tumorsMalignant tumoursMalignant tumours2224-50572587-6813Rosoncoweb10.18027/2224-5057-2017-3-71-80tumors-394Research ArticleОБЗОРЫ И АНАЛИТИКАREVIEWS AND ANALYSISФиброламеллярная карцинома как отдельный подтип гепатоцеллюлярного рака: молекулярно-генетические особенности, диагностика, перспективы леченияFibrolamellar carcinoma as a distinct subtype of hepatocellular carcinoma: molecular genetics features, diagnostics and treatment prospectsШавочкинаД. А.ShavochkinaD. A.

к.б.н, научный сотрудник лаборатории механизмов прогрессии эпителиальных опухолей отдела иммунохимии

PhD, Researcher, Department of Immunochemistry

darya.shavochkina@gmail.comКустоваИ. Ф.KustovaI. F.

к.б.н, научный сотрудник лаборатории иммунохимии отдела иммунохимии

PhD, Researcher, Department of Immunochemistry

innaku74@gmail.comЛазаревичН. Л.LazarevichN. L.

биологический факультет; д.б.н., профессор, заведующая отделом иммунохимии НИИ Канцерогенеза ФГБУ «НМИЦ онкологии им. Н.Н. Блохина» Минздрава России

Department of Biology;  PhD, DSc, Professor, Head of the Department of Immunochemistry, Research Institute of Carcinogenesis, N.N. Blokhin NMRCO, Ministry of Health of the Russian Federation

lazarevich.nl@gmail.comНИИ Канцерогенеза ФГБУ «НМИЦ онкологии им. Н. Н. Блохина» Минздрава РоссииРоссияResearch Institute of Carcinogenesis, N. N. Blokhin NMRCO, Ministry of Health of the Russian FederationRussian FederationМГУ им. М. В. Ломоносова; НИИ Канцерогенеза ФГБУ «НМИЦ онкологии им. Н. Н. Блохина» Минздрава РоссииРоссияResearch Institute of Carcinogenesis, N. N. Blokhin NMRCO, Ministry of Health of the Russian Federation; Moscow State UniversityRussian Federation201717112017037180Copyright © Шавочкина Д.А., Кустова И.Ф., Лазаревич Н.Л., 20172017Шавочкина Д.А., Кустова И.Ф., Лазаревич Н.Л.Shavochkina D.A., Kustova I.F., Lazarevich N.L.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.malignanttumors.org/jour/article/view/394

Фиброламеллярная карцинома (ФлК) описана в 1956 г. как отдельный подтип гепатоцеллюлярного рака (ГЦР), диагностируемый у молодых пациентов, не имеющих хронических заболеваний печени. Морфологически ФлК характеризуется как ГЦР с крупными клетками, большими ядрами и наличием в строме ламеллярных коллагеновых волокон, образующих разветвленную сеть. Механизмы, определяющие развитие ФлК при отсутствии значимых факторов риска, долгое время оставались неизвестными. Высокопроизводительные методы исследования транскриптома позволили описать уникальный профиль экспрессии генов при ФлК, определить основные сигнальные пути, активированные в опухолевых клетках, такие как mTOR, FGFR и EGFR сигнальные каскады, которые могут рассматриваться как потенциальные терапевтические мишени для лечения этого типа опухолей. При полнотранскриптомном анализе в подавляющем большинстве образцов ФлК был впервые выявлен химерный транскрипт DNAJB1-PRKACA, который образуется в результате слияния двух генов при делеции участка 19 хромосомы. Эта перестройка является драйверным событием для возникновения ФлК и определяет ускорение пролиферации, повышение клоногенного потенциала и увеличение популяции опухолевых стволовых клеток. Слитный транскрипт специфичен для ФлК и может быть выявлен рядом клинических лабораторных методов, что открывает возможность для его использования в качестве маркера для дифференциальной диагностики этого типа опухолей. Поскольку слитный белок DNAJB1-PRKACA обладает киназной активностью, он рассматривается как перспективная мишень для разработки таргетных препаратов, способных ингибировать эту функцию. Анализ транскриптомных нарушений в ФлК позволил описать прогностическую сигнатуру из 8 генов, высокий уровень экспрессии которых коррелирует с плохой выживаемостью пациентов после хирургического лечения. В представленном обзоре суммированы современные сведения о молекулярном патогенезе ФлК и открывающихся на их основе возможностях для диагностики и разработки новых схем терапии.

 

Fibrolamellar carcinonoma (FLC) was described in 1956 as a separate subtype of hepatocellular carcinoma (HCC) that affects young adults without underling liver diseases. Morphologically FLC is characterized as HCC with large cells, gross nucleus and fibrous collagen bands organized into branched net. The mechanisms of FLC development in the absence of major risk factors remained obscured for a considerable amount of time. High-throughput transcriptomic analysis allowed to describe the unique profile of gene expression in FLC and to define the main signaling pathways activated in tumor cells which include mTOR, FGFR и EGFR cascades which can be accounted as potential therapeutic targets for this type of tumors. Whole transcriptome sequencing allowed to identify in the majority of FLC samples the new chimeric transcript DNAJB1-PRKACA which appears due to deletion of the part of chromosome 19 which leads to fusion of two genes. This translocation appears to be driving event in FLC development that governs increase of proliferation, colony formation and tumor stem cells population. Fusion transcript is specific for FLC and can be identified through the number of clinical laboratory methods. It opens the opportunity for use of that fusion in differential diagnostics as FLC marker. Due to kinase activity of DNAJB1-PRKACA protein, it is considered to be prospective target for the development of therapeutic compounds which can inhibit this function. Analysis of transcriptome aberrations in FLC allowed to specify the prognostic signature of 8 genes whose overexpression correlates with poor patient survival after the surgery. In this review we have summarized recent data on FLC molecular pathogenesis and possibilities for the development of new methods for diagnosis and treatment based on these findings.

 

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The authors declare that there are no conflicts of interest present.