Long Intergenic Non-Coding RNAs (lincRNA) Impacts Biology and Clinical Outcome in Multiple Myeloma

Abstract RNA has a diverse sets of regulatory functions besides being a messenger between DNA and protein. Recent analysis of RNA repertoire has identified a large numbers of non-coding transcripts. One of which, long intergenic non-coding RNA (lincRNA) with transcripts longer than 200 nucleotides, are located between the protein coding genes and do not overlap exons of either protein-coding or other non-lincRNA genes. lincRNAs have been considered to provide regulatory functions, however, their precise role in cellular biology remains unclear. Here, we have evaluated the lincRNA profile and their clinical role in MM. We performed RNA-seq on CD138+ MM cells from 320 patients and 18 normal bone marrow plasma cells (NBM) and analyzed for lincRNA. Data from Unstranded 50 bp paired-end RNAseq reads were mapped to the human genome and evaluated for frequency and type of lncRNA. Patient data for MM characteristics, cytogenetic and FISH as well as clinical survival outcomes were also analyzed and correlated with lncRNA data. We compared differentially expressed lincRNAs and protein coding genes in MM versus NBM samples. lincRNA and protein coding genes that have more than 2 reads/million reads for at least 50 samples (~15%) were included in the analysis. We identified 192 significantly expressed lincRNA (adj p value <0.05). We evaluated neighborhood protein coding genes for lincRNA within 500kb up/down stream and identified 298 genes within the region, 134 of these also differentially expressed between MM and NBM. Gene enrichment analysis to recognize possible biological processes that may be affected by lincRNAs and genes enriched by several Gene Ontology(GO) terms identified DNA binding, transcription, cell proliferation, and regulation of lymphocyte function. We applied unsupervised clustering method to the differentially expressed lincRNA that are neighbor of these 134 protein-coding genes. We identified four distinct clusters which are being investigated for correlation with clinical subtypes of MM. Finally we checked correlation between lincRNAs and clinical outcome including response and relapse free survival. We compared differentially expressed lincRNA between patients achieving complete response (CR) versus others and identified 16 lincRNAs with significantly different expression values (p value < 0.05). Using univariate cox regression model, 26 lincRNAs were identified as having significant correlation (cox p value < 0.05) with event-free survival (EFS). Three of these lincRNAs were also related with response prediction suggesting high level of functional and biological importance. We have developed a multivariate cox regression model utilizing these individually significant lincRNAs able to predict relapse free survival (Overall Wald test p value = 6.736e-07). Using a training set of 171 patients, we developed a cox regression multivariate survival model and created a risk score. The high and low risk based on lincRNA was validated using this model in 85 independent patients (log-rank p = 0.04). We are in the process of now integrating the gene expression data with lincRNA data to develop an integrated survival model. In summary, we report the first differential lincRNA expression in MM showing a significant role in disease biology as well as clinical outcome. lincRNAs are still functionally poorly characterized and our ongoing integrative approach will provide a link between lincRNAs and protein coding genes in MM. Disclosures Anderson: Celgene: Consultancy; Sanofi-Aventis: Consultancy; Onyx: Consultancy; Acetylon: Scientific Founder, Scientific Founder Other; Oncoprep: Scientific Founder Other; Gilead Sciences: Consultancy.

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Differentially Expressed and Prognostically Significant Lincrnas May Impact Immune System and Tumor Progression in Multiple Myeloma (MM)

Blood ◽

10.1182/blood.v126.23.2989.2989 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2989-2989 ◽

Cited By ~ 3

Author(s):

Mehmet K Samur ◽

Annamaria Gulla ◽

Alice Cleynen ◽

Florence Magrangeas ◽

Stephane Minvielle ◽

...

Keyword(s):

Immune System ◽

Board Of Directors ◽

Differentially Expressed ◽

Support Vector ◽

Strongly Correlated ◽

Advisory Committees ◽

Protein Coding ◽

Free Survival ◽

Protein Coding Genes ◽

Highly Correlated

Abstract Long intergenic non-coding RNA (lincRNA) are transcripts longer than 200 nucleotides which have a diverse sets of regulatory functions but do not get translated into protein. lincRNAs are located between the protein coding genes and do not overlap exons of either protein-coding or other non-lincRNA. However precise role of individual lincRNA in disease biology remains unclear. Here, we have evaluated the lincRNA expression and their potential biological functions in MM. We performed RNA-seq on CD138+ MM cells from 296 newly diagnosed patients and 16 normal bone marrow plasma cells (NBM) and analyzed for lincRNA expression. Data from paired-end RNAseq reads were mapped to the latest human genome, differentially expressed lincRNAs were identified and for each expressed lincRNA event free survival was examined with univariate cox regression model and support vector machine. Finally, we identified protein coding genes that are strongly correlated (cor > 0.5) with lincRNAs with significant altered expression in MM and impact on EFS to identify their biological role. lincRNA and protein coding genes that have more than 10 reads/million reads for at least 15 normal samples or 62 MM samples (20% all MM samples) were included in the analysis. We identified 60 differentially expressed lincRNA (adj p value <0.05), 51 of those had at least 1.5 fold change difference. The differentially expressed lncRNAs were in close proximity of Ig-related genes, genome stability related genes, hosting miRNAs such as mir222 and mir22 and previously reported for other cancers (PVT and TTY15). We evaluated relation of these lincRNAs with event free survival (EFS) and observed 6 lincRNAs associated with shorter EFS. We have developed multivariate signature model to predict EFS by using these 6 lincRNAs. We divided our dataset into training (n=99) and test (n=156) dataset and we utilized support vector machine classification to divide samples into 2 groups using six lincRNAs. This model was able to predict good and poor survival groups in training dataset (p val < 0.001) as well as test dataset (p val = 0.002) (Figure). We examined genome wide correlation between these six differentially expressed and prognostically significant lincRNAs to expressed protein coding genes to identify their biological functions in MM. Four of these lincRNAs strongly correlated with 47 to 504 genes (abs(cor) > 0.5), affecting immune system pathways and pathways in cancer including Jak-STAT signaling pathway. We also found that these lincRNAs are also highly correlated with tumor development genes such as TNFRSF1B,FGR,TP53BP2,TNF and T or B cells related genes PIK3CD, BCL6. In addition, two of these lincRNAs (LINC00936 and CTB-61M7.2) were found highly correlated with their protein coding neighbor genes ATP2B1(cor = 0.45) and FCAR (cor = 0.95) respectively and MIR22HG was host gene for mir22 which may indicate lincRNAs are using different machinery in MM to regulate protein coding genes. In summary, we report that lincRNA is differentially expressed and prognostically significant in myeloma and may function through their impact on immune system and tumor progression. Our ongoing integrative approach will provide further evidence of their regulatory role in MM with potential therapeutic application. Figure 1. Figure 1. Disclosures Anderson: acetylon pharmaceuticals: Equity Ownership; Celgene Corporation: Consultancy; Gilead: Consultancy; Oncocorp: Equity Ownership; Millennium: Consultancy; BMS: Consultancy. Munshi:onyx: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; novartis: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees.

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Aspirin in the prevention of colorectal cancer recurrence.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.578 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 578-578

Author(s):

Nimisha Kumari ◽

Hiren A. Mandaliya ◽

Tiffany Evans ◽

Patrick McElduff ◽

Christopher Oldmeadow ◽

...

Keyword(s):

Colorectal Cancer ◽

Adjuvant Chemotherapy ◽

Regression Model ◽

Propensity Scores ◽

Cox Regression ◽

Colorectal Adenomas ◽

Stage Ii ◽

Single Institution ◽

Relapse Free Survival ◽

Free Survival

578 Background: Aspirin use reduces the incidence of colorectal adenomas, and of colorectal cancer (CRC) in patients with hereditary non-polyposis colorectal cancer. There is limited data on the effect of aspirin in the secondary prevention of CRC, currently the subject of multiple prospective randomized trials. We aimed to test the hypothesis that aspirin reduces disease recurrence in patients diagnosed with early CRC at a high volume, single institution. Methods: A retrospective analysis was conducted of all patients (pts) treated with at least one cycle of adjuvant chemotherapy for stage II or III CRC over a 5yr period (2009–13). Patients with synchronous CRC were excluded. Aspirin use at the onset of adjuvant chemotherapy was sourced from the universal electronic recording of concomitant medications. Kaplan-Meier curves and the log-rank test were used to compare crude relapse free survival (RFS) between pts who were using aspirin to those who were not. Propensity score analyses was used to balance the groups according to potentially confounding variables: tumor site (colon vs rectum), tumor stage (II vs III), and adjuvant chemotherapy (oxaliplatin-based vs no oxaliplatin). The propensity scores were estimated through a multivariable logistic regression model, and a Cox proportional hazards model used to assess the effect of aspirin use on RFS in the sample weighted according to the inverse probability of receiving aspirin. Results: A cohort of 231 pts met eligibility criteria; median age 64yr; 50% colon, 50% rectal; 19% stage II, 81% stage III; 35% received oxaliplatin; 13% (n=31) were using aspirin and 26% of pts (n=61) developed CRC recurrence in median follow-up of 2.9yr. Unadjusted RFS was not significantly different for those using aspirin (log rank p value 0.88). There was good overlap in propensity scores for the two groups. The hazard ratio for RFS with aspirin use from the weighted Cox regression model was 1.2 (95% CI 0.62-2.29), indicating no statistically significant effect of aspirin on CRC relapse. Conclusions: In this single institution series, we did not find evidence that aspirin use at onset of chemotherapy had an effect on CRC relapse free survival. These results do not exclude an aspirin effect that is modest or restricted to select CRC subgroups.

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FRI0181 ORGAN DAMAGE FREE SURVIVAL IN SOUTHERN CHINESE PATIENTS WITH ACTIVE LUPUS NEPHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.2552 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 674.1-674

Author(s):

C. C. Mok ◽

C. S. Sin ◽

K. C. Hau ◽

T. H. Kwan

Keyword(s):

Lupus Nephritis ◽

Regression Model ◽

Cox Regression ◽

Organ Damage ◽

Renal Survival ◽

Cox Regression Model ◽

Free Survival ◽

Renal Response

Background:The goals of treatment of lupus nephritis (LN) are to induce remission, retard the progression of chronic kidney disease, prevent organ complications and ultimately reduce mortality. Previous cohort studies of LN have mainly focused on the risk of mortality and development of end stage renal failure (ESRF) (renal survival). The cumulative frequency of LN patients who survive without organ damage, which correlates better with the balance between treatment efficacy and toxicity, as well as quality of life, has not been well studied.Objectives:To study the organ damage free survival and its predictive factors in patients with active LN.Methods:Consecutive patients who fulfilled ≥4 ACR/SLICC criteria for SLE and with biopsy proven active LN between 2003 and 2018 were retrospectivey analyzed. Those with organ damage before LN onset were excluded. Data on renal parameters and treatment regimens were collected. Complete renal response (CR) was defined as normalization of serum creatinine (SCr), urine P/Cr (uPCR) <0.5 and inactive urinary sediments. Partial renal response (PR) was defined as ≥50% reduction in uPCR and <25% increase in SCr. Organ damage of SLE was assessed by the ACR/SLICC damage index (SDI). The cumulative risk of having any organ damage or mortality since LN was studied by Kaplan-Meier’s analysis. Factors associated with a poor outcome were studied by a forward stepwise Cox regression model, with entry of covariates with p<0.05 and removal with p>0.10.Results:273 LN patients were identified but 64 were excluded (organ damage before LN onset). 211 LN patients were studied (92% women; age at SLE 30.4±13.5 years; SLE duration at LN 1.9±3.1years). 47 (22%) patients had nephrotic syndrome and 60 (29%) were hypertensive. Histological LN classes was: III/IV±V (75.1%), I/II (7.8%) and pure V (17.1%) (histologic activity and chronicity score 7.0±4.2 and 1.8±1.5, respectively). Induction regimens were: prednisolone (33.1±17.5mg/day) in combination with intravenous cyclophosphamide (CYC) (21.4%; 1.0±0.2g per pulse), oral CYC (8.6%; 96.4±37.8mg/day), azathioprine (AZA) (14.3%; 78.6±25.2mg/day), mycophenolate mofetil (MMF) (22.8%; 1.9±0.43g/day) and tacrolimus (TAC) (17.1%; 4.3±1.1mg/day). After a follow-up of 8.6±5.4 years, 94(45%) patient developed organ damage (SDI≥1) and 21(10%) patients died. The commonest organ damage was renal (36.3%) and musculoskeletal (17.9%), and the causes of death were: infection (38.1%), malignancy (19.0%), cardiovascular events (9.5%) and ESRF complications (9.5%). At last visit, 114 (55%) patients survived without any organ damage. The cumulative organ damage free survival at 5, 10 and 15 years after renal biopsy was 73.5%, 59.6% and 48.3%, respectively. The 5, 10 and 15-year renal survival rate were 95.2%, 92.0% and 84.1% respectively. In a Cox regression model, nephritic relapse (HR 3.72[1.78-7.77]), proteinuric relapse (HR 2.30[1.07-4.95]) and older age (HR 1.89[1.05-3.37]) were associated with either organ damage or mortality, whereas CR (HR 0.25[0.12-0.50]) at month 12 were associated with organ damage free survival. Baseline SCr, uPCR and histological LN classes were not significantly associated with a poor outcome. Among patients with class III/IV LN, the long-term organ damage free survival were not significantly different in users of MMF (reference) from CYC (IV/oral) (HR 1.45[0.76- 2.75]) or TAC (HR 1.03[0.26-1.62]) as induction therapy.Conclusion:Organ damage free survival is achieved in 55% of patients with active LN upon 9 years of follow-up. CYC/MMF/TAC based induction regimens did not differ for the long-term outcome of LN. Targeting complete renal response and preventing renal relapses remain important goals of LN treatment.Acknowledgments:NILDisclosure of Interests:None declared

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Hyaluronan heterogeneity in pancreatic ductal adenocarcinoma, primary tumors, and sites of metastasis.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16231 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16231-e16231

Author(s):

Veronica Placencio-Hickok ◽

Marie Lauzon ◽

Natalie Moshayedi ◽

Michelle Guan ◽

Sungjin Kim ◽

...

Keyword(s):

Overall Survival ◽

Liver Metastasis ◽

Regression Model ◽

Cox Regression ◽

Progression Free Survival ◽

Ductal Adenocarcinoma ◽

High Status ◽

Free Survival ◽

Pdac Tissue ◽

Treatment Naïve

e16231 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers with an estimated five-year survival rate of 10%. The dense desmoplastic stroma in PDAC contributes to its aggressive nature and treatment resistance. Among the components comprising the stroma, hyaluronan (HA) has been demonstrated to play a critical role in tumor progression and survival. Previous preliminary studies have suggested differences in HA expression in primary and metastatic foci in PDAC. However, the effects of treatment and location of HA expression as well as the role of CD44, a known receptor for HA, on HA as a biomarker signature remain unknown. Thus, we investigated the potential of HA as a biomarker in primary PDAC and metastases. Methods: PDAC tissue from primary (n = 43) and metastatic (n = 66) sites were obtained from Cedars-Sinai Medical Center along with associated clinical data. Tissue slides were stained with H&E, HA using a histochemical assay, and CD44 by immunohistochemistry. HA staining was scored according to the proportion of stromal staining at an intensity greater than the background stroma. HA status was defined as ≥ 50% staining being HA high and < 50% as being HA low. CD44 staining was recorded as an H-score (percentage of tumor cells staining multiplied by intensity of staining on a scale from 0 to 3). Associations between HA levels and the requested variables were examined with t-test, Wilcoxon rank-sum test, Chi-squared test, Fisher’s exact test, or Cox regression model where appropriate. Kaplan-Meier curves were created to assess progression free survival and overall survival. Analyses were performed using SAS 9.4 with two-sided tests and a significance level of 0.05. Results: HA score was significantly higher in primary PDAC tissue compared to sites of metastases (p = 0.0148). Within the metastases, HA score was significantly higher in liver metastasis compared to other sites of metastasis (p = 0.0478). In the liver metastasis tissue, HA score trended lower in patients with previously treated tissue compared to treatment naïve tissue (p = 0.0622). In the treatment naive liver metastasis cohort, patients with HA high status had decreased progression free survival and overall survival compared to patients with HA low status (p = 0.0032 and p = 0.0478, respectively). Using HA score and CD44 in a Cox regression model demonstrated that for every one unit increase in HA score, the risk for recurrence/progression increased by 4.4% at any fixed point in time, adjusting for CD44 score (p = 0.0049). Conclusions: HA score is variable between primary PDAC, PDAC metastatic to the liver, and PDAC metastatic to other sites. Within liver metastases, patients with HA high status had decreased progression free survival and overall survival compared to patients with HA low status. HA levels can serve as a potential biomarker to guide pancreatic cancer treatments and trial design for agents targeting the stroma.

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Identification of Hypoxia-Related Differentially Expressed Genes and Construction of the Clinical Prognostic Predictor in Hepatocellular Carcinoma by Bioinformatic Analysis

BioMed Research International ◽

10.1155/2021/7928051 ◽

2021 ◽

Vol 2021 ◽

pp. 1-15

Author(s):

Hao Guo ◽

Jing Zhou ◽

Yanjun Zhang ◽

Zhi Wang ◽

Likun Liu ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Regression Model ◽

Molecular Mechanisms ◽

Cox Regression ◽

The Cancer Genome Atlas ◽

Functional Enrichment ◽

Differentially Expressed ◽

Clinical Prognosis ◽

Prognostic Predictor ◽

Key Genes

Background. Hypoxia closely relates to malignant progression and appears to be prognostic for outcome in hepatocellular carcinoma (HCC). Our research is aimed at mining the hypoxic-related genes (HRGs) and constructing a prognostic predictor (PP) model on clinical prognosis in HCC patients. Methods. RNA-sequencing data about HRGs and clinical data of patients with HCC were obtained from The Cancer Genome Atlas (TCGA) database portal. Differentially expressed HRGs between HCC and para-carcinoma tissue samples were obtained by applying the Wilcox analysis in R statistical software. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were used for gene functional enrichment analyses. Then, the patients who were asked to follow up for at least one month were enrolled in the following study. Cox proportional risk regression model was applied to obtain key HRGs which related to overall survival (OS) in HCC. PP was constructed and defined, and the accuracy of PP was validated by constructing the signature in a training set and validation set. Connectivity map (CMap) was used to find potential drugs, and gene set cancer analysis (GSCA) was also performed to explore the underlying molecular mechanisms. Results. Thirty-seven differentially expressed HRGs were obtained. It contained 28 upregulated and 9 downregulated genes. After the univariate Cox regression model analysis, we obtained 27 prognosis-related HRGs. Of these, 25 genes were risk factors for cancer, and 2 genes were protective factors. The PP was composed by 12 key genes (HDLBP, SAP30, PFKP, DPYSL4, SLC2A1, HMOX1, PGK1, ERO1A, LDHA, ENO2, SLC6A6, and TPI1). GSCA results showed the overall activity of these 12 key genes in 10 cancer-related pathways. Besides, CMap identified deferoxamine, crotamiton, talampicillin, and lycorine might have effects with HCC. Conclusions. This study firstly reported 12 prognostic HRGs and constructed the model of the PP. This comprehensive research of multiple databases helps us gain insight into the biological properties of HCC and provides deferoxamine, crotamiton, talampicillin, and lycorine as potential drugs to fight against HCC.

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Relationship between Plasma Endocan Level and Clinical Outcome of Chinese Peritoneal Dialysis Patients

Kidney & Blood Pressure Research ◽

10.1159/000502961 ◽

2019 ◽

Vol 44 (5) ◽

pp. 1259-1270 ◽

Cited By ~ 3

Author(s):

Peter Yam-Kau Poon ◽

Jack Kit-Chung Ng ◽

Winston Wing-Shing Fung ◽

Kai-Ming Chow ◽

Bonnie Ching-Ha Kwan ◽

...

Keyword(s):

Peritoneal Dialysis ◽

Clinical Outcome ◽

Cardiovascular Event ◽

Cox Regression ◽

Event Free Survival ◽

Free Survival ◽

Cox Regression Analysis ◽

Reactive Protein ◽

Inflammatory Conditions ◽

Serum Crp

Background: Endocan is associated with endothelial dysfunction. In peritoneal dialysis (PD) patients, cardiovascular disease is a common cause of mortality. We examined the relationship between serum endocan level and clinical outcome of PD patients. Methods: We recruited 193 new PD patients (118 males, mean age 58.8 ± 11.6 years). Serum endocan levels were determined and stratified into tertile 1 (lowest) to 3 (highest). Nutritional status, arterial pulse wave velocity (PWV) and serum C-reactive protein (CRP) levels were measured. The patients were followed for at least 4 years for clinical outcomes. Results: For the whole cohort, patients with higher serum endocan levels had lower serum albumin and subjective global assessment score, higher carotid-femoral PWV, and higher serum CRP. For patients with suboptimal blood pressure (BP) control, cardiovascular event-free survival was 95.0, 95.5, and 78.5% for tertiles 1, 2, and 3 at 60 months respectively (p = 0.019). Multivariate Cox regression analysis showed that serum endocan level was an independent predictor of cardiovascular event-free survival. No association with cardiovascular event-free survival was found for patients with adequate BP control (95.0, 92.3, and 100% for tertile 1, 2, and 3 at 60 months, respectively, p = 0.6). Conclusions: Higher serum endocan level is associated with unfavourable nutritional, arterial and inflammatory conditions in PD patients. In patients with suboptimal BP control, higher serum endocan is also associated with worse cardiovascular outcome.

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Treatment outcomes in patients less than 2 years of age with small, stage I, favorable-histology Wilms' tumors: a report from the National Wilms' Tumor Study.

Journal of Clinical Oncology ◽

10.1200/jco.1993.11.1.91 ◽

1993 ◽

Vol 11 (1) ◽

pp. 91-95 ◽

Cited By ~ 52

Author(s):

D M Green ◽

N E Breslow ◽

J B Beckwith ◽

J Takashima ◽

P Kelalis ◽

...

Keyword(s):

Wilms Tumor ◽

Stage I ◽

P Value ◽

Relapse Free Survival ◽

Free Survival ◽

Treatment Regimens ◽

Survival Percentage ◽

Favorable Histology ◽

Specimen Weight ◽

Tumor Studies

PURPOSE Retrospective analyses were performed to determine the effect of tumor weight and therapy modifications on outcome in patients less than 2 years of age with stage I favorable-histology Wilms' tumors. PATIENTS AND METHODS The 4-year relapse-free and overall survival percentages for patients randomized to different treatment regimens in National Wilms' Tumor Studies (NWTS)-1, -2, and -3 were calculated and compared. RESULTS The 4-year relapse-free survival percentages of patients whose specimen weight was less than 550 g were found to be 89.1% on NWTS-1, 96.0% on NWTS-2, and 93.2% on NWTS-3. There was no evidence that the relapse-free survival of these patients had improved over time (P value for trend = .99). The 4-year relapse-free survival percentage for similar age and stage patients whose specimen weight was 550 g or greater was significantly poorer than that of patients with smaller tumors (P = .02). CONCLUSION Changes in the NWTS treatment regimens over a period of more than 20 years have not improved on the excellent prognosis of patients who are less than 2 years of age at diagnosis and who have a stage I, favorable-histology Wilms' tumor with specimen weight less than 550 g. These data could be used as the basis for a future trial in which a subgroup of such patients is treated with nephrectomy only.

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A Three Protein-Coding Gene Prognostic Model Predicts Overall Survival in Bladder Cancer Patients

BioMed Research International ◽

10.1155/2020/7272960 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Xiang-hui Ning ◽

Yuan-yuan Qi ◽

Fang-xin Wang ◽

Song-chao Li ◽

Zhan-kui Jia ◽

...

Keyword(s):

Bladder Cancer ◽

Zinc Finger Protein ◽

Risk Model ◽

Cox Regression ◽

The Cancer Genome Atlas ◽

Risk Scores ◽

Lasso Regression ◽

Protein Coding ◽

Protein Coding Genes ◽

Differentially Methylated Genes

Bladder cancer (BLCA) is the most common urinary tract tumor and is the 11th most malignant cancer worldwide. With the development of in-depth multisystem sequencing, an increasing number of prognostic molecular markers have been identified. In this study, we focused on the role of protein-coding gene methylation in the prognosis of BLCA. We downloaded BLCA clinical and methylation data from The Cancer Genome Atlas (TCGA) database and used this information to identify differentially methylated genes and construct a survival model using lasso regression. We assessed 365 cases, with complete information regarding survival status, survival time longer than 30 days, age, gender, and tumor characteristics (grade, stage, T, M, N), in our study. We identified 353 differentially methylated genes, including 50 hypomethylated genes and 303 hypermethylated genes. After annotation, a total of 227 genes were differentially expressed. Of these, 165 were protein-coding genes. Three genes (zinc finger protein 382 (ZNF382), galanin receptor 1 (GALR1), and structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1)) were selected for the final risk model. Patients with higher-risk scores represent poorer survival than patients with lower-risk scores in the training set ( HR = 2.37 , 95% CI 1.43-3.94, p = 0.001 ), in the testing group ( HR = 1.85 , 95% CI 1.16-2.94, p = 0.01 ), and in the total cohort ( HR = 2.06 , 95% CI 1.46-2.90, p < 0.001 ). Further univariate and multivariate analyses using the Cox regression method were conducted in these three groups, respectively. All the results indicated that risk score was an independent risk factor for BLCA. Our study screened the different methylation protein-coding genes in the BLCA tissues and constructed a robust risk model for predicting the outcome of BLCA patients. Moreover, these three genes may function in the mechanism of development and progression of BLCA, which should be fully clarified in the future.

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High Levels of Interleukin-12 Are Associated with Reduced Incidence of Relapse and Death without Increasing Acute Graft-Versus-Host Disease (AGVHD) after Allogeneic Stem Cell Transplantation (SCT).

Blood ◽

10.1182/blood.v104.11.295.295 ◽

2004 ◽

Vol 104 (11) ◽

pp. 295-295

Author(s):

Vijay Reddy ◽

Andrew G. Winer ◽

Erika Eksioglu ◽

Jeffery Levine ◽

Herwig-Ulf Meier-Kriesche ◽

...

Keyword(s):

Stem Cell ◽

Disease Risk ◽

Significant Risk ◽

Interleukin 12 ◽

P Value ◽

Group Level ◽

Relapse Free Survival ◽

Free Survival ◽

Post Transplant ◽

Medium Group

Abstract We recently found that a low number of circulating dendritic cells (DC) is predictive of increased relapse, acute GVHD, and poor survival following allogeneic SCT (Reddy V et al, Blood2004;103(11):4330–5). Interleukin-12 (IL-12) is an immunostimulatory cytokine involved in the activation of naïve T cells by DC (Rissoan et al. Science1999;283(5405):1183–6). We hypothesized that patients with high levels of circulating IL-12 in the post transplant period have improved relapse free survival. We studied 134 patients, 120 of whom were evaluable and transplanted during the period of July 1999 to April 2004. Seventy-two patients had transplants from related and 48 from unrelated donors, for predominantly high risk (88%) hematologic malignancies. Median follow up was 1158 days (range 70–1792). Blood samples were collected as baseline prior to conditioning, on day 0 prior to stem cell infusion and during the first week (day 4 and/or 7) after transplant. Plasma IL-12 levels were measured by ELISA. To determine the independent effect of post-transplant IL-12 levels and clinical outcomes, a cluster analysis was performed on the logarithmically transformed mean IL-12 concentration at days 4 and 7 post-transplant. The analysis generated a low, medium and high IL-12 group. Forty-six patients had low levels of IL-12 (median=2 pg/ml, range 0–6.5), 49 patients had medium (median=20.5 pg/ml, range 7–75.5) and 25 patients had high levels (median=181 pg/ml, range 84–623). There was a significant association between IL-12 level and onset of relapse. Using a multivariate Cox model with the low group level as reference, the high IL-12 group level had an adjusted hazard ratio (HR) of 0.27 (95% C.I. 0.09–0.79) and the medium group level a HR of 0.65 (95% C.I. 0.31–1.36). Incidence of relapse at 500 days by Kaplan-Meier analysis by IL-12 group were 23.0% (high group), 40.3% (medium group), and 48.8% (low group). Covariates in the multivariate models were gender match, disease risk, graft source, patient age, donor relation. There was a significant relationship between IL-12 levels and composite death and relapse, the high IL-12 group had a HR of 0.37 (95%C.I.=0.17–0.80) and the medium group a HR of 0.85 (95%.C.I. 0.50–1.45). There was no association between IL-12 levels and risk of AGVHD (p-value=0.51). In addition to IL-12, disease risk was a significant risk factor for the composite endpoint of relapse or death (HR=5.4, p-value=0.0052). The model generated for the outcome of relapse only did not have any additional significant risk factors. In conclusion, high post-transplant levels of IL-12 are associated with less relapse and improved relapse free survival after transplantation. This data suggests that IL-12 administration should be considered as a possible component in studies addressing treatment of relapse after transplantation. Figure Figure

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Association of Disparities in Known Minor Histocompatibility Antigens with Relapse-Free Survival and Graft-Versus-Host-Disease Upon Allogeneic Stem Cell Transplantation,

Blood ◽

10.1182/blood.v118.21.4136.4136 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4136-4136

Author(s):

Willemijn Hobo ◽

Kelly Broen ◽

Walter J.F.M. van der Velden ◽

Annelies Greupink-Draaisma ◽

Niken Adisty ◽

...

Keyword(s):

Stem Cell ◽

Statistical Analysis ◽

T Cell ◽

Clinical Outcome ◽

Stem Cell Transplantation ◽

Relapse Free Survival ◽

Post Transplantation ◽

Free Survival ◽

Graft Versus Host ◽

Cell Responses

Abstract Abstract 4136 Purpose: Allogeneic stem cell transplantation (allo-SCT) can induce remission in patients with hematological malignancies due to graft-versus-tumor (GVT) responses. This, however, is often accompanied by graft-versus-host disease (GVHD). Both the GVT effect and GVHD are mediated by minor histocompatibility antigen (MiHA)-specific T cells recognizing peptide products from polymorphic genes that differ between recipient and donor. Here, we evaluated whether MiHA mismatches are associated with clinical outcome after partial T cell depleted allo-SCT. Patients and Methods: We retrospectively analyzed the impact of MiHA mismatches in a cohort of 327 patients who received a partially T cell-depleted allo-SCT because of a hematological malignancy. MiHA allele genotyping was performed by fluorescence-based competitive allele-specific PCR. Subsequently, a multivariable statistical analysis of immunogenic MiHA disparity rates and association with clinical outcome was performed. In addition, development of MiHA-specific T cell responses was assessed by dual-color tetramer staining. Results: Statistical analysis revealed that an autosomal MiHA disparity on DNA level associates with increased relapse-free survival in sibling transplants, especially in patients transplanted for multiple myeloma. In addition, mismatches for the ubiquitous Y chromosome-encoded MiHA resulted in more acute GVHD (grade 3–4), while other MiHA mismatches, either ubiquitous or restricted to hematopoietic cells, were not associated with GVHD. Finally, we demonstrated considerable differences between MiHA in the capability to induce in vivo T cell responses post-transplantation. Conclusion: These data support that autosomal MiHA contribute to the induction of GVT immunity providing a rationale for MiHA-based post-transplantation immunotherapy to prevent and treat persistent and recurrent cancer following allo-SCT. Disclosures: No relevant conflicts of interest to declare.

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