Multiple primary malignancies of female genital organs: ways of prevention

Prevention of cancer and its early diagnosis is today one of the promising lines of oncology. The identification of the hereditary forms of malignancies is particularly urgent, which prevents the development of tumor pathology in apparently healthy individuals the rela- tives of whom have cancers

Study of the effect of clinical and genetic factors on progredient current of chronic cerebral ischemia

In order to identify specific and genetic predictors associated with progredient chronic cerebrovascular disease 81 patients of whom 60% were women and 40% of men, aged 55+-30 years, have been examined. The polymorphisms in following genes were analyzed: ACE, SERPINE1, FGB, F5, F7, F12, GP1BA, GPIIIa, MTHFR, CYP11B2, P0N1, P0N2, N0S2, N0S3, PDE4D, HIF1a, LTA, AL0X5AP, TUB. The genotyping procedure included the amplification of selected gene sequences and subsequent hybridization of fluorescently labeled amplicons with allele-specific DNA probes immobilized on the biochip. Analysis of genotyping results using cluster analysis identified two groups of patients with different clinical course of the disease. In the group of patients with more frequent development of progressive hypertension a higher frequency of genotype ТЯ of P0E4D gene (rs966221) was revealed. Further analysis showed direct association of ТЯ genotype with progressive hypertension in total sample of patients with chronic ischemia (0R=6,22; CI=1,86-20,79; p=0,0036).С целью выявления характерных клинико-генетических предикторов, обуславливающих прогредиентность течения хронической ишемии головного мозга, обследован 81 пациент с диагнозом хроническая ишемия головного мозга, из которых 60% составили женщины, а 40% мужчины в возрасте 55+30 лет. У пациентов с хронической ишемией мозга исследован полиморфизм генов АСЕ, SERPINE1, FGB, F5, F7, F12, GP1BA, GPIIIa, MTHFR, CYP11B2, P0N1, P0N2, N0S2, N0S3, PDE4D, HIF1a, LTA, AL0X5AP, TUB. Процедура генотипирования включала амплификацию выбранных последовательностей генов и последующую гибридизацию флуоресцентно меченных участков с аллель-специфичными ДНК-зондами, иммобилизованными на биочипе. Анализ результатов генотипирования с применением кластерного анализа позволил выделить группы пациентов с различным клиническим течением заболевания. В группе пациентов с более частым развитием быстрого прогредиентного течения гипертонической болезни (ГБ) выявлена повышенная частота генотипа ТЯ гена PDE4D (rs966221). Дальнейший анализ показал ассоциацию генотипа ТЯ с быстрым прогредиентным течением ГБ в общей выборке пациентов с хронической ишемией мозга (0Ш=6,22; ДИ=1,86-20,79; р=0,0036)

Clinical features and genetic risk factors in the development of ischemic stroke

Aim: to study the clinical features of the progredient and crisis course of the cerebrovascular process complicated by ischemic stroke, with genetic associations of gene polymorphisms. Methods. A molecular-genetic analysis of the distribution of alleles and genotypes: (ACE (rs1799752), FGB (rs1800790), F5 (rs6025), F7 (rs6046), F12 (rs1801020), GP1BA (rs2243093), GPIIIa (rs5918), SERPINE1 (rs1799768), MTHFR (rs1801133), CYP11B2 (rs1799998), P0N1 (rs662), P0N2 (rs1801282), NOS2 (rs2297518), N0S3 (rs1799983), PDE4D (rs966221, rs2910829), HIF1 a (rs11549465, rs11549467), LTA(rs 909253), ALOX5AP (rs4769874), TUB (rs4578424).) - was conducted for each of the studied polymorphic regions of genes in groups of patients with stroke having different clinical manifestations. Results. The analysis of clinical features, the state of brachiocephalic arteries in patients with chronic cerebrovascular pathology complicated by stroke was carried out. Groups based on the nature of stenosis of brachiocephalic arteries, the pathogenetic subtype of stroke, and molecular genetic analysis, revealed that the allele of the С gene of the GP1BA gene is more common in the group of patients with occlusion of the BCA and severe hemodynamic stenosis (24%) than in the group of patients with hemodynamically insignificant stenosis (8%) (OR = 3.385,95% Cl = 1.118-10.248, p = 0.03). It was found that the allele D of the ACE gene is more common in the group of patients with cardioembolic stroke (67%) compared with patients with atherothrombotic stroke (38%) (OR = 3.333,95% Cl = 1.174-9.464, p = 0.026).Цель. Изучить клинические особенности прогредиентного и кризового течения цереброваскулярного процесса, осложненного ишемическим инсультом, с генетическими ассоциациями полиморфизмов генов. Методы. Проведен молекулярно-генетический анализ распределения аллелей и генотипов (АСЕ (rs1799752), FGB (rs1800790), F5 (rs6025), F7 (rs6046), F12 (rs1801020), GP1BA (rs2243093), GPIIIa (rs5918), SERPINE1 (rs1799768), MTHFR (rs1801133), CYP11B2 (rs1799998), P0N1 (rs662), P0N2 (rs1801282), N0S2 (rs2297518), N0S3 (rs1799983), PDE4D (rs966221, rs2910829), HIF1 a (rs11549465, rs11549467), LTA (rs909253), AL0X5AP (rs4769874), TUB (rs4578424).) для каждого из исследуемых полиморфных участков генов в группах больных с инсультом, имеющих различные клинические проявления. Результаты. Проведен анализ клинических особенностей, состояния брахиоцефальных артерий у пациентов с хронической цереброваскулярной патологией, осложненной инсультом. Выделены группы по характеру стенозирования брахиоцефальных артерий, по патогенетическому подтипу инсульта, проведен молекулярно-генетический анализ, в ходе которого выявлено, что аллель С гена GP1ВА чаще встречается в группе пациентов с окклюзией БЦА и выраженным гемодинамическим стенозом (24%) по сравнению с группой пациентов с гемодинамически незначительным стенозом (8%) (ОШ=3,385,95%ДИ=1,118-10,248, р=0,03). Обнаружено, что аллель D гена АСЕ чаще встречается в группе пациентов с кардиоэмболическим инсультом (67%) по сравнению с пациентами с атеротромботическим инсультом (38%) (0Ш=3,333,95% ДИ=1,174-9,464, р=0,026)

Differences in expression profiles in malingant melanoma patients according to immunotherapy response

One of the most important branch of modern molecular genetics and biomedicine is the search for predictive markers that help choose the most effective way of treatment, drug and also determine its individual dosage. Among the markers, those that can provide the possibility of using a non­invasive, so­called “liquid biopsy” are considered particularly promising. This method allows the condition of the tumor to be assessed by analyzing the body’s natural fluids, such as blood, urine or saliva. Such studies are most convenient in those cases when it is necessary to monitor the effectiveness of therapy in order to record the time of the onset of resistance of tumor cells, the onset of relapse and to move on to the next line of therapy. In the treatment of aggressive and rapidly became metastatic malignant tumors, such as melanoma, the presence of reliable markers that allow quick and accurate determination of treatment tactics is especially important. Nowadays, there is an increasing number of studies devoted to the search for predictive markers of the effectiveness of immunotherapy. Melanoma is one of the most immunogenic tumors and, as a result, has become a model object for research into and introduction of new approaches to immunotherapy. In this study, we compared two groups of patients with metastatic skin melanoma, with different responses to immunotherapy with blockers of immune control points, to identify new predictive expression biomarkers among microRNAs and mRNAs, and to identify the genes responsible for the occurrence of an objective response to therapy. As a result, the study detected several microRNAs with a significant change in expression level within the tumor tissue of patients responding differently to immunotherapy. Differences in the level of expression of their target genes have also been found, that will allow a more detailed analysis of the molecular mechanisms that determine the sensitivity or resistance of malignant melanoma cells to the immunotherapy. Based on the obtained data, we have proposed expression markers (mRNAs and microRNAs) that can be used as predictors of malignant melanoma tumors to immunotherapy

НАСЛЕДСТВЕННЫЙ РАК МОЛОЧНОЙ ЖЕЛЕЗЫ И ЯИЧНИКОВ

The annual incidence of breast cancer (BC) in the world is 1,383,000 cases. Genetic predisposition is one of the major risk factors for breast cancer and ovarian cancer (OC). The proportion of hereditary breast cancer ranges from 5 to 10%, which amounts 69 150-138 000 cases. Family history of accumulation of breast cancer and tumors of the female reproductive system have 25% of patients. Thus, patients with hereditary forms and family breast cancer account 345,700 of all diagnosed cases of breast cancer. Hereditary ovarian cancer occurs in 10-17% cases. Hereditary breast and ovarian cancer are characterized by autosomal dominant inheritance with high (incomplete) penetrance, incidence in early age and pronounced phenotypic and genotypic heterogeneity. According to numerous studies, 20-50% of hereditary breast cancer cases and 90-95% of hereditary ovarian cancer cases in women, and from 4 to 40% of breast cancer cases in men are caused by germinal mutations in the BRCA1 and BRCA2 genes. Considering the syndromic pathology of hereditary BC and OC and can also be associated with mutations in genes TP53, CHEK2, MLH1, MSH2, PALB2, PTEN, NBS1, ATM, BRIP1, RAD50, BLM, FGFR2, and others.Ежегодная заболеваемость раком молочной железы (РМЖ) в мире составляет 1 383 000 случаев. Генетическая предрасположенность является одним из основных факторов риска развития РМЖ и рака яичников (РЯ). Доля наследственно-обусловленного РМЖ колеблется от 5 до 10 %, что составляет 69 150-138 000 случаев. Семейную историю накопления РМЖ и опухолей женской репродуктивной системы отмечают 25 % заболевших женщин. Таким образом, пациенты с наследственными и семейными формами РМЖ в целом составляют 345 700 от всех диагностированных случаев РМЖ [1]. Наследственный рак яичников встречается с частотой 10-17 % [2,3]. Наследственные РМЖ и РЯ характеризуются аутосомно-доминантным типом наследования с высокой (неполной) пенетрантностью, ранним возрастом возникновения и выраженной генотипической и фенотипической гетерогенностью [3-6]. По данным многочисленных исследований, 20-50 % наследственного рака молочной железы (НРМЖ) и 90-95 % — наследственного рака яичников (НРЯ) у женщин, а также от 4 до 40 % РМЖ у мужчин обусловлены герминальными мутациями в генах BRCA1 и BRCA2 [2,3,7,8]. С учетом синдромальной патологии НРМЖ и НРЯ могут быть ассоциированы также с мутациями в генах TP53, CHEK2, MLH1, MSH2, PALB2, PTEN, NBS1, ATM, BRIP1, RAD50, BLM, FGFR2 и др. (таблица 1)

Clinical and genetic characteristics of acute myeloid leukemia with t(8;21) in children and results of therapy according to protocol AML-MM-2000

A t(8;21) is the most frequent abnormality in AML in children. Patients with this genetic abnormality are traditionally expected favorable prognosis with a probability of cure up to 80 %. Known additional cytogenetic abnormalities in AML with t(8;21) not affecting prognosis. These include loss of one sex chromosome and del(9q-). Prognosis impact of additional abnormalities involving chromosomes 7 and 11 in patients with t(8;21) is unknown. The purpose of this study was to analyse of additional anomalies, that occur in patients with t(8;21), and their influence on prognosis. During the study period 173 children with AML have received AML-MM-2000 treatment protocol in Russia and Belarus. Of these, in 33 patients (11 girls and 22 boys, median age — 10.5 years) t(8;21) was detected by chromosome banding or molecular-genetic analysis. In group with t(8;21) CNS leukemia in 8 patients was detected, extramedullary lesion — in 8 patients. In 4 patients CNS leukemia combined with presence of extramedullary lesions. These factors did not influence on therapy outcome. Overall survival of AML patients with t(8;21) was 0,67 ± 0,08 compared to 0,44 ± 0,04 in patients with AML without this translocation (p = 0,04). Special subgroup consist of 5 patients with t(8;21) and identified chromosomal abnormalities affecting chromosome 7 and 11, which were a poor prognostic factor: event-free survival in this subgroup of patients (n = 5) was 0,0 ± 0,0, compared to 0,34 ± 0,16 in patients with t(8;21) without additional anomalies (n = 28) (p = 0,027).</p

Detection of 11q23 (MLL) rearrangements in infant acute lymphoblastic leukemia

117 cases of infant acute lymphoblastic leukemia without Down syndrome (aged from 1 to 365 days) were included in the current study.Rearrangements of 11q23 (MLL) were revealed in 74 (63.2 %) patients. Among this group the most common rearrangement was t(4;11) q21;q23)/MLL-AF4 detected in 63.5 % cases, less frequently was found t(11;19)(q23;p13)/MLL-MLLT1 (in 18.9 % cases), t(10;11) p12;q23)/MLL-MLLT10 and t(1;11)(p32;q23)/ML L-EPS15 (each one in 6.8 %), t(9;11)(p22;q23)/MLL-MLLT3 in 2.7 %. Children under 6 months of age had significantly higher incidence of 11q23 (ML L) rearrangements in comparison with infants olde r than 6 months (84.0 % vs. 47.8 %, p &lt; 0.001). P atients with translocations 11q23 (ML L) more frequently had BI-A LL and less frequently BII-ALL than children without these rearrangements (p &lt; 0.001 f or both). Fusion gene transcript w as sequenced in 26 ML Lrearranged cases. Depending on breakpoint position within ML L and partner genes we detected 7 differ ent types of ML L-AF4 fusion gene transcript, 3 types of MLL-MLLT1, 2 types of MLL-EPS15. The most common fusion site within MLL gene was exon 11, detected in 14 (53.8 %) patients.</p