МУТАЦИИ ГЕНА SMARCB1 В ОПУХОЛЯХ РАЗЛИЧНОЙ ЛОКАЛИЗАЦИИ

In the recent years, the full exome sequencing helped to reveal a  set of mutations in the genes that are not oncogenes or tumor suppressor genes by definition, but play an important role in carcinogenesis and encode proteins involved in chromatin remodeling. Among chromatin remodeling systems, which operate through the ATP-dependent mechanism, the complex SWI/ SNF attracts the great attention. The complex consists of the catalytic ATPase (SMARCA2/4), a group of conservative core subunits (SMARCB1, SMARCC1/2), and variant subunits. Abnormalities in the genes coding for each of these components have been identified as driver mutations in various human tumors. The SMARCB1 gene is of interest for practical oncogenetics, with its typical genotype-phenotype correlations. Germinal inactivating mutations (frameshift insertions/deletions, full deletions of the gene, nonsense mutations) lead to development of rhabdoid tumors in the kidneys and the brain in children in their first years of life, or even in utero. These tumors are highly malignant (Rhabdoid Tumor Predisposition Syndrome 1 – RTPS1). If a mutation carrier survives his/hers four years of life without manifestation RTPS1 with a missense mutation or has the mutation in the "hot spot" of the first or the last exon, then he/she will not develop rhabdoid tumors, but after 20 years of life, shwannomatosis may develop as multiple benign tumors of peripheral nerves. Finally, some point mutations in the exons 8–9 can result in Coffin-Siris syndrome characterized by mental retardation and developmental disorders, but no neoplasms. In this regard, rational referral of patients for direct DNA diagnostics of each of the described disease entities plays an important role, based on respective minimal criteria, as well as necessity of further development of NGS technologies (full genome and full exome sequencing) that are able to sequence not only individual exons, but all candidate genes of the disorders.В последние годы с  помощью полноэкзомного секвенирования обнаружены мутации в  генах, которые не являются по определению онкогенами или генами-супрессорами, но играют важную роль в  канцерогенезе и  кодируют белки, осуществляющие ремоделинг хроматина. Среди систем ремоделинга хроматина, функционирующих по аденозинтрифосфат(АТФ)-зависимому механизму, наибольшее внимание привлекает комплекс SWI/SNF. Kомплекс состоит из каталитической АТФазы (SMARCA2/4), группы консервативных субъединиц (SMARCB1, SMARCC1/2) и  вариантных субъединиц. Изменения в генах каждого из указанных компонентов были идентифицированы как мутации-драйверы в тех или иных опухолях человека. С  точки зрения практической онкогенетики интересен ген SMARCB1, для которого характерны генофенотипические корреляции. Герминальные инактивирующие мутации (ин- серции/делеции со сдвигом рамки считывания, делеции всего гена, нонсенс-мутации) приводят к развитию рабдоидных опухолей в почках и головном мозге у детей первых лет жизни или даже внутриутробно, характеризуются высокой злокачественностью (синдром предрасположенности к  рабдоидным опухолям 1-го  типа  – Rhabdoid Tumor Predisposition Syndrome  1; RTPS1). Если носитель мутации пережил четырехлетний возраст без манифестации RTPS1 с  миссенс-мутацией или имеет мутацию в  «горячей точке» первого или последнего экзона, то у  него не будет рабдоидных опухолей, но после 20 лет может развиться шванноматоз  – множественные доброкачественные опухоли периферических нервов. Наконец, определенные точковые мутации в  районе 8–9-го экзо- нов могут вызвать синдром Коффина – Сириса, характеризующийся умственной отсталостью и  пороками развития, но без возникновения новообразований. В связи с этим большую роль играет аргументированное направление пациента на прямую ДНК-диагностику по каждой из описанных нозологических форм, исходя из соответствующих минимальных критериев, а  также дальнейшее развитие технологий полногеномного и  полноэкзомного секвенирования (next-generation sequencing  – NGS), позволяющих полностью секвенировать не отдельные экзоны гена, а  все гены-кандидаты заболеваний.

Fluorescence diagnosis of bladder cancer with agent hexasens - The results of multicenter trial

The results of multicenter trial for efficacy of fluorescence diagnosis for bladder cancer with agent hexasens (SSC Scientific Research Institute Organic Intermediates and Dyes, Russia) based on hexyl ester of 5-aminolevulinic acid compared with routine cystoscopy are represented in the article. The study included 124 patients. All patients had intravesical instillation of 50 ml of 0,2% hexasens. The exposure time accounted for 1-2 h. After removal of the drug from bladder standard cystoscopy followed by fluorescence diagnosis was performed in every patient. During the local fluorescence spectroscopy the intravesical instillation of the agent hexasens was shown to induce selective accumulation of photoactive protoporphyrin IX in tumor cells comparing with intact bladder mucosa. During 1 h after intravesical instillation of hexasens solution the level of fluorescence of hexasens-induced protoporphyrin IX in the tumor was higher than that in surrounding intact mucosa at average in 5.8 fold. As compared with results of standard cystoscopy, fluorescence diagnosis improved the sensitivity of the method by 24.4% (from 75.6% to 100%), the accuracy - by 15.2% (from 83.3% to 98.5%) and negative predictive value - by 33.5% (from 66.5% to 100%). Fluorescence diagnosis gave an opportunity to detect additional tumor foci, which were invisible in white light, in 27.4% of patients. For fluorescence diagnosis in 4.0% of patients false-positive fluorescence of bladder mucosa was detected that was probably due to inflammation. None of patients received active dose of the drug hexasens had adverse reactions, changes in general well-being and blood and urine parameters. According to the results of the study fluorescence diagnosis with hexasens for bladder cancer is recommended for use in clinical practice

Fluorescence diagnosis of bladder cancer with agent hexasens - The results of multicenter trial

The results of multicenter trial for efficacy of fluorescence diagnosis for bladder cancer with agent hexasens (SSC Scientific Research Institute Organic Intermediates and Dyes, Russia) based on hexyl ester of 5-aminolevulinic acid compared with routine cystoscopy are represented in the article. The study included 124 patients. All patients had intravesical instillation of 50 ml of 0,2% hexasens. The exposure time accounted for 1-2 h. After removal of the drug from bladder standard cystoscopy followed by fluorescence diagnosis was performed in every patient. During the local fluorescence spectroscopy the intravesical instillation of the agent hexasens was shown to induce selective accumulation of photoactive protoporphyrin IX in tumor cells comparing with intact bladder mucosa. During 1 h after intravesical instillation of hexasens solution the level of fluorescence of hexasens-induced protoporphyrin IX in the tumor was higher than that in surrounding intact mucosa at average in 5.8 fold. As compared with results of standard cystoscopy, fluorescence diagnosis improved the sensitivity of the method by 24.4% (from 75.6% to 100%), the accuracy - by 15.2% (from 83.3% to 98.5%) and negative predictive value - by 33.5% (from 66.5% to 100%). Fluorescence diagnosis gave an opportunity to detect additional tumor foci, which were invisible in white light, in 27.4% of patients. For fluorescence diagnosis in 4.0% of patients false-positive fluorescence of bladder mucosa was detected that was probably due to inflammation. None of patients received active dose of the drug hexasens had adverse reactions, changes in general well-being and blood and urine parameters. According to the results of the study fluorescence diagnosis with hexasens for bladder cancer is recommended for use in clinical practice