Наследственно обусловленный рак яичников

Демидова И.А. Наследственно обусловленный рак яичников. Современная онкология. 2015; 17 (3): 70–75.

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Demidova I.A. Hereditary ovarian cancer. Journal of Modern Oncology. 2015; 17 (3): 70–75.

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Аннотация

Эпителиальная карцинома, или рак яичников (РЯ), является пятой по распространенности причиной смертности от онкологических заболеваний среди женщин в мире, причем наследственный/семейный РЯ составляет около 15–20% всех случаев. Примерно 1/2 этих случаев обусловлена герминальными мутациями в генах BRCA1/BRCA2. Для РЯ, ассоциированного с данными мутациями, характерна высокая чувствительность к химиотерапевтическим режимам с включением препаратов платины и новым таргетным препаратам. Мутации, возникающие в генах BRCA1 и BRCA2, весьма разнообразны, однако приводят к одному результату: образованию неполноценного белка, неспособного к участию в гомологичной рекомбинации или восстановлению поврежденной ДНК. Интересным фактом является значительное разнообразие мутаций в различных этнических популяциях. Для российской славянской популяции характерен «эффект основателя» (founder effect) в гене BRCA1, наиболее ярко выраженный при наследственном раке молочной железы. Однако РЯ имеет свои существенные особенности как в распределении частоты фаундерных мутаций в BRCA1 и случайных мутаций в гене BRCA2, так и в частоте встречаемости соматических мутаций указанных генов. Этот феномен требует особого подхода как к выбору популяции и материала для тестирования на наличие мутаций, так и к выбору наиболее адекватной методики исследования.

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

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Epithelial carcinoma or ovarian cancer (OC) is the fifth most common cause of cancer mortality in women, and hereditary/familial OC occurs in 15–20% of all cases. Approximately 1/2 of these cases are developed due to germline mutations in the BRCA1/BRCA2 genes. OC associated with BRCA1/BRCA2 mutations are highly sensitive to platinum based chemotherapy regimens and to chemotherapy with the inclusion of targeted drugs. BRCA1 and BRCA2 mutations are multivarious, but they lead to one result: the synthesis of defective protein which is unable to participate in homologous recombination or damaged DNA reparation. There is an interesting fact that the large variety of mutations can be found in different ethnic populations. The Slavic Russian population is characterized by a "founder effect" in BRCA1 gene, especially in case of hereditary breast cancer. However, OC has its special characteristics as in the distribution of frequency BRCA1 mutations and occasional BRCA2 mutations, and in the incidence rate of somatic mutations in the same genes. This phenomenon requires special approach in case of choice of population, material for mutations testing and in choosing the most appropriate research methodology.

Key words: ovarian cancer, mutations in the genes BRCA1/BRCA2, next-generation sequencing.

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Список литературы

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2. Ovarian cancer, five-year stage-specific relative survival rates (2004– 2008). J Natl Cancer Inst 2011; 103: 1287.
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9. Fong PC, Boss DS, Yap TA et al. Inhibition of poly (ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361: 123–34.
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12. Zhang J. The role of BRCA1 in homologous recombination repair in response to replication stress: significance in tumorigenesis and cancer therapy. Cell Biosci 2013; 3 (1): 11.
13. Maxwell CA, Benítez J, Gómez-Baldó L et al. Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer. PLoS Biol 2011; 9 (11): e1001199.
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27. Górski B, Jakubowska A, Huzarski T et al. A high proportion of founder BRCA1 mutations in Polish breast cancer families. Int J Cancer 2004; 110 (5): 683–6.
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29. Berchuck A, Heron KA, Carney ME et al. Frequency of germline and somatic BRCA1 mutations in ovarian cancer. Clin Cancer Res 1998; 4 (10): 2433–7.
30. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011; 474 (7353): 609–15.
31. 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 (21): 2654–63.
32. Ready K, Gutierrez-Barrera AM, Amos C et al. Cancer risk management decisions of women with BRCA1 or BRCA2 variants of uncertain significance. Breast J 2011; 17 (2): 210–2.
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1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics. CA Cancer J Clin 2010; 60: 277–300.
2. Ovarian cancer, five-year stage-specific relative survival rates (2004– 2008). J Natl Cancer Inst 2011; 103: 1287.
3. Rubin SC, Benjamin I, Behbakht K et al. Clinical and pathological features of ovarian cancer in women with germ-line mutations of BRCA1. N Eng J Med 1996; 335: 1413–6.
4. Sun Ch, Li N, Weng D et al. The Role of BRCA Status on the Prognosis of Patients with Epithelial Ovarian Cancer: A Systematic Review of the Literature with a Meta-Analysis. PLOS ONE 2014; 9 (5): e95285.
5. Bhattacharyya A, Ear US, Koller BH et al. The breast cancer susceptibility gene BRCA1 is required for subnuclear assembly of Rad51 and survival following treatment with the DNA cross-linking agent cisplatin. J Biol Chem 2000; 275: 23899–903.
6. Davies AA, Masson JY, McIlwraith MJ et al. Role of BRCA2 in control of the RAD51 recombination and DNA repair protein. Mol Cell 2000; 7: 273–82.
7. Kowalczykowski SC. Molecular mimicry connects BRCA2 to Rad51 and recombinational DNA repair. Nat Struct Biol 2002; 9: 897–9.
8. Audeh MW, Carmichael J, Penson RT et al. Oral poly (ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet 2010; 376: 245–51.
9. Fong PC, Boss DS, Yap TA et al. Inhibition of poly (ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med 2009; 361: 123–34.
10. Honrado E, Benítez J, Palacios J. The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications. Mod Pathol 2005; 18 (10): 1305–20.
11. Lynch HT, Snyder CL, Lynch JF et al. Family information service participation increases the rates of mutation testing among members of families with BRCA1/2 mutations. Breast J 2009; 15 (Suppl. 1): S20–4.
12. Zhang J. The role of BRCA1 in homologous recombination repair in response to replication stress: significance in tumorigenesis and cancer therapy. Cell Biosci 2013; 3 (1): 11.
13. Maxwell CA, Benítez J, Gómez-Baldó L et al. Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer. PLoS Biol 2011; 9 (11): e1001199.
14. Li D, Ilnytskyy Y, Kovalchuk A et al. Crucial role for early growth response-1 in the transcriptional regulation of miR-20b in breast cancer. Oncotarget 2013; 4 (9): 1373–87.
15. Welcsh PL, King MC. BRCA1 and BRCA2 and the genetics of breast and ovarian cancer, Human Mol Gen 2001; 10 (7): 705–13.
16. Foulkes WD, Shuen AY. In brief: BRCA1 and BRCA2 J Pathol 2013; 230 (4): 347–9.
17. Jacobs IJ, Kohler MF, Wiseman RW et al. Clonal origin of epithelial ovarian carcinoma: analysis by loss of heterozygosity, p53 mutation, and X-chromosome inactivation J Nat Cancer Inst 1992; 84 (23): 1793–8.
18. Hilton JL, Geisler JP, Rathe JA et al. Inactivation of BRCA1 and BRCA2 in ovarian cancer (2002) J Nat Cancer Inst 2002; 94 (18): 1396–406.
19. Mavaddat N, Barrowdale D, Andrulis IL et al. Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: Results from the consortium of investigators of modifiers of BRCA1/2 (CIMBA). Cancer Epid Biomarkers Prevent 2012; 21 (1): 134–47.
20. Levy-Lahad E, Catane R, Eisenberg S et al. Founder BRCA1 and BRCA2 mutations in Ashkenazi Jews in Israel: frequency and differential penetrance in ovarian cancer and in breast-ovarian cancer families. Am J Hum Genet 1997; 60 (5): 1059–67.
21. Johannesdottir G, Gudmundsson J, Bergthorsson JT et al. High prevalence of the 999del5 mutation in Icelandic breast and ovarian cancer patients. Cancer Res 1996; 56: 3663–5.
22. Hamel N, Feng BJ, Foretova L et al. On the origin and diffusion of BRCA1 c.5266dupC (5382insC) in European populations. Eur J Hum Genet 2011; 19 (3): 300–6.
23. 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]
24. Sokolenko AP, Mitiushkina NV, Buslov KG et al. High frequency of BRCA1 5382insC mutation in Russian breast cancer patients. Eur J Cancer 2006; 42 (10): 1380–4.
25. 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.
26. Ratajska M, Krygier M, Stukan M et al. Mutational analysis of BRCA1/2 in a group of 134 consecutive ovarian cancer patients. Novel and recurrent BRCA1/2 alterations detected by next generation sequencing. J Appl Genet 2015; 56 (2): 193–8.
27. Górski B, Jakubowska A, Huzarski T et al. A high proportion of founder BRCA1 mutations in Polish breast cancer families. Int J Cancer 2004; 110 (5): 683–6.
28. Foster KA, Harrington P, Kerr J et al. Somatic and germline mutations of the BRCA2 gene in sporadic ovarian cancer. Cancer Res 1996; 56 (16): 3622–5.
29. Berchuck A, Heron KA, Carney ME et al. Frequency of germline and somatic BRCA1 mutations in ovarian cancer. Clin Cancer Res 1998; 4 (10): 2433–7.
30. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011; 474 (7353): 609–15.
31. 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 (21): 2654–63.
32. Ready K, Gutierrez-Barrera AM, Amos C et al. Cancer risk management decisions of women with BRCA1 or BRCA2 variants of uncertain significance. Breast J 2011; 17 (2): 210–2.
33. Ratajska M, Brozek I, Senkus-Konefka E et al. BRCA1 and BRCA2 point mutations and large rearrangements in breast and ovarian cancer families in Northern Poland. Oncol Rep 2008; 19 (1): 263–8.
34. Rudnicka H, Debniak T, Cybulski C et al. Large BRCA1 and BRCA2 genomic rearrangements in Polish high-risk breast and ovarian cancer families. Mol Biol Rep 2013; 40 (12): 6619–23.

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*

Moscow City Oncology Hospital №62. 143423, Russian Federation, town Istra, d. 27
*dema-80@yandex.ru

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