Exome Sequencing: the Search for Mutations Associated with Hereditary Breast and Ovarian Cancers in the Tuvan Ethnic Group (A Pilot Study).

Whole exome sequencing of peripheral blood samples from Tuvan females diagnosed with breast and ovarian cancers (BC/OC) was performed to search for new genes involved in BC/OC pathogenesis. Considering the high cost of whole exome sequencing and study material requirements, 9 samples were selected from 61 genomic DNA samples. A mutation in the LGR4 gene (rs34804482) involved in the tumor-mediated Wnt signaling pathway and a mutation in the BRWD1 gene (rs147211854) involved in chromatin remodeling were identified in BC patients. A mutation in the CITED2 gene (rs77963348) involved in the pathogenesis of primary ovarian insufficiency was identified in a patient with OC and a history of infertility. A mutation in the PDGFRA gene (rs2291591) was identified in two BC/OC patients. LRG4, BRWD1, PDGFRA, and CITED2 germline pathogenic mutations were discovered in Tuvan women diagnosed with BC/OC for the first time.

New germline mutations in BRCA1, ATM, MUTYH, and RAD51D genes in Tuvans early-onset breast cancer patients.

BACKGROUND: In Russia, more than 50,000 women are diagnosed with breast cancer (BC) every year. Russia is a multinational country - about 200 ethnic groups live on its territory. Khakass, Buryats, Tuvans and other ethnic groups show higher rate of increase in BC incidence and a younger age of first diagnosed BC compared to Caucasian ethnicities. We focused on Tuvan ethnic group to find specific genetic aberrations associated with BC. There are no BC prevention models as well as standards for the treatment of inherited BC in Tuvans. In this context, the search for genetic markers of early cancer detection and the development of criteria for therapy response are relevant. AIM: To identify hereditary mutations in BC-associated genes in Tuvan women. MATERIALS AND METHODS: 24 patients with early-onset BC (range, 25 to 46 years) were enrolled in the study. Genomic DNA isolated from blood samples was used to prepare libraries using a capture-based target enrichment kit covering 27 genes (ATM, APC, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PIK3CA, PMS2, PMS2CL, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53 and XRCC2). Next-generation sequencing was performed using the Illumina NextSeq500 System. RESULTS: In our study, one pathogenic mutation was detected in BRCA1 (rs80357868) gene (prevalence of 4%, 1/24). We identified the truncating 3875_3878delGTCT mutation of BRCA1 gene in Tuvans BC patient aged 34 years. We also detected three mutations that were probably damaging by PolyPhen2 and/or deleterious by SIFT in ATM (rs781023264), MUTYH (rs199840380) and RAD51D (rs145309168) genes. CONCLUSION: To the best of our knowledge, this is the first report that describes the highly pathogenic variant in the BRCA1 gene (rs80357868) and possibly damaging (PolyPhen2) germline variants in the ATM (rs781023264), MUTYH (rs199840380) and RAD51D (rs145309168) genes in young Tuvans BC patient.

[Improving renal cancer care].

The article reviews the rates of incidence, late diagnosis and mortality from kidney cancer in Primorsky Krai. The authors address the issues of improving primary and specialized medical care by introducing a three-level health care system and restructuring of hospital beds. They propose a new medical technology for assessing the individual risk of kidney cancer and present a program of measures and organizational modules for prevention, early diagnosis and reduction of mortality from kidney cancer.

Breast cancer mortality in the Republic of Buryatia.

Breast cancer is the most common cause of cancer death in the Republic of Buryatia as a whole and among urban population (13.3 % and 16.0 %, respectively), and the second place belongs to rural population (11.8). Standardized mortality rates in the Republic of Buryatia (15.5±0.9) are 9.9% lower than the average for Russian Federation (17.0±0.1). The relationship between the national composition of the population of the municipal districts of Buryatia and breast cancer mortality rate has been found. Breast cancer mortality rates are higher for newcomers than for indigenous population (2.4 times higher among urban population and 2.3 times among rural population). Breast cancer mortality rate is expected to be decreased by 9.9% in the Republic as a whole, by 10.0% among urban population and also stability of mortality among rural population (2.3%).

[Survival of breast cancer patients in the Republic of Buryatia].

There was studied population-based survival of 1689 breast cancer patients in the Republic of Buryatia whose had been di- agnosed in 2007-2013 on the basis of cancer registry database. There was performed an estimation and analysis of observed adjusted and relative survival. The higher stage of the disease and older age of women at the diagnosis the lower rates of 1- and 5-year survival. A 5-year relative survival rate was higher in invasive carcinoma of the unspecific type (74.2%), in patients living in Ulan-Ude (76.9%) and representatives of the indigenous population (73.4%).

[Cancer mortality in the Altai Republic].

Cancer mortality rate in the Altai Republic is the lowest among the territories of the Siberian Federal District. Cancer mortality rate in females is 1.9 times lower than that in males. From 2003 to 2012 cancer mortality rate ranged within the confidence interval. Men most often die from tumors localized in the respiratory and digestive systems and women--from tumors of the reproductive and digestive systems. Age-standardized incidence rates are significantly higher in urban males and females than in rural population (p < 0.05). Mortality from lung, liver and kidney cancers is higher for urban than for rural males. For urban females, mortality from breast, stomach and rectum cancers is higher than for rural females. Rural women die of esophageal cancer more often than urban women. Risk to die of cancer in 2012 was 23.6% (33.9% for males and 18.9% for females) being higher in urban than in rural population.

[Oral cavity and pharynx cancer in the region of Siberia and Far East].

The objective of the present work was to study the prevalence of malignant oral cavity and pharynx neoplasms among the population of the region of Siberia and Far East. These neoplasms are the ninth most frequent conditions in the structure of malignant tumours among the male population and rank the eighteenth among the women. On the whole, the morbidity rate of oral cavity and pharyngeal cancer (3.8‱ and 2.0‱ respectively) was consistent with the mean morbidity levels in Russia. The risk of the development of these conditions among the men is significantly higher than among the women. The highest morbidity is recorded among the subjects at the age of 65-69 years. It increases in the subjects of either sex at a rate that is 3.4 times higher in the women than in the men. The study revealed the territories characterized ether by the enhanced or by the reduced risk of oral cavity and pharyngeal cancer development. The prevalence of this pathology was estimated at 28.4 per 100,000 population, with the overall active detectability being 11.8%, that of stage 1 an 2 disease 7.8% and 19.3% respectively. One-year lethality was 35.6%. The radical treatment was completed in 41.1% of the patients; 45.8% of them were followed up during 5 years. It is concluded that the increasing oral cavity and pharyngeal cancer morbidity and the insufficient volume of preventive measures taken together suggest the necessity of closer cooperation of general practitioners and dental surgeons with oncologists.

[The medical demographic situation in the Republic of Altai].

The demographic situation impacts the level of morbidity indirectly. The evaluation of demographic situation if the Republic of Altai was made. In 2010, in the ethnic structure of population the percentage of Russians reduced up to 55.7% and of indigenous population increased up to 35.3%. In the Republic positive dynamics of population size is preserved. More than 3/5 of population live in rural territories. The main factor of increase of population size is its natural growth (11 per 1000 of population). The high level of natal V.M.ity and low death rate are observed. In the age structure of population percentage of persons younger than able-bodied age (25.8%) is larger than in persons of older than able-bodied age (15.4%). The tendency of decreasing of percentage of persons younger than able-bodied age and persons of able-bodied age is marked. The process of aging of population is expressed in deterioration of ratio between age groups younger than able-body age and groups of able-bodied age. The low indicator of life expectancy of population if noted. The neoplasms are at third place among causes of death (140.6 per 100 000 of population) after diseases of cardiovascular system and traumas and intoxications. In the structure of disability neoplasms are at second place (12.3%) after diseases of cardiovascular system. The demographic situation has to be taken into account in the process of organization of medical care of population.

[Cancer incidence in the Altai Republic].

From all regions of the Siberian Federal District (SFD), the Altai Republic is the least urbanized territory, more than third of its population is Altai. The Altai Republic ranks the 11th for cancer incidence among 12 territories of SFD. Cancer incidence rate is 1.4 times less in females than in males. There is a tendency toward increased cancer incidence in the Republic. The two most common cancer sites in males are digestive and respiratory organs. In females, the most common cancer sites are reproductive and digestive organs. Prostate cancer has the highest incidence rate in males and kidney cancer in females. Increase in the cancer incidence rate was observed among male patients who are younger and older than able-bodied age and in female patients who were younger than able-bodied age. Problems related to the improvement of methods for cancer prevention, early detection and treatment are of great importance.

[Ethnic aspects of hereditary breast cancer in the region of Siberia].

BACKGROUND: Ethnic diversity of the population in the region of Siberia suggests the existence of different germline mutations in the BRCA1/2 genes associated with breast and ovarian cancer in different ethnic populations, but spectrum of these mutations has not been studied. OBJECTIVE: Our aim was to evaluate the frequency of the most common mutations BRCA1/2 (BRCA1 5382insC, BRCA1 185delAG, BRCA1 4153delAG, BRCAI T300G, BRCA2 6174delT) in women diagnosed with breast cancer among indigenous people and newcomers living in Siberia. METHODS: We tested 1281 genomic DNA samples for the presence of BRCA1 5382insC mutation in patients diagnosed with breast cancer considering no family history. 72 patients having hereditary cancer signs were tested for the mutations BRCA1 185delAG, BRCA1 4153delAG, BRCA1 T300G, BRCA2 6174delT. RESULTS: Out of 765 patients of Slavic ethnic group, 27 women (3.5%) were carriers of allele BRCA1 5382insC. The frequencies of mutations in patients with signs of hereditary cancer were: 8.3% in group of young patients (under 40 years), 20.0% in patients with bilateral cancer and 5.7% in patients with family history of breast or ovarian cancers. We tested 516 BC patients residing on the territory of the Buryat-Aginsky district, Republics of Tyva and Altai. Out of them, there were 197 patients among the indigenous population (buryats, tuvinians, altaians), and 319 patients among newcomers (Slavic ethnics). Mutations BRCA1 5382insC were detected only in women from Slavic ethnic groups. The frequency of BRCA1 5382insC mutation was 6% in the group where family history was excluded and 14% in the group of patients with characteristics of family cancer. Allele BRCA1 5382insC was not found in indigenous breast cancer patients, although 59 patients had signs of hereditary cancer. In women from Slavic ethnic group, the BRCA1 185delAG, BRCA1 4153delAG and BRCA1 T300G mutations were detected in 9.1% of cases and were not found in patients among the indigenous population. CONCLUSION: studies of mutations in the BRCA1 gene in breast cancer patients from Siberia confirmed data on the high frequency of "founder mutation" BRCA1 5382insC in Slavic population and indicate the advisability of further studies to identify the genes responsible for the occurrence of hereditary breast cancer in the indigenous population.

[Renal cancer in the Primorye Territory. Risk factors].

The epidemiological study in Vladivostok and Primorye Territory in period 1999 to 2013 was performed. In the structure of cancer incidence at the evaluated areas, renal cancer occupies fifth place among male population (5.7 and 5.3%, respectively), and 11th place (3.5%) among female population. The problem of renal cancer in this region and the administrative center is relevant due to the increasing incidence: a standardized measures in the period of 2009-2013 were 12.5 ± 0.3 and 11.7 ± 0.50/0000, respectively. The Increase of the incidence can be explained by the integrating influence of complex of changing demographics and health, social, hygienic and other factors. The questionnaire survey has become one of the main methods to identify risk factors for the development of the disease. Risk factors for renal cancer were identified by the case-control method. 231 patients with renal cancer (mean age 58.2 ± 1.7 years) and 354 healthy men and women (mean age 57.4 ± 2.2 years) underwent questionnaire survey. Specific risk factors for renal cancer were identified: migration (OR = 1.6, P = 0.0149); low socio-economic status (secondary-level education, income per family member less than 10,000 rubles, OR = 1.5, P = 0.0349); started smoking before 18 years of age (OR = 1.5, P = 0.0349); trade with physical activity and occupational hazards (car drivers, sailors, house-painters, OR = 2.0, P = 0.0000); occupational hazard: contact with oil products (OR = 1.6, P = 0.0262), contact with lead, asbestos, dyes (OR = 3.5, P = 0.0000); length of time worked with occupational hazard over 5 years (OR = 1.6, P = 0.0126); occupational hazard in the form of an underground work (OR = 8.0, P = 0.0000) and the presence of large amounts of dust (OR = 1.2, P = 0.0381); location of industrial enterprises within 2 kilometers from homesite (OR = 2.5, P = 0.0000). Based on the identified risk factors, predictive model for the assessment of individual risk and the formation of groups at risk for renal cancer was developed.

[The epidemiology of renal cell carcinoma in the regions of Siberia and the Far East (1994-2008)].

The article presents the results of an epidemiological study of territorial and temporal characteristics of incidence of renal cell carcinoma in population of Siberia and the Far East, taking into account age and gender. In the average, regional incidence of renal cell carcinoma in men was 10.6 +/- 0.1 per hundred thousand; in women--5.6 +/- 0.1 per hundred thousand. During the years 1994-2008, incidence increased by 1.4 times in male and female population. Based on the results of analysis, territories at-risk of renal cell carcinoma were identified--Omsk and Irkutsk regions. The incidence of renal cell carcinoma in child population was also evaluated. Peak incidence at the age of 4 years was revealed; in 2004-2008 it amounted to 1.72 +/- 0.32 per hundred thousand, which in turn has led to the fact that renal cell carcinoma took 2nd place (13.2%) in malignant tumors in this age group after hematological malignancies. The highest incidence and its high growth in infants during the study period were revealed in Kamchatka, Amur and Sakhalin regions.

[Prostatic cancer in males living in the Khabarovsk, Komsomolsk-on-Amur and Khabarovsk region].

In 2004-2008 the Khabarovsk Region was considered as a territory of an increased risk for prostate cancer with the incidence rate of 22.2 +/- 1.6 per 100000 males. The epidemiologic situation in Khabarovsk city corresponded to an average incidence rate registered in the Khabarovsk Region (20.5 +/- 2.3 per 100000 males in 2004-2008). A prostate cancer incidence rate in Komsomolsk-on-Amur city was 1.9 times higher than in Khabarovsk city. An impact of an occupational factor on the risk of prostate cancer in males working in Komsomolsk-on-Amur industry was found.

[Risk factors in the development of hemoblastoses in the population of the Tomsk Region]. / Faktory riska v razvitii gemoblastozov u naseleniia Tomskoi oblasti.

The Tomsk Region belongs to the areas of Siberia and the Far East which show a higher risk for hemoblastoses in the population. Chronic leukemia are prevalent in the structure of oncohematologic morbidity in the Tomsk Region as compared with other areas of Siberia and the Far East. There is a relationship of technogenic environmental pollution to the incidence of some nosological entities of hemoblastoses in the Region. Measures for environmental improvement are gaining in significant importance in the cancer-combating system.

[The electrophysiological characteristics of the plasma membrane of rat macrophages at rest and under exposure to ATP]. / Elektrofiziologicheskie kharakteristiki plazmaticheskoi membrany makrofagov krysy v pokoe i na fone vozdeistviia ATF.

The application of ATP in micromolar concentrations to the macrophages results in a biphasic response in the form of the short-time depolarization followed by a rather long hyperpolarization, the corresponding inward and outward macroscopic currents being observed. The ATP-induced hyperpolarization is accompanied by changes in current kinetics, I/V-curves pattern and shifting in the reversal potential. Such changes may be explained by a supposition that ATP activates an additional fraction of potassium channels with characteristics other than those in cells with initially low value of membrane potential. The data available are suggestive that in resting cells the inward rectification potassium conductance may dominate, whereas during ATP-induced hyperpolarization a certain type of Ca(2+)-dependent potassium conductance prevails. A rather high membrane potential in some part of macrophages, not treated with ATP, may be attributed to the latter type of conductance.

[Changes in the membrane potential of rat peritoneal macrophages under the extracellular action of ATP]. / Izmeneniia membrannogo potentsiala peritoneal'nykh makrofagov krysy pri ékstrkletochnom deistvii ATF.

In rat peritoneal macrophages the patch-clamp technique in whole-cell configuration was used to study modifications of membrane potential as a result of extracellular application of micromolar ATP concentration. The registered changes in membrane potential appeared to be of different form and polarization depending on the presence of Ca2+ in extracellular solution and on the concentration of calcium buffer inside the cell. A mechanism of membrane potential changes and their possible connection with the generation of a Ca2+ signal in the cell are discussed.

[Role of migration processes in oncologic epidemiology of Siberia and Far East]. / Rol' migratsionnykh protsessov v onkoépidemiologii Sibiri i Dal'nego Vostoka.

The paper presents the analysis of the cancer death rates among the population of a Norilsk industrial area and compares the rate and structure among newcomers and natives. The persons who long live in this area more frequently die of cancer diseases than migrants. They have high mortality rates for most sites (the stomach, esophagus, bowel, liver, pancreas). The migrants die younger and chiefly of tumors of respiratory organs, the skin, brain, and female genitals. The lower mortality rates in the newcomers are attributable to their departure to their former residence places.

[Simultaneous operations in the surgical treatment of cancer of the esophagus and cardia]. / Odnomomentnye operatsii v khirurgicheskom lechenii raka pishchevoda i kardii.

In the clinic one-stage operations for cancer of the esophagus of different localizations and cardia were performed on 63 patients. The substitution of the removed esophagus was fulfilled with an isoperistaltic tube made from the greater curvature of the stomach with anastomosis on the neck or in the pleural cavity. After intrapleural plasty lethality was 21%, after total one with extracavital esophagogastroanastomoses--14%. For prevention of ischemic complications an intraoperative assessment of viability of the transplant was performed with the help of microphotoplethysmography. The authors have shown the advantage of endolymphatic route of administration of cytostatic in 25 patients as compared with the intravenous one.

The action of blood serum and its components on potential-dependent sodium channels in neuroblastoma cells.

Blood plasma, serum and its fractions containing components of different molecular weights as well as some identified serum constituents were tested for their action on sodium currents of voltage-clamped, internally dialyzed neuroblastoma cells. Only components with a molecular weight over 50 kDa produced a persistent increase in sodium channel currents (stimulatory effect) and shifts in activation and inactivation curves along the voltage axis towards more negative or positive potentials, respectively (modifying effect). Both modulations taken together provide a somewhat higher level of sodium electro-excitable system activity. Among the identified serum components tested, including those possessing high physiological activity, albumin was the only one which reproduced the effects of whole blood serum both qualitatively and quantitatively. The data obtained allow to assume albumin to play a role of an active substance responsible for the blood plasma or serum effects on the potential-dependent transporting system in the neuroblastoma cell membrane. Albumin seems to be involved in holding the functional activity of sodium channels on a suitable level rather than being involved in any regulatory processes.

[Factors determining the functional activity of Na,K-ATPase]. / Faktory, opredeliaiushchie funktsional'nuiu aktivnost' Na,K-ATFazy.

A comparative estimation was made of modifications of Na,K-ATPase and Mg-ATPase parameters in the process of phylogenesis and as a result of sudden thermal selection. On the basis of our own and literary data a suggestion was put forward about the availability of quite different ways of thermal adaptation in ATP-hydrolyzing enzymes associated with different physiological functions.