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УДК: 618.19-006.6-056.7:575.224.22 DOI: 10.26565/2313-6693-2021-42-08
BRCA1 AND BRCA2 GENES MUTATIONS AMONG WOMEN WITH CLINICAL SIGNS OF HEREDITARY BREAST CANCER IN
WESTERN BELARUS
Savanevich A. L., Vasilkevich M. I., Abdrashitov V. V., Stepuro T. L.
Background: Breast cancer is the most common malignancy in women. In the countries of Central and Eastern Europe founder mutations in the BRCA1 and BRCA2 genes are responsible for a significant proportion of breast cancer cases; however, regional differences in the frequencies of various mutations may occur. The spectrum and frequency of BRCA1 and BRCA2 mutations among breast cancer patients have not yet been fully explored in Belarus.
Aim: In this study, we aimed to estimate the incidence of BRCA1 and BRCA2 causative founder variants in breast cancer female patients with clinical signs of hereditary disease in western Belarus.
Materials and Methods: Blood samples from 71 breast cancer female patients with clinical signs of hereditary disease from the western region of Belarus were examined. We studied 13 causative founder variants in BRCA1 (c.5266dupC, c.4035delA, c.5251C>T, c.181T>G, c.676delT, c.68_69delAG, c.3770_3771delAG, c.1687C>T, c.3756_3759delGTCT) and BRCA2 (c.658_659delGT, c.7910_7914delCCTTT, c.3847_3848delGT, c.5946delT) genes characteristic for the population of Central Europe. The study included 22 female patients with early-onset form, 8 individuals with bilateral and 41 women with multiple primary breast cancer.
Results: 32 out of 71 patients (45 %) had one of the causative founder variants in the BRCA1 and BRCA2 genes. The most common mutation defined in these genes was BRCA1 c.5266dupC; it was detected in 19 women with breast cancer (27 %). The carrier of the pathogenic BRCA1 allele c.4035delA was confirmed in 8 cases (11 %). BRCA1 gene mutations were found to be significantly more common in presence of two or more signs of genetic predisposition to breast cancer. However, among 50 patients with a family medical history of breast and/or ovarian cancer and clinical signs of hereditary cancer, mutations in the BRCA1 and BRCA2 genes were found only in 24 (48 %) cases.
Conclusion: The study showed high incidence of germinal BRCA1 mutations (45 %) among breast cancer patients in the western region of Belarus. Only two BRCA1 mutations (c.5266dupC, c.4035delA) are detectable in approximately 84 % of carriers. It is necessary to continue studying the mutations in the genes associated with development of breast cancer that are typical for Belarusian population, especially in the group of young female patients, since this study has confirmed the genetic predisposition only in every third patient under the age of 50.
KEY WORDS: breast cancer, BRCA1 and BRCA2 gene mutations, Belarus INFORMATION ABOUT AUTHORS
Alena Savanevich, MD, PhD, Associate Professor, Associate Professor of the Obstetrics and Gynecology Department, Grodno State Medical University; 80, Gorki str., Grodno, Belarus, 230009, e-mail: [email protected], ORCID ID: https://orcid.org/0000-0002-3661-2354
Maryia Vasilkevich, Internship doctor, Grodno University Clinic; 52, Boulevard of Lenin Komsomol, Grodno, Belarus, 230017, e-mail: [email protected], ORCID ID: https://orcid.org/0000-0001-5959-9546
Vitalii Abdrashitov, Junior Researcher, Scientific Research Laboratory Scientific and Organizational Department, Grodno State Medical University; 80, Gorki str., Grodno, Belarus, 230009, e-mail: [email protected], ORCID ID: https://orcid.org/0000-0002-3500-6563
Tatiana Stepuro, Ph.D. in Biology, Associate Professor of the Department of Normal Physiology, Grodno State Medical University, e-mail: [email protected] ORCID ID: https://orcid.org/0000-0002-3337-4231
The beginning of the XXI century was marked by a significant increase in female breast cancer cases. This disease is the most common among all malignant neoplasms in women. Breast cancer morbidity has increased by 50 % over the last 20 years [1]. New methods of diagnostics and screening of breast cancer are being developed and
introduced into clinical practice, but this pathology incidence and mortality rates continue to grow steadily. The last decade has been marked by the rapid development of oncogenetics and especially by breast cancer genetics. The study of families with autosomal inherited predisposition to one or more types of cancer pathology revealed
© Savanevich A. L., Vasilkevich M. I., Abdrashitov V. V., Stepuro T. L., 2021
several breast cancer predisposition genes [2, 3]. Hereditary mutations are the cause of breast cancer in 10-15 % of cases [4, 5]. Such forms of cancer are characterized by early age of disease development (on average, 15 years earlier than in the general population), high frequency of bilateral and multiple primary lesions, Mendelian laws of inheritance, prognostic factors, and require individual diagnostic and therapeutic approach [6, 7]. Thus, special attention should be paid to the examination of women in the following cases:
■ aggravated family medical history (presence of two or more relatives with reproductive system cancer)
■ vertical transmission of the disease in the family (mother/daughter)
■ presence of family members with multiple primary tumors, including damage to paired organs (bilateral breast cancer)
■ presence of family members diagnosed with cancer at a young age (up to 40 years)
■ presence of family members with an unusually favorable course of the disease, even at advanced stages
■ presence of signs of hereditary syndromes in the family - Gardner syndrome, Peitz-Jaegers syndrome, nevoid basal cell carcinoma, Stein-Leventhal syndrome, Turner syndrome, neurofibromatosis.
The examination for suspected hereditary cancer syndrome begins with collection of oncological history from relatives and compilation of a pedigree. When drawing up pedigrees, localization of tumors, the age of occurrence of the disease and the presence of multiple primary forms of tumors are taken into account. The next stage is laboratory diagnostics. DNA analysis of mutations provides confirmation of the genetic predisposition to cancer and risk assessment of the pathology development in relatives. It allows determining the disease management tactics, the possibility of disease prevention and its early diagnosis. A single genetic test has a life-long informational value.
Currently, the genes associated with the development of cancer include BRCA1, BRCA2, CHEK2, p53, ATM, and NBS1 genes [8]. The role of the BRCA1 and BRCA2 genes in the occurrence of malignant neoplasms in the mammary gland has been studied most fully. According to the present understanding, the BRCA1 and BRCA2 genes act as classic tumor suppressors. The function of these genes is involved in the repair of double-stranded DNA breaks by homologous recombination, which is
necessary to maintain the stability of the genome [9]. A breakdown in the BRCA1 gene is primarily associated with the development of hereditary breast and ovarian cancer syndrome (HBOC - hereditary breast ovarian cancer). Loss of BRCA2 gene function is associated with hereditary breast cancer syndrome (HBC - hereditary breast cancer). Among women with a germinal mutation of one of the alleles of the BRCA1 gene, the risk of developing breast cancer during the lifetime is associated with age and reaches 55-70 % by the age of 70 years, 72 % by the age of 80 years. For carriers of a mutation in the BRCA2 gene the risk of developing breast cancer is 45-70 %. At the same time, the risk of developing breast cancer in the general population does not exceed 12 %. The highest incidence of breast cancer in carriers of a BRCA1 gene mutation occurs at the age of 30 to 40 years [10, 11].
If a mutation carrier has an aggravated family history, the risk of developing a tumor in the breast increases up to 87 % for BRCA1 gene mutation carriers, up to 84 % for BRCA2 mutation carriers. The risk of contralateral breast cancer in mutation carriers correlates with the young age of the first tumor detection, localization of the gene mutation, Tamoxifen intake and bilateral oophorectomy. L. Verhoog et al. have estimated the annual risk of developing contralateral breast cancer for BRCA1-associated cancer patients younger than 41 years as 4.5 %. When breast cancer manifests in BRCA1 mutation carriers under the age of 40, the risk of developing contralateral breast cancer in the next 25 years is 63 % or more. If the disease develops for the first time in women over 50 years of age, the risk of developing contralateral breast cancer does not exceed 19.6 % [12, 13].
The previous studies of the incidence of several mutations in breast cancer patients in our country were of isolated nature. However, they made it possible to establish a significant «founder effect» for the BRCA1 c.5266dupC [14, 15] mutation in the population of Belarus.
The aim of the study is to estimate the incidence of BRCA1 and BRCA2 causative founder variants in breast cancer female patients with clinical signs of hereditary disease in western Belarus. To increase the likelihood of detecting genetic breakdowns associated with the development of breast cancer, we have focused our attention on patients with early, bilateral, and multiple primary cancers [6].
MATERIALS AND METHODS
The study included 22 female patients with the early-onset form (up to 50 years of age), 8 individuals with bilateral and 41 patients with multiple primary breast cancer. All the women were treated at Grodno State Medical University Clinic. Patient involvement in the research process was implemented in compliance with the principles of voluntariness and confidentiality with the registration of informed consent to participate in the study.
All DNA samples were isolated from peripheral blood leukocytes. The analysis of 13 causative founder mutations in the BRCA1 genes (c.5266dupC, c.4035delA, c.5251C>T, c.181T>G, c.676delT, c.68_69delAG, c.3770_3771delAG, c.1687C>T, c.3756_3759delGTCT) and BRCA2 (c.658_659delGT, c.7910_7914delCCTTT, c.3847_3848delGT, c.5946delT) was performed. Mutations of c.5266dupC and c.4035delA in the BRCA1 gene were determined by allele-specific oligonucleotide polymerase chain reaction. Other mutations of BRCA1 (c.5251C>T, c.181T>G, c.676delT, c.68_69delAG, c.3770_3771delAG, c.1687C>T, c.3756_3759delGTCT) and BRCA2 (c.658_659delGT, c.7910_7914delCCTTT, c.3847_3848delGT, c.5946delT) were genotyped using TaqMan kits (Applied Biosystems/Life Technologies, Carlsbad, CA) on a Roche LightCycler 480. For obtained results validation, direct Sanger DNA sequencing was performed. The BigDye Terminator v3.1 Cycle Sequencing Kit (Life Technologies) was used in accordance with manufacturer's protocol. The sequencing results were analyzed using the ABI Prism 3100 genetic analyzer (Life Technologies).
RESULTS
The average age of 71 patients involved in the study was 45.4 ± 9.2 years. In the group of 22 women (28 to 50 years) with monolateral cancer diagnosed at the age of under 50 years, the average age of the disease was 41.2 ± 7.4 years. Every second patient had an aggravated medical family history of breast cancer and/or ovarian cancer in the first or second degree relatives. Out of 8 women with bilateral breast cancer, only two developed tumors synchronously. The
average age of development of the first tumor was 42.4 ± 9.4 years (31 to 59 years), and that of the contralateral neoplasm was 48.3 ± 11.1 years (40 to 68 years). Only 3 patients had indirect signs of hereditary cancer. Time interval between first and second tumors in the mammary glands was from 1 to 17 years, 8.2 ± 5.3 years on average. The group with multiple primary breast cancers consisted of 4 synchronous and 37 metachronous cases. The average age of breast cancer detection was 48.4 ± 9 years (32 to 73 years), while only 3 women had breast cancer as a second diagnosed tumor. The multiplicity of primary neoplasms in most cases was represented by two localizations - 28 (68 %), less often - by three 12 (29 %). Only 1 patient was diagnosed with four tumors with 7 to 9 years intervals, with first tumor occurring in the mammary gland at the age of 39. Most often, the development of malignant neoplasms in mammary glands was combined with ovarian cancer - 39 cases (95 %), or uterine cancer- 3 (7 %). Bilateral breast tumors in the group of patients with multiple primary cancer occurred in 9 women (22 %). Interval between development of breast cancer and appearance of another neoplasm ranged from 1 year to 19 years, with an average of 7.7 ± 5 years. During the first five years, new malignant neoplasm appeared in 13 women (32%), with interval of 5 to 10 years of follow-up- in 11 (27 %), after 10-15 years -in 7 (17 %). In 6 other patients, tumors of a different localization were diagnosed 15-19 years later (15 %). 23 women with polyneoplasia (56 %) had a family history of breast cancer and/or ovarian cancer of the first or second line of kinship.
The study revealed that 32 out of 71 female patients (45 %) had one of the germinal mutations in the BRCA1 and BRCA2 genes. The most common mutation was BRCA1 c.5266dupC which was detected in 19 women with breast cancer (27 %). The carrier of the pathogenic BRCA1 c.4035delA allele was confirmed in 8 cases (11 %). Two patients had a BRCA2 c.658_659delGT mutation (3 %). Three patients with multiple primary cancer had isolated cases of other genetic defects in the BRCA1 gene (4 %). The average age in the group of mutation carriers was 43.4 ± 9.3 years (from 30 to 73 years). In the group of patients without mutations, the average age of breast cancer
was higher - 47.2 ± 8.8 years (28 to 68 years). Among 22 young women with monolateral breast cancer, the germinal mutation was detected in only 7 cases (32 %), and BRCA1 c.5266dupC was identified in all seven of them. Hereditary mutations were present in 3 out of 8 women (38 %) with bilateral breast cancer and in 22 out of 41 women with primary multiple cancer (54 %).
Patients with polyneoplasia were found to have mutations of c.5266dupC and c.4035delA in the BRCA1 gene with approximately the same frequency-in 24 % and 20 % of cases, respectively (Table 1). One woman with esophageal cancer at 65, breast cancer at 73, and colorectal cancer at 84 was found to have the BRCA2 c.658 659delGT mutation.
Table 1
The frequency of causative founder BRCA1 and BRCA2 mutations in patients with breast cancer
BRCA1/BRCA2 mutation type
Bilateral breast cancer, n = 8
Multiple primary breast cancer, n = 41
Early onset breast cancer, n = 22
Total, n = 71
BRCA1 c.5266dupC 2 10 7 19
BRCA1 c.4035delA - 8 - 8
BRCA1c.3847_3848delGT 1 1
BRCA1c.3770 3771delAG - 1 - 1
BRCA1 c.181T>G - 1 - 1
BRCA2 c.658 659delGT 1 1 - 2
Total 3 (37,5 %) 22 (54 %) 7 (32 %) 32 (45 %)
We evaluated the relation between the probability of mutation identification and the number of indirect clinical signs of hereditary breast cancer (early-onset form of the disease, bilateralism, family and personal history of cancer). BRCA1 gene mutations were found to be significantly more common in presence of two or more signs of genetic predisposition to breast cancer (Table 2).
However, among 50 patients with a family medical history of breast and/or ovarian cancer in first or second degree relatives and clinical signs of hereditary cancer, mutations
in the BRCA1 and BRCA2 genes were found only in 24 (48%) cases. This indicates the need for the patients to undergo an in-depth genetic examination, including determination of the complete nucleotide sequence of genes associated with the development of breast cancer, including BRCA1 and BRCA2. Obviously, these methods are much more complex, more expensive and require serious resources like classical Sanger and the next-generation sequencing methods and highly qualified personnel.
Table 2
Incidence of BRCA1 and BRCA2 mutations in breast cancer by the number of indirect clinical signs of hereditary disease.
Clinical signs of hereditary breast cancer
Bilateral breast cancer + early-onset breast cancer + personal history of cancer + family history of breast/ovarian cancer
Bilateral breast cancer + early-onset breast cancer+ personal history of cancer
Early-onset breast cancer + personal history of cancer + family history of breast/ovarian cancer
Early-onset breast cancer + family history of breast/ovarian cancer
Total, BRCA1 BRCA2 N=71 mutation mutation
4 clinical signs
3 clinical signs
2
2 clinical signs
22
12
1 clinical sign
BRCA1/BRCA2 mutation types
BRCA1 c.5266dupC -2 BRCA1 c.4035delA BRCA2 c.658 659delGT
BRCA1 c.5266dupC -2
BRCA1 c.3847 3848delGT
BRCA1 c.5266dupC - 8 BRCA1 c.4035delA - 3 BRCA1 c.181T>G
Early-onset breast cancer 17 7 - BRCA1 c.5266dupC -5
BRCA1 c.4035delA -2
Family history of breast/ovarian 4 1 - BRCA1 c.4035delA
cancer
Personal history of cancer 1 1 BRCA2 c.658 659delGT
Absence of clinical signs
Breast cancer in women over 50 years of age
8
4
BRCA1 c.5266dupC -2 BRCA1 c.4035delA BRCA1 c.3770 3771delAG
6
3
1
8
2
1
DISCUSSION
In the present study, 13 causative founder variants of BRCA1 and BRCA2 genes have been analyzed in the selected breast cancer patients from Grodno region of Belarus. We have detected that approximately 45 % (32 out of 71 cases) of breast cancer female patients with clinical signs of hereditary disease carried one of only six germinal mutations in the BRCA1 or BRCA2 gene. This has been the third study of BRCA mutations in breast cancer in Belarus. In our previous study we observed three BRCA1 founder mutations only in 38 of 500 (7.6 %) unselected breast cancer patients [14]. Bogdanova and her colleagues reported that any of the three mutations were identified in
4.4 % of the 1945 unselected breast cancer patients and in 0.5 % of the 1019 healthy control female group from Belarus [15]. In all the studies, the BRCA1 c.5266dupC mutation was the most common, it accounted for 57 -71 % of all the detected mutations. The c.5266dupC mutation is the most common mutation in other Slavic countries such as Poland, Russia, Czech Republic, Slovenia as well as in northern Greece. It is the second most common BRCA1 mutation in Ashkenazi Jewish population. BRCA1 c.4035delA mutation is the second most frequent mutation detected in this study, observed in 25 % of carriers. Previously it was also observed in high frequency (18-20 %). The higher incidence of BRCA mutations observed in Belarus compared to other
countries of Central and Eastern Europe may be attributed to the low migration rate. The mean age of breast cancer diagnosis of the 32 cases with BRCA1 or BRCA2 mutations was 43.4 ± 9.3 years, which is slightly higher than it is in other regions.
There are some limitations to our study. Due to the small sample size of the analyzed series we were not able to provide conclusive data on the full spectrum of BRCA1 and BRCA2 mutations in breast cancer patients. We screened 71 breast cancer female patients for 13 causative founder mutations in BRCA1 and BRCA2 genes, but detected only 6 of them. It is possible therefore that the other germinal variants were missed. Further studies based on the sequential testing of BRCA1 and BRCA2 genes as well as other genes that may be associated with a strong predisposition to breast cancer should be carried on. At the same time, identification of several «major» mutations in all the patients with breast cancer is a realistic task for medical institutions at the regional level. Thus, a significant number of hereditary BRCA-associated breast cancers in our region can be detected by a small number of PCR tests. We foresee that target screening of specific causative variants in BRCA1 and BRCA2 genes restricted to a particular ethnic group would be more effective in the future therapeutic approaches for the prevention and
cure of breast cancer. The use of this diagnostic approach and preventive risk-reducing surgery may contribute to the future reduction of morbidity and mortality from breast cancer in Belarus.
CONCLUSIONS
The study showed high incidence of germinal BRCA1 mutations (45 %) among breast cancer patients in western Belarus. It should be noted that only two BRCA1 mutations (c.5266dupC, c.4035delA) are detectable in approximately 84 % of carriers. It is necessary to continue studying the mutations in the genes associated with development of breast cancer that are typical for Belarusian population, especially in the group of young female patients, since this study has confirmed the genetic predisposition only in every third patient under the age of 50.
The study was supported by the Belarusian Republican Foundation for Fundamental Research, grant No. M20R-400.
This research was fulfilled in collaboration with colleagues from the International Hereditary Cancer Center, Department of Genetics and Pathology, headed by Professor J. Lubinski, at Pomeranian Medical University in Szczecin (Poland). We are particularly grateful to Professor J. Gronwald and Dr. A. Ashurek for the cooperation.
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МУТАЦП BRCA1 I BRCA2 ГЕН1В У Ж1НОК З КЛ1Н1ЧНИМИ ОЗНАКАМИ СПАДКОВОГО РАКУ МОЛОЧНОÏ ЗАЛОЗИ У ЗАХ1ДНОМУ РЕГ1ОН1 Б1ЛОРУС1
CaeoHeei4 О. Л., Василькевич М. I., Абдрашитов В. В., Степура Т. Л.
Вступ. Рак молочно! залози лвдируе серед ycix злояшсних новоутворень у жшок. У кранах Центрально].' та Схвдно1 Свропи спадковi мутацп BRCA1 i BRCA2 гешв е одшею з проввдних причин розвитку раку молочно! залози; однак, мають мюце i репональш особливосп в частот рiзних мутацш. Ратше в Бвдорус не проводилося дослвдження широкого спектра i частоти виникнення гермтальних мутацт BRCA1 i BRCA2 гешв у патенток з раком молочно! залози.
Мета. Встановити поширешсть гермтальних мутацт BRCA1 i BRCA2 гешв серед патенток з клшчними ознаками спадкового раку молочно! залози в Бвдорусг
Матерiали та методи. Дослвджено зразки кровi 71 жшок з раком молочно! залози i клшчними ознаками спадкового раку, яш постшно проживають в захвдному репош Бшорусг Виконано аналiз 13 значущих для населения Центрально!' Свропи мутацш засновника в генах BRCA1 (c.5266dupC, c.4035delA, c.5251C> T, c.181T> G, c.676delT, c.68_69delAG, c.3770_3771delAG, c.1687C> T, c.3756_3759delGTCT) i BRCA2 (c.658_659delGT, c.7910_7914delCCTTT, c.3847_3848delGT, c.5946delT). У дослiдження включенi 22 патентки з раннiм монолатеральним раком молочно! залози (до 50 рошв включно), 8 - з бiлатеральним i 41 жшка з первинно-множинним раком молочно! залози.
Результати. У 32 з 71 патенток (45 %) була виявлена одна iз значущих патогенних мутацш в генах BRCA1 i BRCA2. Частше за шших зyстрiчалася мyтацiя BRCA1 c.5266dupC - вона була виявлена у 19 жшок з раком молочно! залози (27 %). Носшство патогенного алелi BRCA1 c.4035delA було пiдтверджено в 8 випадках (11 %). Встановлено, що мyтацiï гена BRCA1 зyстрiчалися достовiрно частiше при наявностi двох i б№ше ознак генетично! схильносп до раку молочно! залози. Разом з тим, серед 50 патенток з обтяженим амейним анамнезом по раку молочно! залози i/або раку яечнишв i клiнiчними ознаками спадкового раку мутаци в генах BRCA1 i BRCA2 були виявлеш пльки у 24 (48 %) оаб.
Висновки. Встановлено високу частоту зус^чальносп гермiнальних мyтацiй гена BRCA1 (45 %) у патенток з раком молочно! залози в захвдному регюш Бвдоруа. становить 25 %. Найбшьш поширеними е мyтацiï c.5266dupC i c.4035delA в генi BRCA1, вони були виявлеш у 84 % в груш носив. Необхвдно продовжити вивчення типових для населення Бшоруа мутацш в генах, асоцшованих
з розвитком раку молочно! залози, особливо в rpyni молодих пащенток, так як справжшм дослвдженням генетична схильнiсть шдтверджена тiльки у кожно! третьо! пащентки у вiцi до 50 рошв.
КЛЮЧОВ1 СЛОВА: рак молочно! залози, мутаци гена BRCA1, BRCA2, Бшорусь
1НФОРМАЦ1Я ПРО АВТОР1В
CaBOHeBi4 Олена Леонтавна, к. мед. н., доцент кафедри акушерства i гшекологп, УО «Гродненський державний медичний унгверситет»; вул. Горького, 80, Гродно, Бшорусь, 230009, e-mail: [email protected], ORCID ID: https://orcid.org/0000-0002-3661-2354
Василькевич Марiя IropiBHa, лжар-стажист УЗ «Гродненська унiверситетська клшжа»; Бульвар Лешнського Комсомолу, 52, Гродно, Бiлорусь, 230017, e-mail: [email protected], ORCID ID: https://orcid.org/0000-0001-5959-9546
Aбдpaшiтoв Вiтaлiй В'ячеславович, м. н. с., науково-дослдао! лаборатори науково-дослдао! частини, УО «Гродненський державний медичний ушверситет»; вул. Горького, 80, Гродно, Бшорусь, 230009, e-mail: [email protected], ORCID ID: https://orcid.org/0000-0002-3500-6563
Степура Тетяна Леонщвна, к. бюл. н., доцент кафедри нормально! фiзiологil УО «Гродненський державний медичний утверситет», вул. Горького, 80, Гродно, Бшорусь, 230009, e-mail: [email protected], ORCID ID: https://orcid.org/0000-0002-3337-4231
МУТАЦИИ BRCA1 И BRCA2 ГЕНОВ У ЖЕНЩИН С КЛИНИЧЕСКИМИ ПРИЗНАКАМИ НАСЛЕДСТВЕННОГО РАКА МОЛОЧНОЙ ЖЕЛЕЗЫ В ЗАПАДНОМ РЕГИОНЕ БЕЛАРУСИ
Савоневич Е. Л., Василькевич М. И., Абдрашитов В. В., Степуро Т. Л.
Введение. Рак молочной железы лидирует среди всех злокачественных новообразований у женщин. В странах Центральной и Восточной Европы наследственные мутации BRCA1 и BRCA2 генов являются одной из ведущих причин развития рака молочной железы; однако, имеют место и региональные особенности в частоте встречаемости различных мутаций. Ранее в Беларуси не проводилось исследование широкого спектра и частоты встречаемости терминальных мутаций BRCA1 и BRCA2 генов у пациенток с раком молочной железы.
Цель. Установить распространенность герминальных мутаций BRCA1 и BRCA2 генов среди пациенток с клиническими признаками наследственного рака молочной железы в Беларуси.
Материалы и методы. Исследованы образцы крови 71 женщины с раком молочной железы и клиническими признаками наследственного рака, постоянно проживающих в западном регионе Беларуси. Выполнен анализ 13 значимых для населения Центральной Европы мутаций основателя в генах BRCA1 (0.5266^^ е.4035ае1А, ^52510^ С.181Т > в, с.67бае1Т, с.68_69ае1АО, а3770_377Ые1Ав, c.1687C > Т, c.3756_3759de1GTCT) и BRCA2 (с.658_659аеЮТ, c.7910_7914de1CCTTT, c.3847_3848de1GT, c.5946de1T). В исследование включены 22 пациентки с ранним монолатеральным раком молочной железы (до 50 лет включительно), 8 - с билатеральным и 41 женщина с первично-множественным раком молочной железы.
Результаты. У 32 из 71 пациенток (45 %) была обнаружена одна из значимых патогенных мутаций в генах BRCA1 и BRCA2. Чаще других встречалась мутация BRCA1 c.5266dupC - она была выявлена у 19 женщин с раком молочной железы (27 %). Носительство патогенного аллеля BRCA1 c.4035de1A было подтверждено в 8 случаях (11 %). Установлено, что мутации гена BRCA1 встречались достоверно чаще при наличии двух и более признаков генетической предрасположенности к раку молочной железы. Вместе с тем, среди 50 пациенток с отягощенным семейным анамнезом по раку молочной железы и/или раку яичников и клиническими признаками наследственного рака мутации в генах BRCA1 и BRCA2 были обнаружены только у 24 (48 %) человек.
Выводы. Установлена высокая частота встречаемости герминальных мутаций гена BRCA1 (45 %) у пациенток с раком молочной железы в западном регионе Беларуси. составляет 25 %. Наиболее распространенными являются мутации c.5266dupC и c.4035de1A в гене BRCA1, они были обнаружены у 84 % в группе носителей. Необходимо продолжить изучение типичных для населения Беларуси мутаций в генах, ассоциированных с развитием рака молочной железы, особенно в группе молодых пациенток, так как настоящим исследованием генетическая предрасположенность подтверждена только у каждой третьей пациентки в возрасте до 50 лет.
КЛЮЧЕВЫЕ СЛОВА: рак молочной железы, мутации гена BRCA1, BRCA2, Беларусь
ИНФОРМАЦИЯ ОБ АВТОРАХ
CaBOHeBm Елена Леонтьевна, к. мед. н., доцент кафедры акушерства и гинекологии, УО «Гродненский государственный медицинский университет»; ул. Горького, 80, Гродно, Беларусь, 230009, e-mail: [email protected], ORCID ID: https://orcid.org/0000-0002-3661-2354
Василькевич Мария Игоревна, врач-стажер УЗ «Гродненская университетская клиника»; Бульвар Ленинского Комсомола, 52, Гродно, Беларусь, 230017, e-mail: [email protected], ORCID ID: https://orcid.org/0000-0001-5959-9546
Aбдрашитов Виталий Вячеславович, м. н. с., научно-исследовательской лаборатории научно-исследовательской части, УО «Гродненский государственный медицинский университет»; ул. Горького, 80, Гродно, Беларусь, 230009, e-mail: [email protected], ORCID ID: https://orcid.org/0000-0002-3500-6563 Степуро Татьяна Леонидовна, к. биол. н., доцент кафедры нормальной физиологии УО «Гродненский государственный медицинский университет», ул. Горького, 80, Гродно, Беларусь, 23000, e-mail: [email protected], ORCID ID: https://orcid.org/0000-0002-3337-4231
Conflicts of interest: author has no conflict of interest to declare. Конфлжт mmepecie: eidcymniu. Конфликт интересов: отсутствует.
Отримано: 24.02.2021 року Прийнято до друку: 17.05.2021 року
