[Landscape of KRAS, BRAF, and PIK3CA Mutations and Clinical Features of EBV-Associated and Microsatellite Unstable Gastric Cancer].

Personalization of gastric cancer (GC) treatment is an urgent problem because of the clinical heterogeneity and aggressive course of the disease. Four GC subtypes were isolated based on molecular characteristics by The Cancer Genome Atlas researchers in 2014: Epstein-Barr virus positive (EBV^(+)), microsatellite unstable (MSI), chromosomally unstable (CIN), and genomically stable (GS). There is no unified method to detect the CIN and GS subtypes today, while MSI and EBV status assessments are used routinely and are of great clinical importance. A total of 159 GC samples were tested for MSI, EBV DNA, and somatic mutations in codons 12-13 (exon 2), 61 (exon 3), and 146 (exon 4) of the KRAS gene; codons 597-601 (exon 15) of the BRAF gene; and codons 542-546 (exon 9), 1047-1049 (exon 20) of the PIK3CA gene. EBV^(+) GC was detected in 8.2% of samples; and MSI, in 13.2%. MSI and EBV+ were found to be mutually exclusive. The mean ages at GC manifestation were 54.8 and 62.1 years in patients with EBV^(+) and MSI GCs, respectively. EBV^(+) GC affected men in 92.3% of cases, 76.2% of the patients were older than 50 years of age. Diffuse and intestinal adenocarcinomas were diagnosed in 6 (46.2%) and 5 (38.5%) EBV^(+) cases, respectively. MSI GC equally affected men (n = 10, 47.6%) and women (n = 11, 52.4%). The intestinal histological type was the most prevalent (71.4%); the lesser curvature was affected in 28.6% of the cases. The E545K variant of PIK3CA was observed in one EBV^(+) GC case. A combination of clinically significant variants of KRAS and PIK3CA was found in all MSI cases. The BRAF V600E mutation, which is specific to MSI colorectal cancer, was not detected. The EBV^(+) subtype was associated with better prognosis. The five-year survival rates were 100.0 and 54.7% for MSI and EBV^(+) GCs, respectively.

[Impact of germline BRCA2 and CHEK2 mutations on time to castration resistance in patients with metastatic hormone-nave prostate cancer].

INTRODUCTION: as shown in previous studies, mutations in the BRCA1/2 and CHEK2 genes are associated with worsened long-term results of the definitive treatment for localized prostate cancer (PCa). AIM: to evaluate the prognostic value of germline BRCA1/2 and CHEK2 mutations on time to castration-resistance in patients with metastatic PCa (mPCa), receiving hormonal therapy in the first-line systemic treatment. MATERIALS AND METHODS: A total of 76 patients with mPCa receiving hormonal therapy with luteinizing hormone-releasing hormone analogue (LHRHa) in N.N. Blokhin National Medical Research Center of Oncology were recruited in our prospective study. All patients were genotyped for germline mutations in the BRCA1/2 and CHEK2 genes by real-time polymerase chain reaction using a set "OncoGenetics" (LLC "Research and Production Company DNA-Technology", Russia, registration certificate No 2010/08415) and the Sanger sequencing using a set "Beckman Coulter enomeLab GeXP". In addition, a histologic grade and volume of metastatic disease were evaluated. RESULTS: Pathogenic and possibly pathogenic mutations in the BRCA2 and CHEK2 gene were identified in 19 (25%) patients. No cases of BRCA1 mutations were detected. Median time to castration resistance was significantly lower in BRCA2 and CHEK2 mutation carriers (7.93 mo, 95% confidence interval (CI) 2.62-13.25), than in non-carriers (48,66 mo, 95% CI 31.05-68.26, p<0,001). Cox analysis confirmed three independent unfavorable prognostic factors. DISCUSSION: The results of our study and other publications have confirmed limited efficacy of standard approach to treatment hormone-sensitive mPCa in germline mutation BRCA2 and CHEK2 carriers. However, the main objective of studies was to assess the survival rates in these patients at the stage of castration-resistant mPCa. CONCLUSION: Our results demonstrated that germline BRCA2 and CHEK2 mutations are independent unfavorable predictors in patients with mPCa which are associated with decreased time to castration resistance (HR 3.04, 95% CI 1.63-5.66, p<0.001), particularly in subgroup with low volume metastatic disease (HR 4.59, 95% CI 2.06-10.22, p<0,001). An evaluation of a prognostic value of mutations in other DNA repair genes requires additional research.

[Impact of PD-L1 status on the long-term outcomes of radical treatment of patients with prostate cancer].

A wide range of variables are associated with poor long-term outcomes of radical treatment in patients with prostate cancer (PCa). Expression of the programmed death-1 ligand 1 (PD-L1) in tumor might be a potential novel marker for PCa. AIM: to evaluate the influence of PD-L1 expression status in tumor cells on long-term results of radical treatment in patients with PCa. MATERIALS AND METHODS: a total of 45 patients with pathologically-proven PCa who undergone radical treatment and followed at N.N. Blokhin National Medical Research Center of Oncology were retrospectively analyzed. In all cases PD-L1 expression in tumor cells was evaluated by immunohistochemical studies of paraffin block sections obtained under direct control of pathologist. Positive expression of PD-L1(+) was defined as expression level in tumor cells more or equal 1%, while hyperexpression was diagnosed when expression level L1 more or equal 5%. RESULTS: PD-L1 expression and hyperexpression in tumor cells were identified in 8 (17.8%) and 6 (13.3%) cases. Median metastasis-free survival in patients with positive PD-L1 expression was 48.918 months (95% CI 42.523-55.313) and was less than in patients with negative PD-L1 expression (68.033 months, 95% CI 48.242- 87.824, p=0.090). Cancer-specific survival in patients with negative PD-L1 expression was significantly longer compared to patients with positive expression (p=0.05) and hyperexpression (p=0.024) of PD-L1 in tumor cells. Multivariate Cox analysis confirmed independent predictive value of positive expression and hyperexpression of PD-L1 in tumor cells for metastasis-free survival (HR 3.461, 95% CI 1.171-10.228, p=0.025, and HR 3.916, 95% CI 1.129-13.591, p=0.032) and cancer-specific survival (HR 7.65, 95% CI 0.69-84.51, p=0.097, and HR 9.73, 95% CI 0.87-108.78, p=0.065). CONCLUSION: According to our study and published data, positive PD-L1 expression in tumor cells is associated with poor prognosis of PCa. Given the lack of association of PD-L1 expression in tumor cells with the routine clinical and pathological characteristics of the disease, it seems reasonable to include the status of PD-L1 expression in the current predictive nomograms for patients with PCa. The results may indicate the potential benefits of developing personalized approaches to PCa treatment, particularly with targeting a PD-L1/PD-1 signaling pathway in tumor cells.

[Li-Fraumeni syndrome in a patient with multiple anaplastic oligodendrogliomas of the brain (a case report and literature review)]. / Sindrom Li-Fraumeni u patsienta so mnozhestvennymi anaplasticheskimi oligodendrogliomami golovnogo mozga (klinicheskoe nabliudenie i obzor literatury).

Li-Fraumeni syndrome (LFS) is a clinically and genetically heterogeneous hereditary syndrome with predominantly oncological manifestations, which is associated with mutations in the TP53, MDM2, and CHEK2 genes. The most common variant is a TP53 mutation. OBJECTIVE: To analyze the literature and present a clinical case of a patient with Li-Fraumeni syndrome and multiple anaplastic oligodendrogliomas of the brain. CLINICAL CASE: A 42-year-old male patient presented with complaints of headaches, word finding difficulty, memory loss, right hemianopsia, and generalized convulsive attacks. For 10 years, he underwent multiple interventions and chemotherapy courses for colon adenocarcinoma and recurrent B-cell lymphoma. MRI revealed multiple space-occupying lesions of the cerebraln hemispheres, which were located in the left temporo-occipital and right frontal regions. RESULTS: The patient underwent resection of multiple space-occupying lesions of the left temporo-occipital and right frontal regions. The postoperative period proceeded without complications. The histological diagnosis was WHO grade III anaplastic oligodendroglioma. The patient and one of his sons were detected with a R248W missense mutation in the TP53 gene. The patient underwent six courses of temozolomide chemotherapy. At a follow-up examination 20 months after surgery and chemotherapy, the patient's condition was satisfactory; he returned to work. Control MRI of the brain revealed no signs of continued tumor growth. CONCLUSION: An analysis of the literature and the clinical case indicate the success of multiple surgical interventions and chemotherapy courses performed for a long time in the patient with Li-Fraumeni syndrome manifested by colon adenocarcinoma, recurrent B-cell lymphoma, and multiple anaplastic oligodendroglioma of the brain. The patient had a good quality of life and returned to professional activity.

[Biochip detection of KRAS, BRAF, and PIK3CA somatic mutations in colorectal cancer patients].

Somatic mutations of KRAS, PIK3CA, and BRAF cause insensitivity of colorectal tumors to therapy with anti-EGFR monoclonal antibodies, necessitating a genetic testing prior to therapy. A biological microchip was developed and validated to allow detection of 19 somatic mutations in KRAS, PIK3CA, and BRAF genes. The method combines LNA-clamp PCR and allele-specific hybridization on a microchip and detects mutant DNA in 100 times wild-type background (1%). A total of 66 DNA samples isolated from colorectal tumors were tested with the biochip. Possible associations between the genetic status of the tumor and the patient's characteristics (age, sex, tumor localization, stage, and TMN) were assessed statistically. KRAS mutations were more common in females (P = 0.02) and in patients with distant metastasis (P = 0.04). Other associations between the presence of mutations and patient characteristics were not observed. The method proved highly sensitive and can be used in oncology to select patients who sensitive to therapy with anti-EGFR monoclonal antibodies.

High incidence of mutations in BRCA1 and BRCA2 genes in ovarian cancer.

The incidence of mutations in the BRCA1 and BRCA2 genes in the studied sampling of 74 patients with ovarian cancer was 19%. The incidence of mutations in the Russian sampling of patients, formed without consideration for the family history, is one of the highest in European countries. Retrospective analysis showed that 9% patients carrying mutation had no family history of ovarian or breast cancer. The majority of mutations (86%) were detected in BRCA1 gene, where 5382insC mutation predominated (58%). These data suggest the possibility and advisability of screening for mutations in the BRCA1/2 genes in patients with ovarian cancer, particularly because this population includes patients without family history of ovarian and/or breast cancer.

Spectrum of mutations in BRCA1 gene in hereditary forms of breast and ovarian cancer in Russian families.

The 5382insC mutation predominated (94%) in the spectrum of detected mutations of BRCA1 gene. High incidence of this mutation in familial breast cancer detected for the first time attested to origination of 5382insC mutation from the European part of Russia. The percentage of families with mutations in BRCA1 gene and familial predisposition to ovarian cancer was significantly higher than in hereditary predisposition to breast cancer (p<0.007). These data suggest that clinical manifestation of the mutation depends on genotypical factors other than the position of this mutation in BRCA1 gene. The results prompt screening for hereditary predisposition to these diseases.