Expression of growth factors and tyrosine kinase receptors in the primary tumor and tumor thrombus cells in patients with renal cell carcinoma

Objective: to assess the expression and prognostic value of vascular endothelial growth factor A (VEGF-A), fibroblast growth factor 2 (FGF-2) and their receptors VEGFR-1, -2; FGFR-1, -2, as well as platelet-derived growth factor receptors (PDGFR-α, PDGFR-β) in paired samples of primary tumors and tumor thrombi in renal cell carcinoma (RCC).Materials and methods. Expression of VEGF-A, FGF-2, VEGFR-1, -2; FGFR-1, -2; PDGFR-α, -β was studied in paired surgical samples of primary tumors and tumor thrombi in 25 patients with clear cell RCC pT3a–T4N0–1M0–1 and tumor venous thrombosis by immunohistochemical assay using the appropriate Abcam/Santa Cruz Biotech antibodies from the immunohistochemical staining kit Invitrogen. Expression levels were evaluated by a semi-quantitative method (H-score). The analysis of the correlation between expression levels of VEGF-A, FGF-2, VEGFR-1, -2; FGFR-1, -2; PDGFR-α, -β and RCC characteristics, as well as evaluation of their influence on the outcome of RCC were performed.Results. VEGF-A, FGF-2, as well as VEGFR-1, -2; FGFR-1, -2; PDGFR-α, -β were expressed in the cytoplasm and on the membrane of the primary tumor and tumor thrombus cells in RCC patients. Tumor thrombus cells were characterized by lower expression of VEGFR-1, VEGFR-2, PDGFR-α (p <0.05 for all) and tendency to lower expression of VEGF-A (p = 0.060), FGF-2 (p = 0.046), FGFR-1 (p = 0.077) and FGFR-2 (p = 0.090) compared with primary tumor cells. RCC Furman grade correlated with the expression levels of VEGFR-1 (p = 0.035) and FGFR-1 (p = 0.022) in the primary tumor cells, tumor invasion into venous wall correlated with the expression levels of VEGFR-1 (p = 0.023) and FGFR-2 (p = 0.005) on the thrombus cells. VEGFR-2 overexpression in the primary tumor cells was associated with significant decrease of overall survival (OS) rate (p = 0.011). There was a tendency to OS deterioration in cases with overexpression of VEGFR-2 (p = 0.093) and VEGF-A (p = 0.095) in the tumor thrombus cells. One-year OS in patients with ³2 identified risk factors was 27.3 %, <2 risk factors – 87.5 % (p = 0.004).Conclusion. Tumor thrombus cells in RCC patients expressed VEGF-A, FGF-2, VEGFR-1, -2; FGFR-1, -2; PDGFR-α, -β less active than the cells of the primary tumor. Overexpression of growth factors and tyrosine kinases correlated with RCC Furman grade and tumor venous wall invasion. Overexpression of VEGFR-2 in both primary tumor and thrombus cells in combination with hypoexpression of VEGF-A in the thrombus negatively influenced on OS.

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Receptor tyrosine kinases and growth factors expression in tumor thrombus cells in patients with renal cell carcinoma (RCC).

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e17073 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e17073-e17073

Author(s):

Maria Volkova ◽

Ilya Tsimafeyeu ◽

Dmitry Khochenkov ◽

Anna Olshanskaia ◽

Niko Vashakmadze ◽

...

Keyword(s):

Growth Factors ◽

Tumor Cells ◽

Primary Tumor ◽

Tyrosine Kinases ◽

Tumor Thrombus ◽

Receptor Tyrosine Kinases ◽

Detection System ◽

Biological Significance ◽

Expression Levels ◽

Lower Expression

e17073 Background: To our knowledge, this is a first study describing the expression of the receptor tyrosine kinases (RTKs) and growth factors (GFs) in venous tumor thrombus cells and comparing results with the expression in primary RCC. Methods: Formalin-fixed paraffin-embedded specimens of tumor thrombus and primary tumor removed from 25 untreated pT3a-T4N0-1M0-1 RCC patients were evaluated by immunohistochemistry with primary antibodies to VEGF-A, FGF2, VEGFR1, VEGFR2, FGFR1, FGFR2, PDGFRα, and PDGFRβ (Abcam/Santa Cruz Biotech) and REAL™ EnVision™ Detection System (Agilent). The extent of expression was compared with 25 specimens of primary tumor tissue (selected from the same patients). Significant differences in the expression among these groups were assessed by chi-squared and Fisher's exact tests using a semi-quantitative method (H-score). The analysis of the correlation between expression levels and RCC characteristics was also performed. Results: Mean age was 62.0 (35-74) years. pT3a, pT3b, pT3c and pT4 stages were detected in 4 (16.0%), 13 (52.0%), 7 (28.0%), and 1 (4.0%) patients. Lymph node metastases were found in 9 (36.0%) cases, 15 (60.0%) patients had 1 or more metastatic sites. All RTKs and GFs were heavily expressed in primary tumor cells. Tumor thrombus cells were characterized by significant lower expression levels of VEGFR1, VEGFR2, and PDGFRα (p < 0.05 for all). Tendency to lower expression of VEGF-A (p = 0.06), FGF-2 (p = 0.046), FGFR1 (p = 0.077), and FGFR2 (p = 0.09) was observed in tumor thrombus cells (Table). VEGFR2 expression levels were 2-times reduced in patients with supradiaphragmatic thrombus (H-score = 21.4±12.0) compared to infradiaphragmatic thrombus (H-score = 55.0±8.5, p = 0.042). Furman grade correlated with the expression levels of VEGFR1 (p = 0.035) and FGFR1 (p = 0.022) in primary tumor cells; tumor invasion into venous wall correlated with the expression levels of VEGFR1 (p = 0.023) and FGFR2 (p = 0.005) in thrombus cells. Conclusions: RCC invasion into veins is accompanied by a decrease in expression of RTKs and GFs. Further studies are needed to understand the biological significance. [Table: see text]

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Metastatic Esophageal Carcinoma Cells Exhibit Reduced Adhesion Strength and Enhanced Thermogenesis

Cells ◽

10.3390/cells10051213 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1213

Author(s):

Zihe Huo ◽

Mariana Sá Santos ◽

Astrid Drenckhan ◽

Stefan Holland-Cunz ◽

Jakob R. Izbicki ◽

...

Keyword(s):

Esophageal Carcinoma ◽

Tumor Cells ◽

Cell Lines ◽

Adhesion Strength ◽

Primary Tumor ◽

Carcinoma Cell ◽

Metastatic Potential ◽

Primary Tumors ◽

Metastatic Cell ◽

Carcinoma Cell Lines

Despite continuous improvements in multimodal therapeutic strategies, esophageal carcinoma maintains a high mortality rate. Metastases are a major life-limiting component; however, very little is known about why some tumors have high metastatic potential and others not. In this study, we investigated thermogenic activity and adhesion strength of primary tumor cells and corresponding metastatic cell lines derived from two patients with metastatic adenocarcinoma of the esophagus. We hypothesized that the increased metastatic potential of the metastatic cell lines correlates with higher thermogenic activity and decreased adhesion strength. Our data show that patient-derived metastatic esophageal tumor cells have a higher thermogenic profile as well as a decreased adhesion strength compared to their corresponding primary tumor cells. Using two paired esophageal carcinoma cell lines of primary tumor and lymph nodes makes the data unique. Both higher specific thermogenesis profile and decreased adhesion strength are associated with a higher metastatic potential. They are in congruence with the clinical patient presentation. Understanding these functional, biophysical properties of patient derived esophageal carcinoma cell lines will enable us to gain further insight into the mechanisms of metastatic potential of primary tumors and metastases. Microcalorimetric evaluation will furthermore allow for rapid assessment of new treatment options for primary tumor and metastases aimed at decreasing the metastatic potential.

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Single Stage Resection of Renal Cell Carcinoma with Right Atrial Extension– A Case Report

Journal of Bangladesh College of Physicians and Surgeons ◽

10.3329/jbcps.v36i2.36070 ◽

2018 ◽

Vol 36 (2) ◽

pp. 77-79

Author(s):

Syed Al Nahian ◽

Sonjoy Biswas ◽

Rezaul Hassan ◽

M Zahid Hasan

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Right Atrium ◽

Primary Tumor ◽

Renal Cell ◽

Renal Vein ◽

Tumor Thrombus ◽

Vena Cava ◽

Single Stage ◽

Right Atrial

Renal cell carcinoma (RCC) is the commonest primary tumor of the kidney which may invade through the renal vein into the inferior vena cava (IVC), and then it can extend intraluminally with subsequent tumor-thrombus formation. Here we report a case involving excision of a primary RCC with tumor-thrombus involving IVC up to right atrium with the use of extracorporeal circulation. Single stage surgical procedure was performed in collaboration with a urological team aiming complete resection of primary tumor, para-aortic lymphadenectomy and removal of IVC thrombus extending to right atrium with the help of cardiopulmonary bypass. After arresting heart, RA was opened and the mass was removed through RA from IVC and hepatic vein level. Abdominal IVC was opened and the entire residual mass was removed from below also small amount of thrombus removed from left renal vein. Postoperative venous doppler showed no residual thrombus in venous system. Histopathology report confirmed papillary renal cell carcinoma. The patient was discharged from hospital in the 12th post-operative day without any complication.J Bangladesh Coll Phys Surg 2018; 36(2): 77-79

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Direct Comparison of Metastasis-Related miRNAs Expression Levels in Circulating Tumor Cells, Corresponding Plasma, and Primary Tumors of Breast Cancer Patients

Clinical Chemistry ◽

10.1373/clinchem.2015.253716 ◽

2016 ◽

Vol 62 (7) ◽

pp. 1002-1011 ◽

Cited By ~ 30

Author(s):

Athina Markou ◽

Martha Zavridou ◽

Ioanna Sourvinou ◽

George Yousef ◽

Sofia Kounelis ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Tumor Cells ◽

Peripheral Blood ◽

Breast Tumors ◽

Breast Cancer Patients ◽

Healthy Individuals ◽

Primary Tumors ◽

Expression Levels ◽

Breast Tissues

Abstract BACKGROUND Circulating tumor cells (CTCs) and microRNAs (miRNAs) are important in liquid biopsies in which peripheral blood is used to characterize the evolution of solid tumors. We evaluated the expression levels of miR-21, miR-146a, miR-200c, and miR-210 in CTCs of breast cancer patients with verified metastasis and compared their expression levels in corresponding plasma and primary tumors. METHODS Expression levels of the miRNAs were quantified by quantitative reverse transcription PCR (RT-qPCR) in (a) 89 primary breast tumors and 30 noncancerous breast tissues and (b) CTCs and corresponding plasma of 55 patients with metastatic breast cancer and 20 healthy donors. For 30 of these patients, CTCs, corresponding plasma, and primary tumor tissues were available. RESULTS In formalin-fixed, paraffin-embedded tissues, these miRNAs were differentially expressed between primary breast tumors and noncancerous breast tissues. miR-21 (P < 0.001) and miR-146a (P = 0.001) were overexpressed, whereas miR-200c (P = 0.004) and miR-210 (P = 0.002) were underexpressed. In multivariate analysis, miR-146a overexpression was significantly [hazard ratio 2.969 (1.231–7.157), P = 0.015] associated with progression-free survival. In peripheral blood, all miRNAs studied were overexpressed in both CTC and corresponding plasma. There was a significant association between miR-21 expression levels in CTCs and plasma for 36 of 55 samples (P = 0.008). In plasma, ROC curve analysis revealed that miR-21, miR-146a, and miR-210 could discriminate patients from healthy individuals. CONCLUSIONS Metastasis-related miRNAs are overexpressed in CTCs and corresponding plasma; miR-21 expression levels highly correlate in CTCs and plasma; and miR-21, miR-146a, and miR-210 are valuable plasma biomarkers for discriminating patients from healthy individuals.

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Estrogen receptor (ER) status of disseminated tumor cells in the bone marrow of breast cancer patients

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.21013 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 21013-21013

Author(s):

F. N. Tanja ◽

N. Krawczyk ◽

D. Wallwiener ◽

S. Becker ◽

E. Solomayer

Keyword(s):

Breast Cancer ◽

Bone Marrow ◽

Cancer Patients ◽

Tumor Cells ◽

Primary Tumor ◽

Hormone Receptor ◽

Primary Breast Cancer ◽

Disseminated Tumor Cells ◽

Breast Cancer Patients ◽

Primary Tumors

21013 Background: The presence of disseminated tumor cells (DTC) in bone marrow (BM) of primary breast cancer patients is associated with poor prognosis. These patients may benefit from adjuvant endocrine therapy since cytotoxic agents are not able to completely eliminate DTCs as previously shown. Only patients with hormone receptor positive breast cancer are eligible for hormonal treatment. The ERa status is routinely defined in primary tumor tissue. However, the ERa status of DTC may differ compared to the primary tumor. Therefore, the aims of this study were (1) to determine the ERa status of DTC in BM of breast cancer patients, (2) and to compare the ERa status of DTC and corresponding primary tumors. Methods: BM aspirates from 251 primary breast cancer patients were included into the study. A double immunofluorescence staining procedure was established for the identification of cytokeratin-positive (CK)/ERa positive cells. ERa status of the primary tumor was immunohistochemically assessed using the same antibody against ERa. Results: In 105 of 251 (42%) breast cancer patients CK-positive cells could be detected in BM. The number of detected cells ranged between 1 and 13 / cells per 2*106 mononuclear cells. Disseminated tumor cells demonstrated ERa positivity in 13 (12%) of these 105 patients. The ERa expression on DTC was heterogeneous in 10 of 13 (79%) patients. Concordance rate of ERa status between primary tumor and DTC was 27%. Only 11 of 83 patients with ER a positive tumors had also ERa positives DTC. Conclusions: (1)The hormone receptor status between primary tumor and corresponding DTC is disconcordant. (2)This discrepancy may explain the rate of non-responders to adjuvant endocrine therapy despite ER-positive primary tumors. (3)These patients may benefit from adjuvant therapy regimens based on antibody strategies or bisphosphonates. No significant financial relationships to disclose.

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PD-L1 expression in primary clear cell renal cell carcinomas (ccRCCs) and their metastases.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.4_suppl.467 ◽

2014 ◽

Vol 32 (4_suppl) ◽

pp. 467-467 ◽

Cited By ~ 8

Author(s):

Marcella Callea ◽

Elizabeth M Genega ◽

Mamta Gupta ◽

André P Fay ◽

Jiaxi Song ◽

...

Keyword(s):

Tumor Cells ◽

Primary Tumor ◽

Clear Cell ◽

Predictive Biomarkers ◽

Primary Tumors ◽

Metastatic Lesions ◽

Formalin Fixed Paraffin ◽

Formalin Fixed Paraffin Embedded ◽

Membranous Staining ◽

Formalin Fixed

467 Background: Clinical trials evaluating anti-PD-1 and anti-PD-L1 antibodies (Abs) in ccRCC have shown promising efficacy in a subset of patients. Preliminary studies have demonstrated that tumor PD-L1 expression increases the likelihood of benefit with anti-PD-1 Ab, but fails to identify all responders. One potential explanation for these results is that predictive biomarkers are usually evaluated in the primary tumors, which are more readily available; however, biomarker expression in nephrectomy samples may not accurately reflect expression in the metastases that are being targeted by therapy. In this study, we compared PD-L1 expression in a series of ccRCCs and their metastases. Methods: Formalin-fixed paraffin-embedded (FFPE) tissue blocks from 34 primary ccRCCs and corresponding metastases were retrieved. Multiple areas of the primary tumors, including areas of predominant and highest Fuhrman nuclear grade (FNG), were selected for analysis. Slides were immunostained with a mouse monoclonal anti-PD-L1 antibody (405.9A11). The assay was validated using FFPE cell line controls known to be positive or negative for PD-L1 expression by flow cytometry. The presence of tumor cells with membranous staining was assessed. A case was considered positive when any tumor cell positivity was detected. Results: Positive membranous PD-L1 expression in tumor cells was observed in 10/34 (29%) primary ccRCCs. In 3 of these 10 cases (30%), the metastases were negative. In 2 cases the primary tumor was negative but the metastases were positive. In twenty-two cases, both the primary tumor and the corresponding metastasis were negative. The pattern of PD-L1 staining was highly heterogeneous in the primary tumors and was restricted to areas of highest FNG. The staining was more homogeneous in the metastases. PD-L1 expression by the tumor infiltrating immune cells is currently being evaluated. Conclusions: Discordant expression of PD-L1 between the primary tumor and the corresponding metastases was detected in 5/34 (15%) cases, suggesting that accurate assessment of predictive biomarkers for PD-1 blockade in ccRCC might require analysis of metastatic lesions. Analysis of a larger patient cohort is ongoing to confirm these findings.

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FGFR2 expression to predict survival outcome in patients with metastatic papillary renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.2_suppl.506 ◽

2016 ◽

Vol 34 (2_suppl) ◽

pp. 506-506 ◽

Cited By ~ 3

Author(s):

Ilya Tsimafeyeu ◽

Alexandra Naumova ◽

Evgenia Stepanova ◽

Alfia Khasanova ◽

Ilya Varlamov ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Tumor Cells ◽

Renal Cell ◽

Objective Response ◽

Progression Free Survival ◽

Papillary Renal Cell Carcinoma ◽

Survival Outcome ◽

Primary Tumors ◽

Metastatic Sites

506 Background: In our previous study we showed that fibroblast growth factor receptor 2 (FGFR2) mutations are rare across papillary types of renal cell carcinoma (pRCC). The aim of the present study is to test FGFR2 expression for association with survival outcome in the largest patient cohort to date. Methods: Formalin-fixed, paraffin-embedded specimens of removed primary tumors from 214 untreated metastatic pRCC patients were evaluated by immunohistochemistry with FGFR2 antibody (Santa Cruz Biotechnology). Expression was quantified by consensus of two independent observers using a four-value intensity score (0, 1+, 2+, and 3+) and the percentage (0-100%) of the extent of reactivity. Expression was scored according to the percentage of positive cells present among all tumor cells in the section. The cytoplasmic and nuclear expression score was obtained by multiplying the intensity and reactivity extension values (range, 0-300). FGFR2 expression was tested for associations with progression-free survival (PFS), overall survival (OS) and best objective response. Results: Expression of FGFR2 was observed in 23% (49/214) of primary pRCC, mostly in cytoplasm of tumor cells. 2 of 214 (1%) patients had nuclear FGFR2 expression. Intensity was 3+ in all cases. Expression of FGFR2 was significant lower in the normal tissue of kidney (1%, P=0.001). FGFR2 expression was strongly associated with a number of metastatic sites (2 and more metastatic sites vs. 0-1), type 2 of pRCC, lower nucleolar grade (P<0.001). FGFR2-positive patients had significantly shorter OS and PFS in first-line therapy (P<0.05; Table). On multivariate analysis, FGFR2 expression, MSKCC risk group, and type of pRCC were found to be independent predictors of survival. Conclusions: In this study, we described immunohistochemical expression of FGFR2 in a large series of pRCC specimens. FGFR2 expression was found to be prognostic factor for survival in patients with metastatic pRCC. Clinical trial information: rosoncoweb2011. [Table: see text]

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Features of tumor heterogeneity in regional metastasis of breast cancer

Kazan medical journal ◽

10.17816/kmj2021-716 ◽

2021 ◽

Vol 102 (5) ◽

pp. 716-725

Author(s):

K K Konyshev ◽

S V Sazonov

Keyword(s):

Breast Cancer ◽

Tumor Cells ◽

Primary Tumor ◽

Tumor Heterogeneity ◽

Tumor Tissue ◽

Clonal Evolution ◽

Clinical Manifestations ◽

Progesterone Receptors ◽

Primary Tumors ◽

Regional Metastases

The review looked at the issues of tumor heterogeneity in breast cancer. Tumor heterogeneity is classified according to the main feature demonstrating regional differences within a tumor (for example, heterogeneity of clinical manifestations, histological heterogeneity, heterogeneity of protein expression, etc.) and by tumor regions (differences between primary tumors and metastases, differences between cell clones within a single tumor node, etc.). Temporal heterogeneity is also distinguished, which manifests itself in the clonal evolution of tumor cells. The review covers the heterogeneity in the expression of four biomarkers from the gold standard for immunohistochemical staining of breast cancer: estrogen receptors, progesterone receptors, Her2/neu and Ki67 in primary tumor tissue and regional metastases. According to various studies, discordance in estrogen receptor status of primary tumor cells and metastases was observed with a frequency of 4 to 62%, progesterone receptors from 12 to 54%, Her2/neu from 0 to 24%, Ki67 from 4 to 39%. The results of studies of changes in the expression levels of individual markers in breast cancer metastases, as well as the heterogeneity of surrogate subtypes of tumor tissue in metastasis, are briefly described. Possible reasons for heterogeneity in the expression of key prognostic and predictive markers by primary tumor and metastatic cells, such as artificial factors at the preanalytic and analytic stages of the study, polyclonality of the primary tumor before metastasis, clonal evolution of tumor cells during metastasis, selection of tumor clones under the therapy are highlighted.

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Comprehensive Genomic Profiling of Pediatric Therapy-Related Myeloid Neoplasms Identifies Mecom Dysregulation to be Associated with Poor Outcome

Blood ◽

10.1182/blood-2019-128665 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1394-1394

Author(s):

Jason R Schwartz ◽

Jing Ma ◽

Michael P Walsh ◽

Xiaolong Chen ◽

Tamara Lamprecht ◽

...

Keyword(s):

Primary Tumor ◽

Lymphoblastic Leukemia ◽

Hematopoietic Cells ◽

Fusion Partner ◽

Genomic Profile ◽

Complex Karyotype ◽

Rna Seq ◽

Primary Tumors ◽

Expression Levels ◽

Myeloid Neoplasms

Therapy-related myeloid neoplasms (tMN) occur in children secondary to cytotoxic therapies used to treat pediatric malignancies, are typically resistant to conventional chemotherapy, require hematopoietic cell transplantation as the only curative option, and have a dismal prognosis. The genomic alterations that drive tMN in children have yet to be comprehensively described, and it is unclear if particular genomic lesions hold prognostic value. We have characterized the genomic profile of 62 pediatric tMN cases (tMDS: n=23, tAML: n=39) obtained from the St. Jude Children's Research Hospital Tissue Bank from patients diagnosed between 1987 and 2018. These cases arose following treatment for a variety of primary tumors (hematological (74%), bone and soft tissue (23%), and brain (3%)). Acute lymphoblastic leukemia was the most frequent primary tumor (n=39, 63%). Conventional cytogenetics (n=60) showed a complex karyotype (≥3 structural alterations) in 19 (32%) cases, and 7 of these cases contained a deletion involving chromosome 7 (del(7)). Eleven (18%) other cases without complex karyotypes had del(7). Deletions of chromosome 5 were present in 9 (15%) cases, but only in the context of a complex karyotype. We hypothesized that the patients' younger age and the different spectrum of primary tumor types and chemotherapy would give rise to a mutational spectrum distinct from adult tMN. We used whole exome (WES), whole genome (WGS), and RNA sequencing (RNA Seq) to describe the mutational profile of our pediatric tMN cohort. WES was completed for 58 tumor/normal pairs using Nextera Rapid Capture Expanded Exome (Illumina). Fifteen cases were analyzed by WGS (11 also had WES). Normal comparator genomic DNA was obtained from flow-sorted lymphocytes. An average of 21 coding variants/patient (range: 1-131) was observed from the gene-coding region, and these include synonymous, non-synonymous, and splice site variants. Ras/MAPK pathway mutations were present in 44% of the cases (43 mutations in 27 cases). Canonical KRAS (n = 16), NF1 (n = 10), and NRAS (n = 7) mutations were the most frequent coding mutations. Eleven (18%) patients had either heterozygous deletion or a copy neutral loss of heterozygosity event involving chromosome 17p and the TP53 locus; 5 of these cases had concurrent TP53 missense mutations identified at allele frequencies near 100%. Unlike tMN in adults, mutations in PPM1D were not identified. RNA-Seq completed on 56 evaluable cases identified 28 (50%) cases with KMT2A rearrangement (KMT2Ar). MLLT3 was the most common fusion partner (n=13, 46%). In addition to KMT2A rearrangements, RNA-Seq also identified a RUNX1-MECOM fusion. Alterations involving the MECOM locus have been described in some myeloid neoplasms like tMN, and its overexpression is associated with a poor prognosis and some AMLs with KMT2Ar. MECOM expression levels were variable in this cohort (FPKM range: 0.004 - 38.4) with 24 cases (43%) having an FPKM>5 (MECOMHigh). In addition to the RUNX1-MECOM event, these 24 MECOMHigh cases included 18 with KMT2Ar (64% of KMT2Ar group) and 1 with a NUP98 fusion (NUP98-HHEX). The remaining 4 MECOMHigh cases demonstrate allele-specific MECOM expression, suggesting a cis-regulatory element is driving this expression. Two of these 4 cases have WGS and were found to contain a t(2;3)(p21;q26.2) involving MECOM on chromosome 3 and noncoding regions of chromosome 2 adjacent to ZFP36L2, a gene highly expressed in hematopoietic cells. ENCODE data supports that this region of the genome is an active enhancer in hematopoietic cells, suggesting a proximity effect in which this enhancer has been hijacked to drive high levels of MECOM expression. In our cohort, MECOM expression levels are predictive of a worse outcome (overall survival (OS) at 2 years: High=14.6% vs. Low=46.3%; log rank p<0.01). Although KMT2Ar was frequently present in our cohort and enriched in the MECOMHigh group (High=75% (18/24) vs. Low=31% (10/32); p<0.01), high MECOM expression did not confer a significant survival difference within the KMT2Ar group (OS at 2 years: High=16.7% vs Low=40%; log rank p=0.33). Further, the presence of a KMT2Ar or a complex karyotype did not significantly affect the OS in this cohort. In conclusion, we report the genomic profile of a large cohort of pediatric tMN cases and show that high levels of MECOM expression, a portion of which is driven by enhancer hijacking, predicts a worse outcome. Disclosures Gruber: Bristol-Myers Squibb: Consultancy.

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Markers of a metastatic niche in the omentum in ovarian cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e18081 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e18081-e18081

Author(s):

Tatiana I. Moiseenko ◽

Elena M. Frantsiyants ◽

Irina V. Kaplieva ◽

Valeria A. Bandovkina ◽

Natalia D. Cheryarina ◽

...

Keyword(s):

Ovarian Cancer ◽

Growth Factors ◽

Tumor Cells ◽

Comparison Group ◽

Metastatic Tumor ◽

Main Group ◽

Control Group ◽

Metastatic Niche ◽

Primary Tumors ◽

Igf I

e18081 Background: Ovarian cancer spreads intraperitoneally due to the interaction of tumor cells and the omental mesothelium, creating a metastatic niche and supporting elements of cancer cell expansion such as adhesion, proliferation, migration, and neoangiogenesis. The purpose of the study was to analyze levels of VEGFA, IGF-I, IGF-II and TGFβ1 in omental tissues in ovarian cancer (OC). Methods: The main group included 23 patients with metastatic OC T3-4аN0-3M1; the comparison group – 21 patients with non-metastatic OC T3-4аN0-3M0; the control group – 19 non-cancer patients. Levels of VEGFA, IGF-I, IGF-II and TGFβ1 were measured by standard ELISA methods in tissues of primary tumors and the omentum. Results: Levels of growth factors in the comparison group were not elevated compared to control values. Growth factors in omental tissues in the main group were increased compared to control values: VEGFA – by 2.5 times, IGF-I – by 3.4 times, IGF-II – by 2.5 times, TGFβ1 - by 3.1 times. In the comparison group, the levels in omental tissues were lower than in the main group: VEGFA – by 1.7 times (p < 0.05), IGF-I – by 2.1 times, IGF-II – by 1.6 times (p < 0.05); TGFβ1 did not differ from the levels in the main group. Conclusions: Higher expression of VEGFА in the omentum with metastases can be considered a significant factor in the formation of signaling pathways between metastatic tumor cells and local non-cancer cells. IGF-I and IGF-II trigger the endothelial growth factor. The TGFβ1 activation in the omentum in metastatic ovarian cancer is necessary for the paracrine induction and transition of disseminated tumor and/or stem cells from the "sleeping" to the active state.

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