Modern ideas about the mechanisms of malignant transformation lung cancer

The last 30 years have witnessed of truly revolutionary events in fundamental oncology. The rapid development of molecular genetics, in particular the discovery of oncogenes and anti-oncogenes, radically modified the concepts of the mechanisms appearance tumors. Nevertheless, it is assumed that progress in the field of theoretical barely affected by the state of affairs in practical oncology. Contents of this paper are intended to demonstrate the failure of such statements. Indeed, if the 70s and 80s. XX century were characterized by progress predominantly in the experimental area, the symbol of the last decade it became practical achievements of molecular oncology. By now the most notable successes marked in the development of laboratory methods for detection of cancer risk groups, search for diagnostic and prognostic markers neoplasm’s develop pathogenetic approaches to chemoprevention and chemotherapy of lung cancer

Breast cancer therapy for BRCA1 carriers: moving towards platinum standard?

Recently Byrski et al. reported the first-ever breast cancer (BC) study, which specifically selected BRCA1-carriers for the neoadjuvant treatment and used monotherapy by cisplatin instead of conventional schemes. Although the TNM staging of the recruited patients was apparently more favorable than in most of published neoadjuvant trials, the results of Byrski et al. clearly outperform any historical data. Indeed, 9 of 10 BRCA1-associated BC demonstrated complete pathological response to the cisplatin treatment, i.e. these women have good chances to be ultimately cured from the cancer disease. High sensitivity of BRCA1-related tumors to platinating agents has been discussed for years, but it took almost a decade to translate convincing laboratory findings into first clinical observations. With increasing stratification of tumor disease entities for molecular subtypes and rapidly growing armamentarium of cancer drugs, it is getting technically and ethically impossible to subject all promising treatment options to the large randomized prospective clinical trials. Therefore, alternative approaches for initial drugs evaluation are highly required, and one of the choices is to extract maximum benefit from already available collections of biological material and medical charts. For example, many thousands of BC patients around the world have already been subjected to second- or third-line therapy with platinum agents, but the association between BRCA status and response to the treatment has not been systematically evaluated in these women. While potential biases of retrospective studies are widely acknowledged, it is frequently ignored that the use of archival collections may provide preliminary answers for long-standing questions within days instead of years. However, even elegantly-designed, small-sized, hypothesis-generating retrospective studies may require multicenter efforts and somewhat cumbersome logistics, that may explain the surprising lack of historical data on the platinum-based treatment of BC in BRCA1 carriers

Estimating the Probability of Clonal Relatedness of Pairs of Tumors in Cancer Patients

Next generation sequencing panels are being used increasingly in cancer research to study tumor evolution. A specific statistical challenge is to compare the mutational profiles in different tumors from a patient to determine the strength of evidence that the tumors are clonally related, i.e. derived from a single, founder clonal cell. The presence of identical mutations in each tumor provides evidence of clonal relatedness, although the strength of evidence from a match is related to how commonly the mutation is seen in the tumor type under investigation. This evidence must be weighed against the evidence in favor of independent tumors from non-matching mutations. In this article we frame this challenge in the context of diagnosis using a novel random effects model. In this way, by analyzing a set of tumor pairs, we can estimate the proportion of cases that are clonally related in the sample as well as the individual diagnostic probabilities for each case. The method is illustrated using data from a study to determine the clonal relationship of lobular carcinoma in situ with subsequent invasive breast cancers where each tumor in the pair was subjected to whole exome sequencing. The statistical properties of the method are evaluated using simulations, demonstrating that the key model parameters are estimated with only modest bias in small samples

Ассоциация полиморфизма гена IL12Bс предрасположенностью к псориазу в популяцииСеверо-Западного региона России

The IL12B gene encodes protein р40 being a common subunit of interleukin-12 and interleukin-23 playing an important part in the pathogenesis of psoriasis. The IL12B gene has polymorphism rs12188300, which can be associated with the risk of psoriasis development. The goal of the study was to assess the distribution of alleles of polymorphism rs12188300 in psoriatic patients in the Northwestern region of Russia. Genotyping was carried out using the real-time allele-specific polymerase chain reaction. An increased occurrence of a rare allele T in psoriatic patients as compared to healthy people was observed (OR = 1.96, р = 0.0007). The occurrence of the rare allele T in patients with psoriatic arthritis was higher than in the control group (OR = 3.49, р = 0.005). These results suggest that rs12188300 polymorphism of the IL12B gene is a new genetic marker of psoriasis and psoriatic arthritis.Ген IL12B кодирует белок р40, являющийся общей субъединицей интерлейкина-12 и интерлейкина-23, играющих важную роль в патогенезе псориаза. Ген IL12B содержит полиморфизм rs12188300, который может быть ассоциирован с риском развития псориаза. Целью работы явилось изучение распределения аллелей полиморфизма rs12188300 у больных псориазом Северо-Западного региона России. Генотипирование проводилось методом аллельспецифической полимеразной цепной реакции в режиме реального времени. Выявлено повышение встречаемости редкого аллеля Т среди больных псориазом по сравнению со здоровыми лицами (OR = 1,96, р = 0,0007). Частота редкого аллеля Т среди больных псориатическим артритом была выше, чем в группе контроля (OR = 3,49, р = 0,005). Полученные результаты позволяют предположить, что полиморфизм rs12188300 гена IL12B является новым генетическим маркером псориаза и псориатического артрита

Молекулярная патология рака легкого: клинические аспекты

Discovery of tyrosine kinase inhibitor sensitizing mutations in lung cancer (LC) appears to be the main event in clinical oncology of the last decade. Activating lesions in epidermal growth factor receptor (EGFR) gene almost guarantee tumor response to gefitinib, erlotinib or afatinib.ALK translocations are strongly associated with efficacy of crizotinib or otherALK inhibitors. Instances of success of targeted therapy have been demonstrated for LC harboring mutations in ROS1, RET, HER2, BRAF and KRAS oncogenes. Whole genome sequencing of LC-derived DNAhas revealed a number of novel potentially druggable molecules. Rapid progress in understanding of lung cancer molecular pathogenesis allows to expect that several new targeted agents for LC treatment will become available already within this decade.Обнаружение мутаций, ассоциированных с беспрецедентной чувствительностью карцином лёгкого к ингибиторам тирозинкиназ, представляется наиболее важным событием клинической онкологии в прошедшем десятилетии. Активирующие повреждения в гене, кодирующем рецептор эпидермального фактора роста (EGFR), практически гарантируют ответ на лечение гефитинибом, эрлотинибом или афатинибом. Перестройки гена ALK ассоциированы с выраженным эффектом на терапию кризотинибом или другими ALK-ингибиторами. Продемонстрирована результативность таргетной терапии по отношению к опухолям, содержащим мутации в генах ROS1, RET, HER2, BRAF и KRAS. Изучение карцином лёгкого посредством полногеномного секвенирования позволило выявить новые перспективные мишени для лечебных воздействий. Тенденции накопления сведений о молекулярном патогенезе РЛ дают основания полагать, что спектр потенциально эффективных таргетных препаратов для лечения РЛ многократно расширится уже в этом десятилети

ПОТЕНЦИАЛЬНАЯ ЧУВСТВИТЕЛЬНОСТЬ К МЕТФОРМИНУ У БОЛЬНЫХ ДИАБЕТОМ, ИМЕЮЩИХ СОПУТСТВУЮЩУЮ ОНКОПАТОЛОГИЮ И БЕЗ ТАКОВОЙ: ФАРМАКОГЕНЕТИЧЕСКИЙ АНАЛИЗ

The group (totally156 postmenopausal women) used for the study of ‘standard’ (S) and ‘associated’ (A) genetic markers of potential sensitivity to metformin (MF) consisted of 37 healthy females, 32 — with diabetes (DM) without cancer, 64 cancer patients with DM, and 23 cancer patients without DM. No significant difference in carrying of S-polymorphisms was found between DM patients without and with cancer. In cancer patients without DM most characteristic data regarding potential MF-response were detected with polymorphisms of STK11 gene while data on OCT1_rs622342 and OCT1_R61C variants showed opposite trends. In regard of A-markers, the tendency to the more often finding of GC genotype of OLR1_G501C in DM patients carrying ‘MF-positive’ variant of OCT1_R61C deserves to be underlined. In patients with new-onset diabetes who carried S-markers of potential response to MF higher insulin resistance (OCT1_R61C and OCT1_rs622342) as well as lower estradiolemia (STK11 and C11orf65) were discovered. Thus, according to genetic S-criteria of sensitivity to MF, DM patients with and without cancer differ in lesser degree than they differ from cancer patients without DM. It can not be excluded, that The efficiency of such criteria might be increased due to combination with A-markers and certain hormonal-metabolic indices. Пациенты и методы. Обследовано 156 постменопаузальных женщин, среди которых было 32 больные сахарным диабетом 2-го типа (СД2), 64 — с сочетанием СД2 и нелеченной злокачественной опухоли (по большей части — рак толстой кишки, молочной железы или эндометрия), 23 — с онкологическим заболеванием без диабета и 37 здоровых. Изучено носительство 8 генетических полиморфизмов — четырех, обозначенных как «стандартные» (С), поскольку в отношении них ранее имелись сведения о связи преимущественно с метаболическим ответом на противодиабетический препарат из группы бигуанидов метформин, и еще четырех, причисленных к «ассоциированным» (A). Результаты. Между больными СД2, не страдающими или страдающими злокачественными новообразованиями, достоверных различий в носительстве С-вариантов найдено не было. Потенциальную склонность к ответу на метформин у онкологических больных без диабета наилучшим образом характеризовало носительство вариантов генов STK11, а исследование у них же полиморфизмов OCT1_rs622342 и OCT1_R61C обнаружило противоположные по направленности результаты. Страдающие впервые выявленным СД2 носители потенциально «метформин-позитивных» полиморфных вариантов OCT1_R61C и OCT1_rs622342 характеризовались более выраженной инсулинорезистентностью, в то время как аналогичного характера подгруппа носителей полиморфизмов генов STK11 и C11orf65 — умеренно сниженной эстрадиолемией. Выводы. Больные СД2, имеющие и не имеющие злокачественные новообразования, по генетическим критериям потенциальной чувствительности к метформину между собой отличаются меньше, чем от онкологических больных без диабета. Предиктивная эффективность С-критериев может быть повышена путем их сочетания с оценкой А-полиморфизмов и некоторых гормонально-метаболических параметров.

PALB2 mutations in German and Russian patients with bilateral breast cancer

Since germline mutations in the PALB2 (Partner and Localizer of BRCA2) gene have been identified as breast cancer (BC) susceptibility alleles, the geographical spread and risks associated with PALB2 mutations are subject of intense investigation. Patients with bilateral breast cancer constitute a valuable group for genetic studies. We have thus scanned the whole coding region of PALB2 in a total of 203 German or Russian bilateral breast cancer patients using an approach based on high-resolution melting analysis and direct sequencing of genomic DNA samples. Truncating PALB2 mutations were identified in 4/203 (2%) breast cancer patients with bilateral disease. The two nonsense mutations, p.E545X and p.Q921X, have not been previously described whereas the two other mutations, p.R414X and c.509_510delGA, are recurrent. Our results indicate that PALB2 germline mutations account for a small, but not negligible, proportion of bilateral breast carcinomas in German and Russian populations

GENETICS OF SUSCEPTIBILITY TO INFECTIOUS DISEASES

Genetic characteristics of host organism may cause susceptibility to a variety of bacteria, viruses and fungi, as well as influence the course of infectious diseases. Multiple studies indicate the existence of alleles predisposing to infections. Furthermore, there are about 300 nosological entities of primary immunodeficiencies (PID), i.e., inherited defects of immunity. Timely diagnosis of such conditions is quite challenging; however, it is vital for improving quality of patient care. Modern methods of DNA analysis allow establishing genetic causes of vulnerability to certain infectious agents in many individual