibitors: synthetic lethality in the clinic. Science 2017; 355: 1152–8.
7. Pennington KP, Walsh T, Harrell MI et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res 2014; 20: 764–75.
8. Ledermann J, Harter P, Gourley C et al. Olaparib maintenance therapy in patients with platinum- sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol 2015; 16 (4): e158.
9. Oza AM, Cibula D, Benzaquen AO et al. Olaparib combined with chemotherapy for recurrent platinum-sensitive ovarian cancer: a randomised phase 2 trial. Lancet Oncol 2015; 16 (1): 87–97.
10. Liubchenko L.N. Nasledstvennyĭ rak molochnoĭ zhelezy i/ili iaichnikov: DNK-diagnostika, individual'nyĭ prognoz, lechenie i profilaktika. Avtoref. dis. ... d-ra med. nauk. M., 2009. [in Russian]
11. Suspitsin EN, Sherina NY, Ponomariova DN et al. High frequency of BRCA1, but not CHEK2 or NBS1 (NBN), founder mutations in Russian ovarian cancer patients. Hered Cancer Clin Pract 2009; 7 (1): 5.
12. European Institute of Oncology. Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013; 24 (6): 24–32.
13. U.S. Preventive Services Task Force (USPSTF). Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventice Services Task Force recommendation statement. Ann Intern Med 2014; 160 (4): 271–81.
14. Gadzicki D, Evans DG, Harris H et al. Genetic testing for familial/hereditary breast cancer-comparison of guidelines and recommendations from the UK, France, the Netherlands and Germany. J Community Genet 2011; 2 (2): 53–69.
15. Eccles D, Balmana J, Clune J et al. Selecting Patients with Ovarian Cancer for Germline BRCA Mutation Testing: Findings from Guidelines and a Systematic Literature Review. Adv Ther 2016; 33 (2): 129–50.
16. National Comprehensive Cancer Network (NCCN). Genetic/familial high-risk assessment: breast and ovarian – clinical practice guidelines in oncology: National Comprehensive Cancer Network (NCCN), 2014.
17. Genetic testing for breast and ovarian cancer susceptibility: evaluating direct-to-consumer marketing – Atlanta, Denver, Raleigh-Durham, and Seattle, 2003.
18. Scottish Intercollegiate Guidelines Network (SIGN). Management of epithelial ovarian cancer (SIGN 135), 2014.
19. Tiuliandin S.A., Dengina N.V., Kolomiets L.A. i dr. Prakticheskie rekomendatsii po lekarstvennomu lecheniiu raka iaichnikov/pervichnogo raka briushiny/matochnykh trub. DOI: 10.18027/2224-5057-2016-4s2-123-134 [in Russian]
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21. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011; 474 (7353): 609–15.
22. Informatsionnyi portal molekuliarno-geneticheskoi diagnostiki onkologicheskikh zabolevanii www.cancergenome.ru [in Russian]

Авторы

И.А.Демидова*

ГАУЗ «Московская городская онкологическая больница №62» Департамента здравоохранения г. Москвы. 143423, Россия, пос. Истра, д. 27
*dema-80@yandex.ru

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I.A.Demidova*

The Moscow city cancer hospital No. 62 of the Department of health of Moscow. 143423, Russian Federation, pos. Istra, d. 27
*dema-80@yandex.ru

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