Dmitriy I. Vodolazhsky

Rostov Research Institute of Oncology

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Oleg I. Kit

Rostov Research Institute of Oncology

Denis S. Kutilin

Ministry of Health of the Russian Federation

Leonid Kharin

Rostov Research Institute of Oncology

Svetlana Panina

The University of Texas at Austin

ОБ

Олеся Богданова

Rostov Research Institute of Oncology

Vyacheslav A. Sustretov

Rostov Research Institute of Oncology

Yaroslav S. Enin

Rostov Research Institute of Oncology

Ilya Tsimafeyeu

Presidential Executive Office

Anna V. Chubaryan

Ministry of Health of the Russian Federation

ИД

Ирина Демидова

Moscow City Oncology Hospital №62

Cooperative Institutions

Rostov Research Institute of Oncology

Ministry of Health of the Russian Federation

Russian Academy of Sciences

Russian Cancer Research Center NN Blokhin

Russian Society of Clinical Oncology

Cancer Research Center

Research Medical Center

National Medical Research Center of Cardiology

Moscow City Oncology Hospital №62

Southern Federal University

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LINE-1 hypomethylation in colon cancer.

Journal of Clinical Oncology (2018)

Dmitriy I. Vodolazhsky Natalya N. Timoshkina Svetlana Panina

588 Background: Global hypomethylation of the genome is one of the causes of chromosomal instability and aneuploidy and is associated with an increased risk of colorectal cancer (CRC). The long interspersed nucleotide element-1 (LINE-1) is the main part of the mobile repeated elements of the genome, and the level of its methylation is concordant with genome-wide methylation. The aim of the study was to assess the methylation of LINE-1, as well as methylation of the promoter of six cancer-associated genes adjusting for the clinical and pathological characteristics in colorectal cancer (CRC). Methods: Using pyrosequencing (PyroMark Q24 analysis system, Qiagen, Germany) DNA methylation levels of LINE-1 and 6 genes ( APC, CDH13, MLH1, MGMT, P16 and RASSF1A) were measured in tumoral and normal tissues of 50 patients with CRC. Results: The level of LINE-1 methylation was 66.8 ± 0.89% in tumors, 72.5 ± 0.45% in normal tissues ( p = 0.0013). The differences in LINE-1 methylation level were not associated with age, differentiation grade, tumor localization, and the presence of activating mutation within the KRAS gene. At the same time, the MGMT methylation was positively associated with age ( p = 0.04), and the hypermethylation of the CDH13 gene was more common in tumors of the proximal colon ( p = 0.004). Methylation of the CDH13 promoter negatively correlated with methylation level of LINE1 ( r = -0.427, p < 0.05). Hypomethylation of LINE-1 was associated with progression of TNM-stages of the tumors ( r = +0.606, p < 0.001). The cancer-associated genes were hypermethylated in 70% of CRC cases when compared with normal epithelium, and hypomethylation of LINE-1 was observed in 90% of CRC cases. Conclusions: The present study demonstrated the association of LINE-1 methylation with the TNM tumor stage, which may be used as a biomarker for early diagnosis and prognosis of sporadic CRC, together with assessment of hypermethylation of tumor suppressors.

MLH1

Microsatellite Instability

Chromosome instability

10.1200/jco.2018.36.4_suppl.588

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Copy number variation of MDM2 and p53 genes in extracellular DNA as potential marker for lung adenocarcinoma diagnostics.

Journal of Clinical Oncology (2017)

Denis S. Kutilin Yaroslav S. Enin Dmitriy I. Vodolazhsky Vyacheslav A. Sustretov Tamara G. Ayrapetova

e23094 Background: Today, the problem of early diagnostics of lung cancer remains unsolved as every fourth patient diagnosed with the disease already has distant metastases. Studying gene copy number variation (CNV) in extracellular DNA in the blood plasma can become a basis for a new effective and low invasive method for predictive diagnostics and disease prognosis. The purpose of the study was to examine the copy number of the MDM2 and p53 genes in extracellular DNA of patients with metastatic and non-metastatic lung cancer and healthy donors. Methods: The blood samples of 30 patients with lung adenocarcinoma (collected before surgery) and 30 healthy donors (without cancer) were studied. Each sample was centrifuged to obtain blood plasma. DNA was isolated from plasma using a phenol-chloroform extraction method. Detection of relative copy number of the MDM2 and p53 genes (reference gene - GAPDH) was performed by RT-qPCR using CFX96 thermocycler (Bio-Rad, USA). The groups were compared by the Mann-Whitney U- test. Results: Reduction of the p53 gene copy number by 57% (p < 0.05), as well as increasing of the MDM2 gene copy number by 160% (p < 0.05), were found in the extracellular DNA of patients with lung adenocarcinoma compared with healthy donors. As a result, the ratio of copy number of pro-/anti-apoptotic genes p53:MDM2 in extracellular DNA of patients with lung adenocarcinoma (1:23 ratio) was different from that of healthy donors (1:4 ratio). The MDM2 gene copy number in extracellular DNA of patients with metastases exceeded the value in non-metastatic patients two-fold (p < 0.05). The p53 gene copy number in extracellular DNA of patients with metastatic and non-metastatic cancer did not differ significantly. Conclusions: CNV of the p53 and MDM2 genes in extracellular DNA has a high potential for low invasive diagnostics and prognosis of lung adenocarcinoma.

Gene dosage

10.1200/jco.2017.35.15_suppl.e23094

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Characteristics of proteomic patterns in patients with metastatic and non-metastatic colorectal cancer.

Journal of Clinical Oncology (2017)

Dmitriy I. Vodolazhsky Denis S. Kutilin Leonid Kharin Evgeniy N. Kolesnikov Олеся Богданова

e23007 Background: Over the past 20 years, the number of deaths from colorectal cancer (CRC) increased by 46% worldwide: every year more than 1 million people are diagnosed with this pathology. Proteomic studies using protein microarrays are a very attractive strategy for the screening of new highly specific biomarkers which can improve prognosis prediction of CRC. We performed a screening proteomic study to find new informative biomarkers for metastatic and non-metastatic colorectal cancer which can be further used in routine histochemical studies. Methods: The samples of tumor and non-tumor tissues of 20 patients with histologically confirmed adenocarcinoma of the colon were studied. Extraction, labeling and hybridization of proteins on the slide containing 224 antibodies for key cellular proteins were performed using the Panorama Antibody Microarray - Cell Signaling Kit, and the GenePix 4100A scanner was used for scanning. The data were analyzed using GenePixTMPro 6.0. Results: We revealed a significant (p < 0.05) increase in expression of such proteins as C-myc, SMAD4, PCAF, Adaptin (b1 + b2), FAK Phospho (pY577), PKC g and Phospho-Pyk2 (pY579/580) by 2.1; 1.5; 1.5; 1.5; 2.7 and 1.6 times, respectively, in tumor tissue of patients with metastatic colorectal cancer compared to non-tumor colon tissues. A significant increase (p < 0.05) in expression of proteins NGFR p75 (Nerve Growth Factor Receptor) by 3.8 times and Phospho-Ta (pS199 / 202) by 1.9 times was found in tumor tissue of patients with non-metastatic CRC in comparison with non-tumor colon tissue. Conclusions: The study showed changes in proteomic profile of malignant colon tissue, and proteomic profile differed significantly in tumor tissues of patients with metastatic and non-metastatic cancer. We found changes in expression of 9 proteins, differential in each group of patients (with metastatic and non-metastatic CRC). These proteins have a high potential as biomarkers for CRC prognosis prediction.

Tissue microarray

10.1200/jco.2017.35.15_suppl.e23007

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EGFR analysis of 21,039 patients with NSCLC: Age-related gradual increase of the L858R mutation frequency in adenocarcinomas and high occurrence of ex19del/L858R mutations in squamous cell carcinomas from females and/or nonsmokers.

Journal of Clinical Oncology (2017)

Е. Н. Имянитов Ирина Демидова M. Gordiev М. Л. Филипенко Т. В. Кекеева

9040 Background: EGFR testing in Russia is carried out upon the patronage of Russian Society of Clinical Oncology (RUSSCO), and the results are accumulated in a centralized database. Squamous cell carcinomas (SCC) constitute 60-70% of NSCLC incidence in Russia, however physicians are often discouraged to send NSCLC-SCC for EGFR testing due to low frequency of mutations. Methods: We considered all NSCLC patients analyzed by means of PCR for the presence of EGFR mutations (ex19del and L858R) within years 2012-2017. Results: 21,039 NSCLC patients were tested. EGFR analysis was successful in 20,768 patients (98.7%). EGFR mutations were detected in 3566/17717 (20.1%) adenocarcinomas (AdCa) of the lung (ex19del: 2203 (12.4%); L858R: 1363 (7.7%)). There was an evident age-related increase in the frequency of L858R substitution in AdCa patients (p =0.000, Table). This set of patients included 1,139 NSCLC-SCC cases, and the EGFR mutation was observed in 41 (3.6%) subjects. Among 189 females with NSCLC-SCC, ex19del or L858R were detected in 25 (13.2%) cases. Stratification by smoking status revealed EGFR mutation in 19/242 (7.9%) non-smokers. Conclusions: Elderly NSCLC patients have particularly increased probability to be diagnosed with L858R mutation. In the real-world setting, patients with NSCLC-SCC may have high frequency of EGFR mutations, either due to imprecise histological subtyping or due to yet unknown reasons. All female and non-smoking patients with NSCLC have to undergo EGFR testing irrespectively of tumor histology. [Table: see text]

Subtyping

Histology

10.1200/jco.2017.35.15_suppl.9040

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A proteomics analysis of cell signaling pathways in colon cancer.

Journal of Clinical Oncology (2018)

Oleg I. Kit Dmitriy I. Vodolazhsky Denis S. Kutilin Yaroslav S. Enin Yuri Gevorkyan

608 Background: Colorectal cancer is the second most common cancer in women and third most common cancer in men. Major signaling pathways are known to be deregulated in cancer, however, there are only a few studies addressing activation status of more than one or two pathways in colorectal cancer in comparison with the normal tissue. The present study aims to compare the expression pattern of proteins associated with cell signaling in paired tumor and non-tumor samples of patients with colon cancer, as well as to define the cluster of proteins to differentiate patients with non-metastatic (Dukes’ grade B) and metastatic (Dukes’ grade C&D) colon cancer. Methods: Frozen tumor and non-tumor samples were collected after tumor resection from 19 patients with colon cancer. The "Panorama" (Sigma-Aldrich) Antibody Microarray-Cell Signaling kits were used for the analyses. The expression ratios of paired tumor/non-tumor samples were calculated for the each protein. We employed R packages ‘samr’, ‘gplots’, ‘supclust’ ( pelora, wilma algorithms), ‘glmnet’ for the differential expression analysis, supervised clustering and penalized logistic regression, respectively. Results: Significance analysis of microarrays revealed 9 up-regulated proteins, including protein kinase C gamma, c-Myc, MDM2, bCOP, p14ARF, p57kip2, GRB2, APP, pan cytokeratin, and 1 down-regulated protein (GAP1) in tumoral mucosa. Pan cytokeratin and amyloid precursor protein were up-regulated in tumor vs. non-tumor tissue, and were selected in the predictive cluster to discriminate colon cancer type. Higher levels of S-100b and phospho-Tau-pSer199/202 were confirmed as the predictors of non-metastatic colon cancer by all of employed regression/clustering methods. Conclusions: Deregulated proteins in colon cancer are involved in oncogenic signal transduction, cell cycle control, and regulation of cytoskeleton formation/transport. Further studies are needed to validate potential protein markers of colon cancer development and metastatic progression.

Tissue microarray

Protein microarray

10.1200/jco.2018.36.4_suppl.608

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Comparative characteristics of the genes expression of cancer-testis antigens in tumor and non-tumor breast tissues.

Journal of Clinical Oncology (2017)

Khava A. Mogushkova Dmitriy I. Vodolazhsky Denis S. Kutilin Oleg I. Kit

e23085 Background: Breast cancer (BC) is the most common cancer among women. The development of immunotherapy which targets cancer-testis antigens (CTA) is needed for the decreasing in breast cancer mortality. Therefore, the aim of this work was the study of specific CTA of breast cancer tissue among CTA-family, role of which has been previously mentioned. Methods: The paired surgical biopsies of tumor and non-tumor breast tissue of 25 patients (50 samples) residing in the South of Russia and treated in Rostov Research Institute of Oncology were included in the present study. Total RNA was extracted from tissue samples by P. Chomczynski and N. Sacchi (2006) method. cDNA library was synthesized using reagent kit "Reverta-L» (Russia, "InterLabService"). Primers were designed using the NCBI GenBank database. The relative expression of 17 genetic loci ( MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-B1, MAGE-B2, GAGE1, GAGE3, GAGE4, MAGE-C1, BAGE, CTAG-1B, XAGE3, NY -ESO1, SSX2, SYCP1, PRAME1) was determined by Real-Time qPCR (reference gene - GAPDH) using CFX96 thermal cycler (Bio-Rad, USA). Statistical analysis was performed using nonparametric Mann-Whitney U-test. Results: The expression of CTA genes MAGE-A4, MAGE-B1, MAGE-B2 and GAGE3 was found to be significantly (p < 0.05) increased by 1.4; 9.5; 4.0 and 9.8 fold, respectively, in tumor tissue compared with non-tumor breast tissue. The expression of other CTA genes were not differed between tumor and non-tumor samples. Conclusions: Detected increasing of the expression levels of MAGE-A4, MAGE-B1, MAGE-B2 and GAGE3 genes evidences that these CTA may serve as the effective immunotherapeutic targets in breast cancer.

10.1200/jco.2017.35.15_suppl.e23085

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