Prognostic Implications Of PRAME Expression Levels In Myelodysplastic Syndromes

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2814-2814
Author(s):  
Masayuki Shiseki ◽  
Mayuko Ishii ◽  
Kenjiro Mitsuhashi ◽  
Norina Tanaka ◽  
Kentaro Yoshinaga ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Clinical Outcomes ◽  
Clinical Significance ◽  
Myelodysplastic Syndromes ◽  
Biological Significance ◽  
High Expression ◽  
Expression Level ◽  
High Expression Group ◽  
Low Expression

Abstract The preferentially expressed antigen of the melanoma (PRAME) gene was first identified in melanoma tissue as a tumour-associated antigen recognized by autologous cytotoxic T cells against a melanoma surface antigen. While expression level of PRAME is quite low in most of normal tissues of human, including bone marrow normal CD34+ cells, except for testis, PRAME overexpression is observed in various human cancers, including hematological malignant disorders. Although clinical and biological significance of PRAME expression in human cancers has not been fully elucidated, it has been demonstrated that high PRAME expression is associated poor clinical outcomes in a number of solid cancers. Association between PRAME expression and clinical outcomes in hematological malignancies has not been clarified. In acute myeloid leukemia, high expression of PRAME was shown to be associated with worse progression-free survival or overall survival by some research groups but not by other groups. Our previous study demonstrated that inhibition of PRAME expression in leukemic cells results in cell cycle arrest and induction of apoptosis, suggesting oncogenic function of PRAME expression in leukemogenesis. Clinical significance of PRAME expression in myelodysplastic syndromes (MDS) also has not been fully elucidated. In the present study, we examined PRAME expression of bone marrow cells in MDS patients to clarify clinical significance of PRAME expression. Bone marrow samples of MDS patients were used for analysis. Samples were taken at the time of diagnosis with written informed consent from patients. Total RNA extraction, cDNA synthesis and quantitative real-time RT-PCR by the TaqMan probe method using an ABI 7500 real-time PCR system (Applied Biosystems) with co-amplification of the endogenous control gene, human GAPDH (Applied Biosystems), were performed. Expression levels were obtained using the standard curve method in each experiment, after normalization with the GAPDH gene for each sample in duplicate wells. The human PRAME primer-probe sets were from Applied Biosystems (assay ID: Hs00196132_m1). Data including patients’ demographic, disease status, medical history, clinical and laboratory findings, and outcome, were collected from medical records and laboratory data base. A total of 111 MDS patients, 68 males and 43 females with median age of 69 years (range: 20-91 years) were included in the present study. They were classified as RCUD (n=15), RCMD (n=61), RARS (n=8), RAEB-1 (n=15), and RAEB-2 (n=12) according to WHO classification. Based on the IPSS, they were categorized in four risk groups, low risk (n=29), intermediate-1 risk (n=55), intermediate-2 risk (n=23), and high risk(n=4). Expression level of PRAME was varied among the MDS patients analyzed. Median value of relative PRAME expression level of 111 MDS patients and that of 19 control subjects were 0.073 and 0.07, and there was no significant difference in distribution of expression level of PRAME. However, when we compared expression patterns of PRAME among five WHO-subtypes, statistical difference was observed (P=0.0116). Relative PRAME expression level in WHO-subtypes with high blast counts (RAEB-1 and RAEB-2) was significantly higher than that in WHO-subtypes with less blast counts (RCUD, RCMD, RARS) (median value: 0.44 vs. 0.05, P=0.0012). To investigate prognostic implication of PRAME expression in MDS, we analyzed impact of PRAME expression on overall survival (OS). Based on PRAME expression level, 111 patients were divided into two categories, ‘high expression group’ (above median value) and ‘low expression group’ (below median value). Kaplan-Meier analysis demonstrated that high expression group showed significantly poorer overall survival than low expression group (P=0.0165). The estimated 5-year OS rates in high expression group and low expression group were 63.5% and 78.4%, respectively. The present study demonstrated that high PRAME expression is associated with poorer clinical outcome, indicating that PRAME expression could be a useful prognostic marker in MDS. Biological significance of PRAME expression in MDS is unclear. Expression level of PRAME was higher in WHO-subtypes with high blasts counts, suggesting that PRAME may play role in disease progression in MDS. Further studies should be necessary to clarify clinicopathological and biological significance of PRAME expression in MDS. Disclosures: No relevant conflicts of interest to declare.

Action of SDF-1/CXCR4 axis in liver metastasis of colorectal cancer.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 530-530 ◽  
Author(s):  
Shinichiro Yamada ◽  
Mitsuo Shimada ◽  
Toru Utsunomiya ◽  
Satoru Imura ◽  
Yuji Morine ◽  
...  
Keyword(s):  
Liver Metastasis ◽  
Colorectal Liver Metastasis ◽  
Normal Liver ◽  
High Expression ◽  
Expression Level ◽  
Expression Levels ◽  
High Expression Group ◽  
Cxcr4 Axis ◽  
Low Expression ◽  
Liver Tissues

530 Background: It has recently been suggested that the SDF-1/CXCR4 axis is involved in tumor progression, angiogenesis, metastasis, and survival in various cancer. In this study, we investigate the possible role of SDF-1/CXCR4 axis in colorectal liver metastasis. Methods: Both primary colorectal tumors and liver metastatic tumors were obtained from 12 patients with colorectal liver metastasis. Expression levels of CXCR4 and SDF-1 were determined using RT-PCR. In 4 patients with benign liver disease, the expression level of SDF-1 in normal liver tissues was also determined. We divided the 12 patients into two groups; high expression group (n=6) and low expression group (n=6) according to each expression level of SDF-1 and CXCR4, and compared the clinicopathological factors between the two groups. Results: 1. CXCR4 expression levels in primary tumor: The frequency of the peritoneal dissemination in the CXCR4 high expression group was higher than in the low expression group (p=0.07). Moreover, overall survival rate in the CXCR4 high expression group was significantly lower than that in the low expression group (3 year-survival rate: 67% vs. 100%, p<0.05). 2. CXCR4 in metastatic tumor tissues and SDF-1 in non-tumor liver tissues: The expression level of SDF-1 in non-tumor liver tissues was significantly higher than that in normal liver tissues (p<0.01). A significant correlation between the CXCR4 expression levels in metastatic tumor tissues and SDF-1 expression levels of non-tumor liver tissues (p<0.05). The number of metastatic liver tumors in the SDF-1 high expression group tended to be larger than that in the low expression group (p=0.12). Conclusions: The present data suggest that there is a significant association of the SDF-1/CXCR4 axis with enhanced liver metastasis and poor prognosis of the patients with colorectal liver metastasis. Furthermore, an enhanced expression of SDF-1 in non-tumor liver tissues may have an important role in the formation of liver metastasis.

scholarly journals Prognostic significance of esterase gene expression in multiple myeloma

2021 ◽  
Author(s):  
Romika Kumari ◽  
Muntasir Mamun Majumder ◽  
Juha Lievonen ◽  
Raija Silvennoinen ◽  
Pekka Anttila ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Prognostic Markers ◽  
Prognostic Significance ◽  
Genomic Variation ◽  
High Expression ◽  
Genetic Profile ◽  
Esterase Gene ◽  
Low Expression

Abstract Background Esterase enzymes differ in substrate specificity and biological function and may display dysregulated expression in cancer. This study evaluated the biological significance of esterase expression in multiple myeloma (MM). Methods For gene expression profiling and evaluation of genomic variants in the Institute for Molecular Medicine Finland (FIMM) cohort, bone marrow aspirates were obtained from patients with newly diagnosed MM (NDMM) or relapsed/refractory MM (RRMM). CD138+ plasma cells were enriched and used for RNA sequencing and analysis, and to evaluate genomic variation. The Multiple Myeloma Research Foundation (MMRF) Relating Clinical Outcomes in MM to Personal Assessment of Genetic Profile (CoMMpass) dataset was used for validation of the findings from FIMM. Results MM patients (NDMM, n = 56; RRMM, n = 78) provided 171 bone marrow aspirates (NDMM, n = 56; RRMM, n = 115). Specific esterases exhibited relatively high or low expression in MM, and expression of specific esterases (UCHL5, SIAE, ESD, PAFAH1B3, PNPLA4 and PON1) was significantly altered on progression from NDMM to RRMM. High expression of OVCA2, PAFAH1B3, SIAE and USP4, and low expression of PCED1B, were identified as poor prognostic markers (P < 0.05). The MMRF CoMMpass dataset provided validation that higher expression of PAFAH1B3 and SIAE, and lower expression of PCED1B, were associated with poor prognosis. Conclusions Esterase gene expression levels change as patients progress from NDMM to RRMM. High expression of OVCA2, PAFAH1B3, USP4 and SIAE, and low expression of PCED1B, are poor prognostic markers in MM, suggesting a role for these esterases in myeloma biology.

The Clinicopathological Significance and Prognostic Value of Obg-Like Atpase 1 (OLA1) in Gastric Cancer

2021 ◽  
Author(s):  
Juan Wang ◽  
Zihan Zheng ◽  
Qinghua Cao ◽  
Xiufen Liu ◽  
Zhiqing Wang
Keyword(s):  
Gastric Cancer ◽  
Overall Survival ◽  
Cancer Patients ◽  
Prognostic Value ◽  
Biological Significance ◽  
High Expression ◽  
Cancer Tissue ◽  
Cox Regression Analysis ◽  
Gastric Cancer Patients ◽  
Cancer Tissues

Abstract Backgroud Obg-like ATPase 1 (OLA1) is a member of the Obg family of P-loop NTPases and has recently been detected in several human cancer cells. However, its expression type and clinical relevance in gastric cancer remains unclear. Methods In the present study, 2 datasets downloaded from the open Gene Expression Omnibus database were used to evaluate the mRNA level of OLA1 in gastric cancer. Quantitative Reverse Transcription PCR further validated the mRNA expression in gastric cancer tissues. Immunohistochemistry was performed on gastric cancer tissue microarray to assess OLA1 protein expression type, prognostic value, biological significance and its association with Snail in 334 patients of gastric cancer. The prognostic value of combination of OLA1 and Snail has been evaluated. Results The results showed that OLA1 mRNA and protein were elevated in gastric cancer tissues. High expression of OLA1 was significantly associated with aggressive features, such as tumor size, lymph node metastasis and TNM stage (P = 0.0146, P = 0.0037, P < 0.001, respectively). Moreover, high levels of OLA1 predicted worse overall survival. Multivariate Cox regression analysis indicated that high expression of OLA1 was an independent prognostic factor for poor overall survival (hazard ratio, 0.573; 95% confidence interval, 0.376–0.872; P = 0.009). Additionally, OLA1 expression was positively correlated with Snail, and combination of them revealed improved prognostic accuracy for gastric cancer patients. Conclusions Our results suggested that OLA1 high expression was considered as an independent factor for the prediction of unfavorable prognosis in gastric cancer patients, and we believe that OLA1 could serve as a biomarker of poor prognosis and a novel target in treating gastric cancers.

The effect of miRNAs and MALAT1 related with the prognosis of Her-2 positive breast cancer patients with lymph node metastasis

2020 ◽  
Author(s):  
Zhao Hongcan ◽  
Yang Hongjian ◽  
Zhang Xiping
Keyword(s):  
Lymph Node ◽  
Lymph Node Metastasis ◽  
Lymph Nodes ◽  
High Expression ◽  
Expression Level ◽  
Lymph Nodes Metastasis ◽  
Node Metastasis ◽  
Her 2 ◽  
Proliferation And Invasion ◽  
Low Expression

Abstract Background: To analyze and screen the miRNAs associated with lymph node metastasis of breast cancer (BC), and to explore the roles of these miRNAs in the proliferation, invasion and prognosis of BC. Methods: MicroRNAs associated with lymph node metastasis in Her-2 positive BC was screened by TCGA database. The qRT-PCR was used to verify theses 5 miRNAs in 30 cases of Her-2 positive BC with lymph node metastasis of different degree. The tumor tissue samples were divided into non-lymph node metastasis group, ≤ 3 lymph node metastasis group and > 3 lymph node metastasis group. In addition, 10 cases of paracancerous tissues were considered as paracancerous control group. Pearson correlation analysis was used to analysis the relationship of 5 miRNAs and MALAT1 with Her-2 positive BC patients' clinicopathological characteristics and prognosis. CCK8 and Transwell experiments were used to detect the effects of miR-143 and miR-455 on the proliferation and invasion of Her-2 positive BC cells (MDA-MB-453). Results: Five kinds of miRNA (miR-143, miR-196a, miR-455, miR-9 and miR-92a) related with Her-2 positive BC with lymph node metastasis were screened by TCGA database. The detecting results of qRT-PCR showed that the levels of miR-143, miR-196a, miR-9 and MALAT1 increased with the increased number of lymph nodes. The expression level of miR-143 in the group of ≤ 3 lymph nodes metastasis and > 3 lymph nodes metastasis was significantly higher than that in the group of non-lymph nodes metastasis (P<0.001), and that in the group of > 3 lymph nodes metastasis was significantly higher than that in the group of ≤ 3 lymph nodes metastasis (P<0.001). The expression level of miR-196a in the group of ≤ 3 lymph nodes metastasis and > 3 lymph nodes metastasis was significantly higher than that in the group of non-lymph nodes metastasis (P<0.001), and that in the group of > 3 lymph nodes metastasis was significantly higher than that in the group of ≤ 3 lymph nodes metastasis (P<0.001). The expression level of miR-455 in the group of ≤ 3 lymph nodes metastasis and > 3 lymph nodes metastasis was significantly lower than that in the group of non-lymph nodes metastasis (P<0.001), and that in the group of > 3 lymph nodes metastasis was significantly lower than that in the group of ≤ 3 lymph nodes metastasis (P<0.001). The expression level of MALAT1 in the group of ≤ 3 lymph nodes metastasis and > 3 lymph nodes metastasis was significantly higher than that in the group of non-lymph nodes metastasis (P<0.001), and that in the group of > 3 lymph nodes metastasis was significantly higher than that in the group of ≤ 3 lymph nodes metastasis (P<0.01). Pearson correlation analysis showed that the expression levels of miR-455-5p, miR-196a-5p and MALAT1 were negatively correlated, positively correlated and positively correlated with the pathological stages of Her-2 positive BC, respectively. The results of survival analysis showed that RFS of patients with high expression of miR-196a, miR-92a and MALAT1 was significantly lower than that of patients with low expression (P<0.05), and OS and RFS of patients with high expression of miR-9 were significantly lower than those of patients with low expression, while OS and RFS of patients with high expression of miR-455 were significantly higher than those of patients with low expression (P<0.05). Cytological experiments showed that up regulation of miR-455 significantly inhibited the proliferation and invasion of BC cells, while down regulation of miR-143 significantly inhibited the proliferation and invasion of BC cells and the expression of MALAT1 (P<0.05). Conclusion: High expression of miR-143, miR-9, miR-196a, MALAT1 and low expression of miR-455 are related to the degree of lymph node metastasis of Her-2-positive BC patients, indicating poor prognosis. Down-regulation of miR-455 and up-regulation of miR-143 and MALAT1 can promote the cell proliferation and invasion of Her-2-positive BC.

scholarly journals Clinical significance ofTFR2andEPORexpression in bone marrow cells in myelodysplastic syndromes

2016 ◽  
Vol 176 (3) ◽  
pp. 491-495 ◽  
Author(s):  
Augusta Di Savino ◽  
Valentina Gaidano ◽  
Antonietta Palmieri ◽  
Francesca Crasto ◽  
Alessandro Volpengo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Significance ◽  
Myelodysplastic Syndromes ◽  
Bone Marrow Cells ◽  
Marrow Cells

scholarly journals Prognostic roles of microRNA 143 and microRNA 145 in colorectal cancer: A meta-analysis

2019 ◽  
Vol 34 (1) ◽  
pp. 6-14 ◽  
Author(s):  
Chenyao Li ◽  
Guoqiang Yan ◽  
Libin Yin ◽  
Tao Liu ◽  
Chao Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Cancer Patients ◽  
Hazard Ratio ◽  
High Expression ◽  
Cochrane Library ◽  
Event Free Survival ◽  
Free Survival ◽  
High Event ◽  
Low Expression

Background: A systematic analysis was conducted to clarify the relationship between miR-143/145 and the prognosis of colorectal cancer. Materials and methods: We searched four databases: PubMed, EMBASE, Web of Science, and the Cochrane Library. We extracted and estimated the hazard ratios for survival outcomes, which compared low and high expression levels of miR-143/145 in colorectal cancer patients in the available studies. Each individual hazard ratio was used to calculate the pooled hazard ratio. Results: A total of 17 articles including 5128 patients were ultimately included. The results showed that there was no significant difference between low expression and high expression of miR-143 in the overall survival of colon cancer patients. However, low expression of miR-143 was significantly associated with high event-free survival (hazard ratio (HR) 0.6; 95% confidence interval (CI) 0.40, 0.88). Low expression of miR-145 was associated with poor prognosis of patients (HR 1.92; 95% CI 1.45, 2.54); those with low expression of miR-145 were at 1.92-fold higher risk for short-term overall survival than those with high expression of miR-145. MiR-145 was an unfavorable factor for the prognosis of colorectal cancer. There were no significant differences between low expression of miR-145 and high expression of miR-143 in event-free survival. Conclusion: miR-143 and miR-145 have promising prognostic value for colorectal cancer. Low expression of miR-143 can predict high event-free survival, and low expression of miR-145 can predict poor overall survival.

Clinical Relevance of Bone Marrow Fibrosis and CD34-Positive Cell Clusters in Primary Myelodysplastic Syndromes

2009 ◽  
Vol 27 (5) ◽  
pp. 754-762 ◽  
Author(s):  
Matteo Giovanni Della Porta ◽  
Luca Malcovati ◽  
Emanuela Boveri ◽  
Erica Travaglino ◽  
Daniela Pietra ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Myelodysplastic Syndromes ◽  
Scoring System ◽  
Transfusion Requirement ◽  
Free Survival ◽  
Cell Clusters ◽  
Multilineage Dysplasia ◽  
Poor Risk ◽  
Marrow Fibrosis

Purpose We studied bone marrow (BM) histologic abnormalities in myelodysplastic syndromes (MDS) classified according to WHO criteria to determine their clinical correlates and prognostic value. Patients and Methods Three hundred one consecutive patients were retrospectively evaluated for BM fibrosis and CD34 immunoreactivity. Marrow fibrosis was assessed following the European consensus guidelines. Results Moderate to severe BM fibrosis was detected in 17% of cases and was associated with multilineage dysplasia (P = .001), high transfusion requirement (P < .001), and poor-risk cytogenetics (P = .007). CD34+ cell clusters were found in 23% of patients and were associated with WHO categories with excess of blasts (P < .001) and poor-risk cytogenetics (P = .001). In multivariable analysis, BM fibrosis and presence of CD34+ cell clusters had independent negative impact on overall survival (P < .001 and P = .019, respectively) and leukemia-free survival (P < .001 and P = .004, respectively). A hierarchical clustering analysis identified three subsets of patients with distinct clinical features. One cluster consisted mainly of patients with BM fibrosis, multilineage dysplasia, and high transfusion requirement; these individuals had lower overall survival and leukemia-free survival (P = .001 and P < .001, respectively). Within patients stratified according to International Prognostic Scoring System and WHO classification–based Prognostic Scoring System categories, BM fibrosis involved a shift to a one-step more advanced risk group. Conclusion BM fibrosis identifies a distinct subgroup of MDS with multilineage dysplasia, high transfusion requirement, and poor prognosis and represents an independent prognostic factor that may be useful in clinical decision making. Furthermore, the presence of CD34+ cell clusters is an independent risk factor for progression to acute leukemia.

Molecular Mechanism Of Regulation Of Extramedullary Infiltration In AML1/ETO Positive Acute Myeloid Leukemia By APP/ERK/MMP-2

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3769-3769
Author(s):  
Guopan Yu ◽  
Fan Yi Meng ◽  
Ling Jiang ◽  
Changxin Yin ◽  
Zhixiang Wang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Molecular Mechanism ◽  
Myeloid Leukemia ◽  
High Expression ◽  
Control Group ◽  
Expression Levels ◽  
High Expression Group ◽  
App Gene ◽  
Acute Myeloid

Abstract Amyloid precursor protein (APP) has been reported to be highly expressed in AML1/ETO positive acute myeloid leukemia (AML1/ETO+ AML), and we found it express even higher in those with extramedullary infiltration in our previous study. But it’s still unknown what role APP plays and how it works in AML1/ETO+ AML. This study was designed to investigate the effect of APP gene on the prognosis and its molecular mechanism of extramedullary infiltration in the patients with AML1/ETO+ AML. 44 cases of AML1/ETO+ AML patients with median age of 29 years old, who were admitted to our hospital from February, 2006 to February, 2012 and made the diagnosis according to WHO2008 diagnosis standard, and had completed conventional induction, consolidation and intensive therapy, were investigated in this study. They were divided into high expression group (n=22) and low one (n=22) according to APP mRNA median expression level from bone marrow cells before the first chemotherapy by QRT-PCR. Some of bone marrow samples were checked by Western Blot, and 5 biopsy specimens from extramedullary infiltration were tested by APP antibody immunohistochemistry staining. Incidence of extramedullary leukemia (EML), complete response (CR), overall survival (OS), and recurrence free survival (RFS) was differentiated between the two groups. Differences of cell ultrastructure, migration, proliferation, apoptosis and expression of ERK, MMP-2, MMP-9 and CXCR4 were studied on Kasumi-1 cell line between wild, negative control (NC) and si-APP group in which the expression levels of APP gene were down regulated with application of siRNA technology.Çå The incidence of EML was significantly different (45.5% versus 9.1%) in the two groups (P=0.007) and it was positively correlative with the expression levels of APP mRNA (rp=0.435, P=0.004). Extramedullary infiltration site also showed high expression of APP by immunohistochemistry, while the control group was negative. Not only CR rate after two courses of chemotherapy, but also OS and RFS with median follow-up of 28(4-70) months, of high expression group was all significantly lower than that of low expression group (Table 1). Compared with the wild and NC group, cell apoptosis of si-APP group was significantly increased (12.33 ± 0.75 vs 19.80 ± 1.51, P=0.000); the number of microvilli on the surface of the cell membrane significantly reduced; the ability of the cell migration by Tanswell chamber migration assay significantly decreased (P=0.004); and expression of P-ERK, c-MYC, MMP-2 decreased significantly which was confirmed by ERK and c-MYC blocker treatment (Figure 1). In sum, incidence of EML is significantly higher and the prognosis is poor in the patients with AML1/ETO+ AML with high expression of APP gene. We first describe that APP gene may mediate AML1/ETO+ leukemia cells in the development of extramedullary infiltration by up-regulation of the ERK/MMP-2 pathway. Disclosures: No relevant conflicts of interest to declare.

Concordant Underexpression of Fanconi Anemia/BRCA1 Pathway Proteins in a Major Proportion of Myelodysplastic Syndromes

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4311-4311
Author(s):  
Fatemeh Majidi ◽  
Judith Neukirchen ◽  
Ulrich Germing ◽  
Ron-Patrick Cadeddu ◽  
Stefan Braunstein ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Protein Expression ◽  
Fanconi Anemia ◽  
Myelodysplastic Syndromes ◽  
Research Funding ◽  
Repair Pathway ◽  
Hematopoietic Stem ◽  
Normal Controls ◽  
Low Expression

Abstract Introduction: BRCA1 plays a key role in maintaining genomic stability and interacts directly with several proteins that regulate hematopoietic stem cell functions and are part of the Fanconi anemia (FA) double-strand break (DSB) repair pathway. Loss of BRCA1 in murine bone marrow causes hematopoietic defects similar to those seen in FA (Vasanthakumar, Blood 2016). BRCA1 is highly expressed in hematopoietic tissues, whereas its expression is lost in CML (Deutsch et al, Blood 2003) and t-AML (Scardocci et al, Br J Cancer 2006). Since FA is associated with an increased risk of developing myelodysplastic syndromes (MDS), we examined the protein expression of BRCA1 and three other important components of the FA DNA repair pathway, as well as PARP-1, whose co-alteration with BRCA causes synthetic lethality. Methods: We recently established a tissue microarray (TMA) with bone marrow biopsies from 119 MDS patients, 40 AML patients, and 11 normal controls. Biopsy material was retrieved from the Institute of Pathology, Heinrich-Heine-University Düsseldorf, Germany. The TMA was produced at SciLifeLab Tissue Profiling Facility in Uppsala, Sweden. Immunohistochemistry (IHC) protocols were established in our lab for the detection of BRCA1, BRCA2, FANCD2, H2AX, and PARP1. Semi-quantitative analysis was done according to Remmele-Stegner immunoreactive score (IRS) with a point system from 0 to 12. Expression was categorized as absent (0-2), weak (3-4), moderate (5-8) or strong (9-12). For correlating protein expression with clinical data from the Düsseldorf MDS Registry, samples were dichotomized into 'low expression' (1-4) and 'higher expression' (5-12). Prognostic analysis was restricted to 80 MDS patients who did not receive disease-modifying therapy. Results: Similar to normal controls, most patients with AML showed strong expression of the proteins under consideration (Fig. 1). In contrast, low expression was found in about 60% of MDS patients. Most MDS patients showed concordant, dichotomous expression of all five proteins (either all up or all down). Correspondingly, the protein expression landscapes look similar (Fig. 1). Almost perfect concordance was noted for PARP1 and H2AX. Low expression of FA/BRCA pathway proteins was not correlated with MDS type (WHO 2008) or IPSS-R risk group. Patients with higher expression of at least 3 of the 5 proteins survived longer (45 vs. 26 months) and had a longer time to AML development (median not reached at 180 months vs. 53 months), but the differences did not reach statistical significance (p=0.108 and p=0.159, respectively). Interestingly, patients with low expression of PARP1 were significantly more likely to show any chromosomal aberration (p=0.02) or an unfavourable karyotype (intermediate, high-risk or very high risk according to IPSS-R) (p=0.016). The same was true for patients with low expression of H2AX (p=0.013 and p=0.01). Conclusions: This is the first TMA-based investigation of FA/BRCA pathway protein expression in MDS. In stark contrast to AML, 60% of MDS patients showed low protein expression in a concordant manner. This could reflect synexpression of genes that share common cis- and trans-acting control elements. Alternatively, it could be the result of aberrant splicing, since at least 50% of MDS patients have spliceosome mutations that render a large spectrum of messenger RNAs susceptible to nonsense-mediated decay. Abnormal splicing factors may also influence the stability (and thus expression) of certain proteins through abnormal protein-protein interactions. Further IHC analyses will show whether the dichotomous protein synexpression pattern we observed in MDS extends to proteins that are unrelated to DNA maintenance. Underexpression of FA/BRCA pathway proteins may cause chromosomal instability, as suggested by our finding of significantly more frequent karyotype anomalies in patients with low PARP1 or H2AX expression. This is in accordance with the known role of H2AX as suppressor of oncogenic chromosome translocations, and with an accelerating effect of PARP1 deficiency on centrosome amplification in BRCA1-deficient cells. FA/BRCA pathway protein underexpression may not only contribute to a better understanding of MDS versus AML pathogenesis, but may also have therapeutic implications, e.g. by affecting the response to treatment with hypomethylating agents, which are known to promote DNA double strand breaks. Figure 1 Figure 1. Disclosures Gattermann: Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: travel, accomodation expenses, Research Funding.

scholarly journals Exploration of Various Roles of Hypoxia Genes in Osteosarcoma

2021 ◽  
Author(s):  
Jimin Ma ◽  
Yakun Zhu ◽  
Ziming Guo ◽  
Xuefei Yang ◽  
Haitao Fan
Keyword(s):  
High Risk ◽  
Immune Cells ◽  
Prognostic Model ◽  
Cox Regression ◽  
High Expression ◽  
Cox Regression Analysis ◽  
Model Based ◽  
Survival Difference ◽  
High Expression Group ◽  
Low Expression

Abstract Background: Osteosarcoma is a primary malignant tumor that often metastasizes in orthopedic diseases. Although multi-drug chemotherapy and surgical treatment have significantly improved the survival and prognosis of patients with osteosarcoma, the survival rate is still very low due to frequent metastases in patients with osteosarcoma. In-depth exploration of the relationship between various influencing factors of osteosarcoma is very important for screening promising therapeutic targets. Methods: This study used multivariate COX regression analysis to select the hypoxia genes SLC2A1 and FBP1 in patients with osteosarcoma, and used the expression of these two genes to divide the patients with osteosarcoma into high-risk and low-risk groups. Then, we first constructed a prognostic model based on the patient's risk value, and compared the survival difference between the high expression group and the low expression group. Second, in the high expression group and the low expression group, compare the differences in tumor invasion and inflammatory gene expression between the two groups of immune cells. Finally, the ferroptosis-related genes with differences between the high expression group and the low expression group were screened, and the correlation between these genes was analyzed. Results: In the high-risk group, immune cells with higher tumor invasiveness, macrophages M0 and immune cells with lower invasiveness included: mast cell resting, regulatory T cells (Tregs) and monocytes. Finally, among genes related to ferroptosis, we found AKR1C2, AKR1C1 and ALOX15 that may be related to hypoxia. These ferroptosis-related genes were discovered for the first time in osteosarcoma. Among them, the hypoxia gene FBP1 is positively correlated with the ferroptosis genes AKR1C1 and ALOX15, and the hypoxia gene SLC2A1 is negatively correlated with the ferroptosis genes AKR1C2, AKR1C1 and ALOX15. Conclusion: This study constructed a prognostic model based on hypoxia-related genes SLC2A1 and FBP1 in patients with osteosarcoma, and explored their correlation with immune cells, inflammatory markers and ferroptosis-related genes. This indicates that SLC2A1 and FBP1 are promising targets for osteosarcoma research.

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