Oncogenic human papillomaviruses (mostly HPV types 16 and 18) are the major cause of cervical intraepithelial neoplasia (CIN), which progresses into cervical cancer (CC). To reveal early genetic alterations of chromosome 6 that are important for CC progression, we analyzed the loss of heterozygosity (LOH) in DNAs from 45 CIN cases, 47 microcarcinomas, and 19 invasive squamous cell carcinomas stage IB. LOH analysis of DNA samples prepared with microdissection from all CIN foci, as well as from CC lesions and synchronous CIN, permitted investigation of CIN and CC heterogeneity. Out of all CC stage I cases, 79% showed LOH with six microsatellite markers at chromosome 6. LOH with the microsatellite markers D6S276 (6p22) and TNFa (6p21.3) was found in 50% of the CC cases. LOH frequency in CIN lesions synchronous with CC was higher then in CIN cases without cancer; the statistical significance (P = 0.004) was shown for D6S291 (6p21.2). The finding suggests that the high frequency of LOH in CIN lesions is a marker of unfavorable prognosis for CIN. Progression from microcarcinoma to invasive CC of stage IB was associated with a higher LOH frequency at D6S344 (6p25) and TNFa (6p21.3). Early genetic alterations were found in CIN with microsatellites D6S273 and TNFa located at 6p21.3. Moreover, LOH frequency at D6S273 remained the same in both CIN and CC cases. Based on HPV typing, LOH analysis, and X-chromosome inactivation, the polyclonality of CC lesions, as well as CIN, was observed in a few patients.

Gastrointestinal stromal tumors (GISTs) are the most spread mesenchymal tumors located within the gastrointestinal tract that have particular clinico-morphological, immunohistochemical and molecular characteristics. The distinguishing mark of GISTs is the presence of the cell-surface antigen CD117 (KIT receptor tyrosine kinase), identified by immunohistochemistry. GISTs consist of tumors with various activating mutations in KIT (75–80 %) or PDGFRA (5–15 %) receptor tyrosine kinases. Numerous KIT and PDGFRA mutations are associated with specific GIST morphology, histologic phenotype, metastasizing and prognosis. 10–15 % of GISTs contain KIT and PDGFRA wild type genes, some of them have driver BRAF, IGF1R or PIK3CA mutations. The other GISTs patients have familial syndromes (neurofibromatosis type 1, Carney–Stratakis syndrome, Carney triad) and contain germline mutations of NF1 or the genes coding for the succinate dehydrogenase subunits SDHA, SDHB, SDHC, and SDHD. GISTs are first and the most studied model for development of principles and methods of personalized targeted therapy of solid tumors with tyrosine kinase inhibitors.

Tumor-necrosis factor (TNF) is an inflammatory cytokine that is involved in pathogenesis of different malignancies. The single-nucleotide polymorphism −238(G/A)TNF (rs361525) has been investigated for detection of a predisposition to infectious, autoimmune, and oncological diseases. The goal of the study was to investigate the association of -238(G/A)TNF polymorphism (rs361525) with breast cancer (BC) prognosis. TNF allelic variants were detected by restriction fragment length polymorphism polymerase chain reaction (RFLP-PCR). We did not reveal genotype-distribution disparities among groups with various stages of the disease and various levels of expression of estrogen, progesterone, and epidermal growth factor receptors. The AG genotype frequency was about 10%, and there were no BC patients with the AA genotype in all groups. However, the 5-year survival was significantly lower for AG than GG carriers with stage II or ER-positive BC. Our data suggest that −238(G/A)TNF polymorphism is not involved in the initiation of malignancies but is a substantial factor of BC prognosis.

Introduction. Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract the character diagnostic feature of which is CD117 (KIT) expression. GISTs are clinically diverse and have different genetic alterations that may have predictive and prognostic significance.Aim – the study of clinical, morphological and genetic features of GISTs to assess the overall survival (OS) of patients with various profiles of genetic disorders for elucidation the factors contributing to prognosis.Materials and methods. A total 244 GIST patients who received combined treatment were enrolled in the study and their clinical characteristics and mutational status of KIT, PDGFRA, BRAF were analyzed. SDH-deficient GISTs were detected using IHC-analysis of SDHB expression.Results. Stromal tumors developed in stomach (50 %), small intestine (37.7 %), colon or rectum (8.6 %), esophagus (0.4 %) and extraorganically (EGIST, 5.7 %). Overall survival correlated with gastric site (p = 0.005), tumor size 10 cm (p = 0,0001) and mitotic count HPF 10 / 50 (p = 0.007). KIT mutations were found in 168 (68.9 %) and PDGFRA – in 31 (12.1 %) of GISTs, 14 novel mutations were detected. Mutations in KIT exon 11 were found in 140 (57.4 %) tumors, 10-year OS, 51 %, median 124 months. Patients with deletions had lower OS than patients with substitutions or duplications in KIT exon 11 (p = 0,023). The lowest OS was in patients with primary mutations in KIT exons 13 or 17 (median 28 months) and duplications in KIT exon 9 (median 71 months). There was a low OS of young patients with homozygous KIT mutations, mutations that begin in intron and two simultaneous KIT mutations. GISTs with PDGFRA mutations were located in stomach and had no metastases, 10-year OS, 63 %, median 175 months. KIT / PDGFRA mutations were not observed in 45 (18.4 %) patients (wild-type GIST), 10-year OS, 59 %, median 250 months. Wild-type GISTs with BRAF, NF1 mutations and SDH deficiency were detected. The better OS was demonstrated by patients with BRAFV600E (10-year ОS, 84 %, median 97 months) and SDH deficiency (10-year and 15-year OS, 82 %).Conclusion. Genetic analysis is necessary to clarify GIST prognosis and predict the effectiveness of targeted therapy. The clinical, morphological and genetic diversity of GISTs was confirmed. Wild-type GISTs with BRAF mutations and SDHdeficiency were identified in the Russian population for the first time. The long-term 10- и 15-year OS of GIST patients were evaluated.

Melanoma is the most lethal malignancy of skin, which is comprised of clinically relevant molecular subsets defined by specific "driver" mutations in BRAF, NRAS, and KIT genes. Recently, the better results in melanoma treatment were obtained with the mutation-specific inhibitors that have been developed for clinical use and target only patients with particular tumor genotypes. The aim of the study was to characterize the spectrum of "driver" mutations in melanoma subtypes from 137 patients with skin melanoma and 14 patients with mucosal melanoma. In total 151 melanoma cases, the frequency of BRAF, NRAS, KIT, PDGFRA, and KRAS mutations was 55.0, 10.6, 4.0, 0.7, and 0.7%, respectively. BRAF mutations were found in 69% of cutaneous melanoma without UV exposure and in 43% of cutaneous melanoma with chronic UV exposure (p=0.045), rarely in acral and mucosal melanomas. Most of melanomas containing BRAF mutations, V600E (92%) and V600K (6.0%) were potentially sensitive to inhibitors vemurafenib and dabrafenib. NRAS mutations were more common in cutaneous melanoma with chronic UV exposure (26.0%), in acral and mucosal melanomas; the dominant mutations being Q61R/K/L (87.5%). KIT mutations were found in cutaneous melanoma with chronic UV exposure (8.7%) and mucosal one (28.6%), but not in acral melanoma. Most of KIT mutations were identified in exon 11; these tumors being sensitive to tyrosine kinase inhibitors. This is the first monitoring of BRAF, NRAS, KIT, PDGFRA, and KRAS hotspot mutations in different subtypes of melanoma for Russian population. On the base of data obtained, one can suppose that at the molecular level melanomas are heterogeneous tumors that should be tested for "driver" mutations in the each case for evaluation of the potential sensitivity to target therapy. The obtained results were used for treatment of melanoma patients.