MODERN CONCEPTS OF THE MOLECULAR GENETIC MARKERS OF PROSTATE CANCER

Purpose of the study: to present up-to-date data on molecular genetic studies aimed to identify the risks of developing prostate cancer in representatives of various ethnic groups. Material and Methods. Literary sources were searched in databases such as PubMed, Medline, Google Scholar. We had analyzed 60 sources on the risks of developing prostate cancer. The epidemiological data on the prostate cancer incidence and risk factors depending on age characteristics, hormonal status and hereditary predisposition were shown. Results. The pathogenetic features of prostate cancer depending on ethnicity were described. The paper presents data from both European and Asian ethnic groups. In a number of studies, significant genetic differences in single nucleotide polymorphisms associated with the development of prostate cancer were identified. Conclusion. Research in the field of determining the risks of developing prostate cancer becomes more and more relevant due to the emergence of new molecular genetic markers, as well as the influence of various ethnic characteristics. Nevertheless, many questions of modern diagnosis of prostate cancer are still open, therefore, research in this area remains promising.

Prevalence of well-characterized and putative marker mutations in benign and malignant thyroid neoplasms

Недостаточная точность дооперационной дифференциальной диагностики путём цитологического исследования материала, полученного при тонкоигольной аспирационной биопсии, и низкая доля случаев злокачественных новообразований, описываемых молекулярно-генетическими маркерами с известной диагностической значимостью, обуславливают актуальность поиска новых молекулярно-генетических маркеров и необходимость оценки их ассоциации с риском рака и клинико-морфологическими характеристиками. Целью работы явилось исследование распространенности расширенного спектра известных и новых предполагаемых драйверных и вторичных мутаций в доброкачественных и злокачественных новообразованиях щитовидной железы. Материал исследования: свежезамороженный хирургический материал злокачественных (64 образца) и доброкачественных (16 образцов) новообразований щитовидной железы. Для поиска точковых вариантов, коротких инсерций/делеций, изменений копийности выполнено таргетное высокопроизводительное секвенирование ДНК по технологии AmpliSeq на платформе NextSeq 550 (Illumina). Поиск перестроек выполнен по наличию транскрипта методом таргетного высокопроизводительного секвенирования по технологии AmpliSeq на платформе MiSeq (Illumina). Мутации в генах BRAF, KRAS, NRAS, HRAS выявлены в 62% случаев рака. В 12% случаев рака выявлены перестройки CCDC6-RET (3 случая) и PAX8-PPARG (2 случая), TPM3-NTRK1, ETV6-NTRK3, STRN-ALK - по одному случаю. Во всех случаях выявленные перестройки были взаимоисключающие с другими известными драйверными мутациями. При доброкачественных новообразованиях перестройки не выявлены. Мутации промотора гена TERT выявлены в 10% случаев рака щитовидной железы и были представлены совместно с известными драйверными мутациями. Известная миссенс мутация EIF1AX выявлена в одном случае доброкачественного новообразования, при злокачественных новообразованиях мутации в гене EIF1AX не выявлены. Предполагаемые драйверные мутации в онкогенах PPM1D, PDGFRA, KDR выявлены в образцах рака щитовидной железы и не выявлены при доброкачественных новообразованиях щитовидной железы. Выводы: дана характеристика распространенности драйверных мутаций с известной диагностической значимостью и мутаций в генах, описанных в литературе без установленной диагностической значимости, при доброкачественных и злокачественных новообразованиях щитовидной железы. Insufficient accuracy of preoperative differential diagnostics by cytological examination of fine-needle aspiration biopsy material and low proportion of cases of malignant neoplasms described by molecular genetic markers with known diagnostic significance determine the relevance of the search for new molecular genetic markers with an assessment of their association with cancer risk and clinical and morphological characteristics. The aim of the work was to study the prevalence of an expanded spectrum of known and new putative driver and secondary mutations in benign and malignant thyroid neoplasms. Material: fresh frozen surgical material of malignant (64 samples) and benign (16 samples) thyroid neoplasms. Methods: search for point variants, short insertions/deletions, and copy number variations was performed via targeted high-throughput sequencing using AmpliSeq technology on the Illumina NextSeq platform. Fusions were by the presence of fused transcript by targeted high-throughput sequencing using AmpliSeq technology on the Illumina MiSeq platform. Results: mutations in genes BRAF, KRAS, NRAS, HRAS were detected in 62% of cancer cases. In 12% of cancers we detected rearrangements of CCDC6-RET (3 cases) and PAX8-PPARG (2 cases), TPM3-NTRK1, ETV6-NTRK3, STRN-ALK - one case each. In all cases, the identified rearrangements were mutually exclusive with other known driver mutations. In benign neoplasms, no rearrangements were found. Mutations in the TERT gene promoter have been identified in 10% of thyroid cancers and have been associated with known driver mutations. The well-known missense mutation EIF1AX was detected in one case of a benign neoplasm of the thyroid gland; in malignant neoplasms, no EIF1AX mutation were detected. Putative driver mutations in the PPM1D, PDGFRA, KDR oncogenes were detected in thyroid cancer samples and were not detected in benign thyroid neoplasms. Conclusions: the work characterize the prevalence of driver mutations with a known diagnostic significance and mutations in genes described in the literature without a known diagnostic significance in benign and malignant thyroid neoplasms.

Evaluation of VDR and PAI allelic genes in patients with avascular necrosis of the femoral head

Objective To evaluate the informative value of the carrier status for allelic variations that determine the sensitivity of tissues to calcitriol (VDR) and are involved in familial thrombophilia and hypofibrinolysis (PAI-1) as molecular genetic markers of avascular necrosis of the femoral head (AVNFH). Material and methods A clinical and laboratory study of 300 AVNFH patients, residents of European Russia, was carried out. A comparative analysis of the alleles and genotypes frequency distribution of polymorphisms rs11568820 and rs1544410 of the VDR gene, as well as rs1799889 of the PAI‑1 gene in AVNFH patients was performed. Results AVNFH patients showed a significant increase in the frequencies of the G/G genotype (P = 3.0E‑9) and the G allele (P = 0.05) of the rs11568820 VDR polymorphism (P = 2.10E-08) as compared to controls. The frequency of the A/A genotype of the rs1544410 VDR locus in AVNFH individuals was higher than that in controls (P = 0.05). Discussion Carriers of the genotype G / G A-3731G (Cdx2) of the VDR gene were shown to have a 2.1-fold increased risk of developing AVNFH; carriers of the G allele appeared to have a 2.3-fold increased risk of AVNFH. The findings showed that the carriership of the 5G allele of the polymorphic locus PAI-1 -675 4G > 5G (rs1799889) is detected 1.4 times more often in AVNFH patients than in individuals from the population sample. The risk of developing the pathology is increased 2 times with the carriership of the 5G/5G genotype of this polymorphic locus. Conclusion Carriers of genotypes G/G rs11568820 VDR (allele G), A/A rs1544410 VDR and 5G/5G (allele 5G) at the polymorphic locus rs1799889 PAI-1 have an increased risk of developing AVNFH. This allows the use of the molecular genetic markers in the early diagnosis of AVNFH in individuals who are at greater risk for the disease.