T134 Allelic imbalance and epigenetic changes as a marker of tumor spreading into the adjacent tissue

Non-small cell lung cancer (NSCLC) is characterized by multiple genetic alterations such as loss of heterozygosity (LOH), microsatellite instability (MSI), promoter hypermethylation and changes of miRNA expression. According to a field cancerization (FC) phenomenon the adjacent histologically normal tissue plays a role in tumor progression by triggering the transformation process.The aim of the study was the analysis of genetic alterations in tumor and adjacent tissue to determine the FC size and to reveal associations with clinico-morphological features of patients.The study group included 135 patients with NSCLC. From each patient 4 FFPE samples were analyzed: tumor, adjacent normal lung tissue at 2, 5, 10cm. LOH/MSI analysis was evaluated by PCR using 7 microsatellite loci. Promoter hypermethylation in genes RASSF1A FHIT, DAPK1, CDH1, CD44, TIMP3, MGMT was investigated by methyl-sensitive PCR. The expression levels of miRNAs let-7a, miR-155, miR-205 were measured by real-time PCR.Our results demonstrated that LOH/MSI occurs only in tumor while promoter hypermethylation occurs also in adjacent tissue at 2, 5cm, but not at 10cm. The downregulation of let-7a, miR-155 in adjacent tissue is lower than in tumor. The levels of investigated miRNAs in adjacent tissue vary depending on tumor differentiation – in patients with differentiated tumors it is higher than in the group with poorly differentiated tumors.We postulate that FC size in NSCLC is at least 5cm from tumor and includes only epigenetic but not structural (LOH/MSI) alterations. The evaluation of epigenetic changes in adjacent tissue (e.g., surgical margins) can potentially be used for postsurgical prognosis

Наследственные онкологические синдромы с повышенным риском развития рака почки

Renal cancer (RC) is one of the three most common diseases in oncologic urology. Its accurate diagnosis and prognosis remain difficult and important problems. Some cases of RC are associated with hereditary cancer syndromes and are caused by germline mutations. This review describes monogenic forms of hereditary RC (von Hippel–Lindau syndrome, Birt–Hogg– Dubé syndrome, hereditary leiomyomatosis and renal cell cancer, hereditary papillary renal carcinoma, BAP1 tumor predisposition syndrome) and diseases with several candidate genes (SDH-mutated tumors, tuberous sclerosis complex). Additionally, the review discusses the increased risk of RC in patients with frequent hereditary cancer syndromes predisposing to the development of a wide range of tumor types: Lynch and Li-Fraumeni syndromes. RC in combination with other carcinomas can develop in patients carrying pathogenic mutations in the candidate genes of different hereditary cancer syndromes –  multi-locus inherited  neoplasia  allele syndrome (MINAS)  –  which is especially important  due to the growing role of high-throughput sequencing in practical oncologic genetics. Additionally, guidelines on modern laboratory genetic diagnostics and active surveillance are presented for each syndrome.Рак почки (РП) – одно из 3 частых онкоурологических заболеваний, своевременная диагностика и прогноз которого остаются актуальными задачами. Часть случаев РП связана с наследственными онкологическими синдромами и обусловлена герминальными  мутациями.  В настоящем  обзоре охарактеризованы моногенные формы наследственного РП (синдромы  Хиппеля–Линдау, Берта–Хогга–Дюбе, наследственный лейомиоматоз и почечно-клеточный рак, наследственная папиллярная карцинома почки, ВАР1-ассоциированный онкосиндром) и синдромы с несколькими генами-кандидатами (опухоли с мутациями генов семейства SDH, туберозный склероз). Отдельно рассмотрен вопрос о повышенном риске РП у пациентов с частыми онкосиндромами, предрасполагающими к развитию широкого патоморфологического спектра опухолей: синдромом Линча, Ли-Фраумени. Описаны случаи РП и других карцином у носителей патогенных мутаций в генах-кандидатах разных наследственных форм рака – мультилокусного наследственного онкологического синдрома (MINAS), что особенно актуально в связи с растущей ролью высокопроизводительного секвенирования в практической онкогенетике. Для каждого синдрома приведены рекомендации по современной лабораторной генетической диагностике и динамическому наблюдению

Modern strategy of tumor suppressor gene cloning: B-cell chronic lymphocytic leukemia candidate genes search as an illustration

Genes that normally function to prevent or suppress malignancy are known as "tumor suppressor genes" or TSG. It is supposed that the chromosomal region lost in the tumor cells harbors TSG preventing cancer. The examination of this region in the normal chromosome would permit identification of the particular suppressor gene. The methods employed in such search are diverse. As a rule, success is achieved by combining cytogenetic, genetic and physical genome mapping with analysis of genomic and cDNA clones. We have constructed a cosmid contig in the 13q14.3 region which is expected to contain a putative B-cell chronic lymphocytic leukemia (BCLL) TSG, cDNA clones corresponding to new human gene Leu5 have been found to locate nearby the borders of homo- and hemizygous deletions in BCLL patients. Gene Leu5 encodes a zinc-finger protein that shares homology with some mammalian genes taking part in early embryogenesis and tumor progression. Leu5 gene could be an interesting candicate for BCLL TSG