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Mamarasulova Dilfuzahon Zakirjanovna, Head of the Department of Oncology, Radiology and Phtiziatry, Andijan state medical institute, PhD in Medicine E-mail: dilya_o@mail.ru Mamadalieva Yashnar Solievna, Head of the Department Oncology with Ultrasaund Diagnosis,
Tashkent Improvement Training Medical Doctors Institute, Doctor of Science Ergasheva Zumrad Abdukaumovna, Head of the Department Pharmacology, PhD in Medicine
Azizov Uryi Dalimovich, Head of the Department Microbiology, Doctor of Science, professor
Assessment of BRCA 1,2 gene mutation as genetic risk factor for ovarian cancer
Abstract: The analysis was conducted pathological preparations 204 patients with verified diagnosis of ovarian cancer. Prevailed 5382insC mutation (BRCA1) 4.0 % of the sample of breast cancer patients, 11.6 % of the sample of patients with ovarian cancer, which is consistent with the data of numerous works of domestic and foreign authors, which have been shown the prevalence of mutations 5382insC gene BRCA1 in various areas ofAndizhan region. Five mutations — 4153delA, 5382insC, Cys61Gly, 2080delA, 3819delGTAAA, in BRCA1-gene have been reported in patients with ovarian cancer and healthy risk 5382delA mutation.
Kewords: ovarian cancer, gene mutation, BRCA1,2, survival.
Introduction
To date, we identified and characterized two genes inherited mutation which give rise to family forms ovarian cancer and breast cancer — BRCA1 and BRCA2 (from BReast CAncer — breast cancer) [4; 6; 7]. All the relatives of the family having the same abnormal gene variant increases the risk of developing cancer. This risk for life, according to some estimates, close to 90 % [1; 2]. More importantly, the risk of developing the disease at a young age in carriers of mutations in approximately 10 times exceeds overall risk in the population. Often found in the same family and cases of breast and ovarian cancer [3; 5]. Identification of mutations followed by clinical examination of patients will allow, is to prevent the development of disease in patients with mutations and their relatives [2; 4]. We should not think that all cases of cancer are due to inherited mutations, and susceptibility to disease are always inherited. About 85 % of breast cancers arise sporadically and only 15 % have a hereditary genesis [6].
Material and methods
The analysis was conducted in the city of Tashkent Immunnogen-test led by Khegai TR The material of the study was archival pathological preparations 204 patients with verified diagnosis of ovarian cancer, derived from remote during surgery patients tumor tissues. The blocks were brought to the city of Tashkent in Immunogen-test. DNA extraction was performed using a standard protocol. Using a microtome sections were prepared 20 microns thick, which deparaffinized by incubation in three changes of500 ml. ofxylene at 37 °C. Duration of incubation, each change in xylene was 20 minutes. Partial rehydration tissues was performed by incubation for 10 minutes in three changes of ethanol (96 %, 80 % and then 70 % — 500 l) at room temperature. After removal section ethanol air dried and placed in 200 ul oflysis solution (YutM Tris-HCl, pH = 8.3; 1 mM EDTA; 2 % Triton X 100, proteinase K — 500 ug/ml). Lysis was carried out at 60 °C for 12-24 hours after which samples were incubated for 10 minutes at 95 °C to complete inactivation ofproteinase K. The resulting lysate was diluted tenfold with bidistilled water.
Results
When testing for the presence of mutations in the presence
of BRCA1 : BRCA 1_4153delA, BRCA1_5382insC, BRCA1_
3819delGTAAA, BRCA1_300T > G (Cys61GLY), BRCA1_ 2080delA, BRCA1_185delA, BRCA1_3875delA, BRCA2_ 2080delA, 6174delT no statistically significant association between patients and nearest relatives, but at a total correlation of all mutations detected a statistically significant difference between groups. Mutations in a group of cancer patients was 11.1 % in the group of healthy and 2 %, which was statistically significant difference x2 = 3.92; p = 0.048. Thus, the presence of any mutations in alleles tested in any combination found in 24 of 258 (9.3 %) cases. In the group of healthy mutation found in 2 % of cases and in patients with ovarian cancer 11.1 %. This suggests that the presence of mutations at BRCA1,2 tend association with ovarian cancer may nevertheless not be sensitive diagnostic marker. There is a need to identify other factors play a role in tumorigenesis, along with the above genetic markers (tab. 1).
Prevailed 5382insC mutation (BRCA1) 4,0 % of the sample of breast cancer patients, 11.6 % of the sample of patients with ovarian cancer, which is consistent with the data of numerous works of domestic and foreign authors, which have been shown the prevalence of mutations 5382insC geneBRCA1 in various areas of Andizhan region. In healthy close relatives increased risk of ovarian cancer, met at 2 %, which indicates a high risk for malignant neoplasms.
Five mutations — 4153delA, 5382insC, Cys61Gly, 2080delA, 3819delGTAAA, in BRCA1-gene have been reported in patients with ovarian cancer and healthy risk 5382delA mutation.
Also of interest is the presence of the identified mutations in different histological groups. Among patients with clear histological tumor incidence of mutations was found in 10 (20 %) in the form of papillary tumors in 2 (17.5 %) as dysgerminoma, 13.3 % to 12.5 % fetal teratoblastome tumor, granulosa and 5, 6 % and 5 % respectively (Table 2).
Assessment of BRCA 1,2 gene mutation as genetic risk factor for ovarian cancer
Table 1. - Frequency of occurrence of mutations in the gene BRCA1,2 in groups of patients with ovarian cancer and healthy relatives
Ovarian cancer Healthy
BRCA1_185delAG nn 208 (100) 50 (100)
ndel 0 0
BRCA1_4153delA nn 202 (97.1) 50 (100)
ndel 6 (2.9) 0
BRCA1_5382insC nn 190 (91.3) 49 (98)
Nins 18 (8.7) 1 (2)
BRCA1_3819delGTAAA nn 205 (98.6) 50 (100)
ndel 3 (1.4) 0
BRCA1_3875delGTCT nn 208 (100) 50 (100)
ndel 0 0
BRCA1_300T>G (Cys61GLY) nn 206 (99) 50 (100)
ndel 2 (1) 0
BRCA1_2080delA nn 205 (98.6) 50 (100)
ndel 3 (1.4) 0
BRCA2_6174delT nn 208 (100) 50 (100)
ndel 0 0
BRCA 1,2 No mutation 185 (88.9) 49 (98.0) (X2=3.92)
Has a mutation 23 (11.1) 1 (2.0) p=0.048
Table 2. - The presence of mutations in various histological groups
No mutation Have a mutation
n Column, % Row, % n Column, % Row, %
clear cell 4 1(0.7) (80.0) 1 (4.2)* (20)*
Papillary 47 (20.1) (82.5) 10 (41.7)* (17.5)*
Dysgerminoma 13 (5.6) (86.7) 2 (8.3)* (13.3)*
Embrion 7 (3.0) (87.5) 1 (4.2)* (12.5)*
Undifferentiated 23 (9.8) (88.5) 3 (12.5)* (11.5)*
Serous 39 (16.7) (90.7) 4 (16.7)* (9.3)*
Teratoblastoma 17 (7.3) (94.4) 1 (4.2) (5.6)
Granulosa 19 (8.1) (95.0) 1 (4.2) (5.0)
In reviewing data on the survival of patients with ovarian cancer in the groups with or without BRCA1,2 analysis by Kaplan-Mey-eru revealed no statistically significant import ance. The interval of reliability (CI 95 %) in both groups vary widely, it is possible to talk about the influence of other factors (fig. 1). Conclusion
The diagnostic panel including five mutations (4153delA, 5382insC, 3819delGTAAA, Cys61Gly, 2080delA in the gene BRCA1), can be recommended as a standard for primary genetic screening of patients referred for examination to the health facility to identify genetic predisposition to ovarian cancer and validate the genetic diagnosis of hereditary forms of cancer (EOC). Genetic screening can identify most cases of hereditary forms ovarian cancer patients, followed by individualization of the treatment of patients and to focus efforts on prevention and early diagnosis of disease at detection ofmutations in the BRCA1 and BRCA2 genes in healthy women.
References:
1. Badgwell D. and Bast R. C. Early detection of ovarian cancer//Dis. Markers. -2007. - Vol. 23, no. 5-6. - P. 397-410.
2. Berkowitz Z., Rim S. H. and Peipins L. A. Characteristics and survival associated with ovarian cancer diagnosed as first cancer and ovarian cancer diagnosed subsequent to a previous cancer//Cancer Epidemiol. - 2011. - Vol. 35, no. 2. - P. 112-119.
3. Cragun J. M. Screening for ovarian cancer//Cancer Control. - 2011. - Vol. 18, no. 1. - P. 16-21.
4. Konstantinopoulos P., Spentzos D. and Cannistra S. Gene-expression profiling in epithelial ovarian cancer//Nat. Clin. Pract. Oncol. -2008. - Vol. 5, no. 10. - P. 577-587.
5. Menon U., Griffin M. and Gentry-Maharaj A. Ovarian cancer screening - current status, future directions//Gynecol. Oncol. - 2014. -Vol. 132, no. 2. - P. 490-495.
Months
Fig. 1. Survival Kaplan Meier Group Media BRCA1,2 mutations
6. Ramus S.J. and Gayther S. A. The Contribution of BRCA1 and BRCA2 to Ovarian Cancer//Molecular Oncology. - 2009. - Vol. 3, no. 2. - P. 138-150.
7. Rodriguez A. O., Llacuachaqui M., Pardo G. G., Royer R., Larson G., Weitzel J. N., and Narod S. A. BRCA1 and BRCA2 mutations among ovarian cancer patients from Colombia//Gynecol. Oncol. -2012. - Vol. 124, no. 2. - P. 236-243.
Maksudova Laylo Bakhtiyarovna, neurologist of Department of emergency neurology № 1, seeker of doctoral degree, Republican Research Centre of Emergency Medicine, Tashkent, Uzbekistan E-mail: laylo26@mail.ru
Clinical-pathogenic analysis of brain arteriovenous malformation neurologic manifestations
Abstract: Retrospective analysis of 109 patients with arteriovenous malformations (AVM) of brain has been carried out. Men were 67 (61.4 %) and women were 42 (38.6 %). Brain AVM are detected two times frequently in men than in women and are appeared in them at younger age. Prevalence ofAVM small and big sizes with sinistrocerebral lateralization has been revealed at the analysis. The most frequent manifestation of AVM are cephalgic and epileptic syndromes.
Keywords: arteriovenous malformations, brain, sinistrocerebral lateralization, cephalgia, epilepsy.
Introduction
Vascular malformations (VM) of central nervous system (CNS) are local or extensive abnormalities of vascular system. For the first time VM of CNS were described by U. Gunter in 1757 who offered «malformation» term which means «defect of development» [7]. Brain AVM is not frequently occurred nosological form but capable to provoke severe neurologic disorders and even a death. In majority of cases brain AVM are manifested by intracranial hemorrhage, epileptic attacks and hard headache. Due to up-to-date diagnostic methods of CNS AVM are often diagnosed at pre-hospital stage, surgical treatment methods of patients with CNS AVM are significantly improved, facilities of malformations intravascular occlusion have been increased and radiologic surgery has been available.
Views on brain malformations have been changed for recent decades. Viewpoint stating absolutely congenital nature of disease is subject to be reviewed. Majority of facts pointing on possibility of AVM appearance in postembryonal period and evidences of AVM features significant changes within a period of time have appeared. Increased activity of mitogen of endothelial growth factor of vessels in malformations and surrounding brain endotheliocytes has been proved and it confirms continued neoangiogenesis in malformations, partially explains their slow growth and recurrence [21]. AVM refers to the more frequent variant of vascular angiomatous defect of nervous system development and is an effect of dysontogenetic metamorphosis initiated by unknown factors. The real frequency of vascular malformations, particularly AVM, in population is unknown. It is supposed that a carrier ofAVM can be up to 0.1 % of population [5]. By autopsy data, AVM are revealed in 1.4-4.3 % of autopsies [16], semeiotic ones makes 12.2 % ofthem [18; 22]. Clinical manifestation of AVM in population is rather stable and due to various data makes up 0.94-1.2 cases for 100 thousand ofpopulation a year [5; 6]. Characteristics ofAVM by sex is unspecific: ration of men and women varies from 1.09:1 to 1.91:1, at average 1.4:1 [17].
Long-term prognosis at conservative treatment of brain AVM is unfavorable: deep invalidism becomes in 48 % ofAVM carriers, and 23 % ofpatients die [20]. Survivability of patients with AVM makes up 85 % during first 10 years, 65 % — during 30 years from the time of diagnosis confirmation. Active treatment tactics promotes
decrease of annual mortality from 3.4 % at conservative treatment up to 1.2 % at radical intervention [14].
Mostly symptomatology of vascular malformations is observed at young and middle age — from 20 to 40 years but it can manifest itself practically at any age. If a pathology has been detected by chance at elderly age, there is a chance that it will not be manifested. In women vascular malformation's course can be worsened during pregnancy. In majority of cases AVM is manifested by hemorrhages (~50 % patients) and convulsive attacks (25 %), rarely patients complain on headache (15 %), increasing neurologic deficiency (5 %), pulsatile noise and etc. [12]. Hemorrhages origins at AVM are mostly strictly very thin, varicose vessels in the structure of malformation's glome. Due to AVM glome localization and its structure, the form of hemorrhage can be different: combined ones (31 %) and subarachnoidal (30 %) occur more frequent, rarely — parenchymatous (23 %) and ventricular (16 %) hemorrhages [13].
Key points of pathogenesis of formation primary epileptic nidus connected with brain AVM is cortical localization of AVM; blood supply with medial cerebral artery (MCA) branches, afferents from cortical arteries, varicose-draining vein, aneurisms absence in malformation glome [23]. The nature of attacks can indirectly point on AVM localization.
AVM clinical presentation, as a rule, can be manifested in two types of the disease's course: torpid and hemorrhagic ones. Torpid or pseudotumorous type ofAVM course is characterized by convulsive syndrome's début, cluster headaches, semiotics of progressing neurologic deficiency. Symptomatic convulsive attacks are mostly observed (up to 67 % patients with AVM), which in 87.9 % patients remains as the first manifestation till the age of 30 years. Simple partial attacks are observed in 10 % patients, complex partial ones — in 4.3 %, partial ones with secondary generalization — in 22.4 %, generalized — in 63.3 % patients.
From other symptoms there are observed progressive neurologic disorders (19.6 %), headache (11.8 %). In 27.5 % observations torpid course is complicated by hemorrhages which stipulate the following development of convulsive syndrome in 18 % patients. Torpid course is more typical for big AVM of the 4th and the 5th category by Spetzler-Martin.
