Low ERG Research Articles

Abstract 2346: Prostate cancer castrate resistant progression usage of non-canonical androgen receptor signaling and ketone body fuel

Abstract Prostate cancer (PCa) that progresses after androgen deprivation therapy (ADT) remains incurable. The intricacy of metabolic pathways associated with PCa progression spurred us to develop a metabolism-centric analysis. Using PCa patient-derived xenografts (PDXs) we assessed the metabolic changes after castration of tumor-bearing mice. We found that relapsed tumors had a significant increase in fatty acids and ketone body content compared with baseline. We confirmed that critical ketogenic/ketolytic enzymes (ACAT1, OXCT1, BDH1) were significantly augmented after castrate-resistant progression. Further, these enzymes are increased in the human donor tissue after progressing to ADT. Increased ACAT1 and OXCT1 was also observed for a subset of PCa patients that relapsed with low AR and ERG expression. These factors were associated with decreased biochemical relapse and progression free survival. In summary, our studies reveal the key metabolites fueling castration resistant progression in the context of a partial or complete loss of AR dependence. Citation Format: Estefania Labanca, Juan Bizzotto, Jun Yang, Pablo Sanchis, Peter Shepherd, Alejandra Paez, Valeria Antico-Arciuch, Nicolas Anselmino, Sofia Lage-Vickers, Anh Hoang, Mark Tituts, Eleni Efstathiou, Javier Cotignola, Christopher Logothetis, Elba Vazquez, Nora Navone, Geraldine Gueron. Prostate cancer castrate resistant progression usage of non-canonical androgen receptor signaling and ketone body fuel [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2346.

5hmC Level Predicts Biochemical Failure Following Radical Prostatectomy in Prostate Cancer Patients with ERG Negative Tumors.

This study aimed to validate whether 5-hydroxymethylcytosine (5hmC) level in combination with ERG expression is a predictive biomarker for biochemical failure (BF) in men undergoing radical prostatectomy (RP) for prostate cancer (PCa). The study included 592 PCa patients from two consecutive Danish RP cohorts. 5hmC level and ERG expression were analyzed using immunohistochemistry in RP specimens. 5hmC was scored as low or high and ERG was scored as negative or positive. Risk of BF was analyzed using stratified cumulative incidences and multiple cause-specific Cox regression using competing risk assessment. Median follow-up was 10 years (95% CI: 9.5–10.2). In total, 246 patients (41.6%) had low and 346 patients (58.4%) had high 5hmC level. No significant association was found between 5hmC level or ERG expression and time to BF (p = 0.2 and p = 1.0, respectively). However, for men with ERG negative tumors, high 5hmC level was associated with increased risk of BF following RP (p = 0.01). In multiple cause-specific Cox regression analyses of ERG negative patients, high 5hmC expression was associated with time to BF (HR: 1.8; 95% CI: 1.2–2.7; p = 0.003). In conclusion, high 5hmC level was correlated with time to BF in men with ERG negative PCa, which is in accordance with previous results.

Abstract B098: Genomic variations associated with prostate cancer in large cohort of African American men

Abstract Background: Racial disparities in prostate cancer (PCa) incidence and mortality are well known. PCa is known to be more aggressive in African American men (AAM) compared to European American men (EAM) in terms of higher incidence and mortality rates. Here we validate a tumor gene expression pan-cancer race model in men with PCa and further characterize genomic differences that may contribute to disparate clinical outcomes. Methods: We obtained deidentified genome-wide expression profiles from clinical use of the Decipher RP test in 9,953 men from the GRID registry database. A subset of men (n=313) had known race status. A pan-cancer race model, developed to predict patient AAM race from analysis of gene expression patterns in 4,162 tumors from retrospective cohorts with known race status, was applied to the prospective cohort for race prediction. Hallmarks of cancer, immune modulators, AR activity, and prognostic gene signatures available in the GRID were used to gain a molecular perspective on PCa racial disparities. Results: The race model was independently validated in the subset of men with known race and had an AUC of 0.98 for differentiating AAM from EAM. The model was then applied to the 9,640 GRID patients with unknown race status and classified 6,831 as EAM, 1,058 as AAM, and 1,751 as having indeterminate race. Characterizing the molecular subtypes, we found known and predicted AAM to be enriched with SPINK1+ tumors (21% and 24%, respectively) compared to predicted EAM (8%). In contrast, while ERG+ was found 22% and 19% in known and predicted AAM, respectively, compared to 46% in predicted EAM. Based on PAM50 prostate cancer classifier, 61% of AAM were classified as basal-like tumors, whereas 41% were basal-like in EAM. Similarly, 28% of AAM had low AR-A while only 11% of EAM had low AR-A. AAM tumors had higher levels of immune infiltration signatures as well as higher scores for inflammatory and interferon gamma responses, NF-KB mediated tumor necrosis factor (TNF) activity, and interleukin 6 (IL6) signaling activity scores. AAM had lower DNA repair glycolysis scores compared to EAM. Conclusion: Known and predicted AAM were enriched with SPINK1+ tumors, higher immune infiltration and activation but lower ERG+, DNA repair, and AR activity tumors. Using such large GRID data with known race, we will further understand the underlying causes associated with prostate cancer racial disparities. Citation Format: Walter Rayford, Jennifer Jordan, Mandeep Takhar, Mohammed Alshalalfa, Darlene Dai, Nicholas Erho, Mark D. Greenberger, Elai Davicioni. Genomic variations associated with prostate cancer in large cohort of African American men [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B098.

Abstract LB-309: Evaluation of ERG as a biomarker of responsiveness in a randomized trial of enzalutamide in combination with androgen deprivation in metastatic hormone sensitive prostate cancer

Abstract Background: TMPRSS2-ERG fusions are highly prevalent in prostate cancer patients, where androgen responsive TMPRSS2 gene promoter fused with coding sequence of ERG transcription factor resulting in androgen mediated expression of ERG factor. Metastatic cancer patients harbor the TMPRSS2-ERG fusions and presence of fusions associate with poor overall survival. The association between ERG transcription factor and anti-androgen therapy (enzalutamide (arm A) vs. bicalutamide (arm B)) responsiveness was evaluated in a randomized trial in metastatic hormone sensitive prostate cancer (mHSPC). Methods: 40 of 71 patients had evaluable tissue from metastatic biopsy. 18 patients were on enzalutamide arm (A) and 22 patients were on bicalutamide arm (B). PSA was monitored monthly for first 7 months and then every 3 months. Total RNA was isolated from biopsy specimens, QPCR analysis was performed for ERG gene. A standard curve was developed with ERG expressing plasmid in QPCR experiment and the copy number of ERG was determined in the metastatic biopsies. Seven month PSA Response (SMPR) rates were calculated for the high and low subset categories of median-dichotomized ERG copy number. The odds of SMPR was modeled as a function of continuous ungrouped correlative via univariable logistic regression. Results: 15/40 patients had both pre and post treatment biopsies available. The mean ERG copy number was increased in post treatment biopsy in both arms (enzalutamide, n=10 and bicalutamide, n=5). The mean copy increased (pre= 8541 and post =9789) upon enzalutamide treatment and also increased (pre=17186 and post = 23368) upon bicalutamide treatment. SMPR rates show that low copy number patients responded better (19/20) compared to high copy number patients (14/20). In arm A response rate is 100% (18/18), whereas in arm B, low ERG copy number patients responded better (8/11) compared to high copy number patients (7/11). Finally, the SMPR odds ratio remained close to 1.000 even for large copy number increase. Selective ERG responsive gene expression levels were determined in metastatic biopsies and will be associated with clinical endpoints. Conclusions: Enzalutamide improved the likelihood of PSA remission in mHSPC and follow up is ongoing. Metastatic biopsy specimen analysis show that higher ERG copy number had a lower likelihood of PSA response with ADT and may serve as a prognostic or predictive marker, but further analysis is warranted. Citation Format: Sreenivasa R. Chinni, Ulka N. Vaishampayan, Lance K. Heilbrun, Louie Semaan, Daryn Smith, Dipenkumar Modi, Paul Monk, Shiela Tejwani, Guru Sonpavde, Kimberlee Dobson, Brenda Dickow, Elisabeth Heath, Joseph Fontana, Micheal L. Cher. Evaluation of ERG as a biomarker of responsiveness in a randomized trial of enzalutamide in combination with androgen deprivation in metastatic hormone sensitive prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-309.

Genomic variations associated with prostate cancer in large cohort of African American men.

20 Background: Racial disparities in prostate cancer (PCa) incidence and mortality are well known. PCa is known to be more aggressive in African American men (AAM) in terms of higher incidence and mortality rates. Here we validate a tumor gene expression pan-cancer race model in men with PCa and further characterize genomic differences that may contribute to disparate clinical outcomes Methods: We obtained de-identified genome-wide expression profiles from clinical use of the Decipher RP test in 9,953 men from the GRID registry database. A subset of men (n = 313) had known race status. A pan-cancer race model, developed to predict patient AAM race from analysis of gene expression patterns in 4,162 tumors from retrospective cohorts with known race status was applied to the prospective cohort for race prediction. Gene expression data was used to define genomic differences. Results: The race model has an AUC of 0.98 discriminating EAM from AAM in independent PCa cohort. The model was then applied to the 9,640 GRID patients with unknown race status and classified 6,831 as EAM, 1,058 as AAM with 1,751 as having indeterminate race. Characterizing the molecular subtypes, we found known and predicted AAM to be enriched with SPINK1+ tumors (21% and 24%, respectively) compared to predicted EAM (8%). In contrast, while ERG+ was found 22% and 19% in known and predicted AAM, respectively compared to 46% in predicted EAM. Based on PAM50 prostate cancer classifier, 61% of AAM were classified as basal-like tumors, whereas 41% were basal-like in EAM. Similarly, 28% of AAM had low AR-A while only 11% of EAM had low AR-A. AAM tumors had higher levels of immune infiltration signatures as well as higher scores for inflammatory and interferon gamma responses, and Interleukin 6 (IL6) signaling activity scores. AAM had lower DNA repair and glycolysis pathway activity compared to EAM Conclusions: Known and predicted AAM, were enriched with SPINK1+ tumors, higher immune infiltration and activation but lower ERG+, DNA repair and AR activity tumors. Using such large GRID data with known race, we will further understand the underlying causes associated with prostate cancer racial disparities which could lead to personalized diagnosis and treatment.

Unsupervised Cluster Analysis of Antigen Expression Patterns Identifies Subgroups with Distinct Biological and Clinical Features in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation

Characterisation of antigen expression patterns is part of the standard diagnostic work-up in acute myeloid leukemia (AML). But the biological & clinical implication of such antigen expression patterns have not been studied extensively & remain unclear in AML patients (pts) undergoing allogeneic stem cell transplantation (SCT).We analyzed the diagnostic antigen expression patterns of 162 AML pts (median age 64.7 years [y, range 46.6-76.2y]) with available data who received allogeneic peripheral blood SCT after non-myeloablative conditioning (NMA-SCT) between 2001 & 2013 at our institution. Conditioning regimen was fludarabine 3x30mg/m2 & 2Gy total body irradiation. Donors were human leukocyte antigen (HLA) matched related (12%) or HLA matched (59%) or mismatched unrelated (29%). Mutation (mut) status of the NPM1, CEBPA, IDH1, IDH2 &DNMT3A gene, presence of FLT3 -ITD &FLT3-TKD & the expression status of BAALC, ERG, MN1, EVI1, miR-9 &miR-181a at diagnosis were accessed. Pts were grouped according to the European LeukemiaNet (ELN) genetic classification in 22% favorable (fav), 24% intermediate-I (int-I), 21% intermediate-II (int-II) & 32% adverse (adv). Median follow up was 3.2y. To assess antigen expression patterns at diagnosis for all pts, flow cytometric analysis utilizing a standard panel (CD2, CD7, CD11b, CD13, CD14, CD15, CD33, CD34, CD38, CD45, CD56, CD61, CD64, CD65, CD117 & Glycophorin A) of mononuclear cells in bone marrow (BM) was performed. Using R's gplot package we performed unsupervised hierarchical clustering of the antigen expression which revealed 4 subgroups with distinct antigen expression patterns (Figure 1).At diagnosis, pts grouped in cluster 1 (n=19) had higher white blood count (WBC, P =.004) & lower peripheral blood (PB) blast count (P =.03) & were more likely to have de novo AML (P =.05). They were also less likely to have trisomy 8 (P =.08) by trend & more likely to have normal karyotype (KT, P =.05), to have ELN fav risk (P =.04), to be NPM1 mut (P =.002) & to be DNMT3A mut by trend (P =.08) & had lower miR-181a (P =.04), lower BAALC (P<.001), lower ERG (P =.01) & lower MN1 expression (P<.001).Pts grouped in cluster 2 (n=35) had higher WBC (P<.001), PB blasts (P<.001) & BM blasts (P =.005) at diagnosis. They were less likely to have trisomy 8 (P =.008) & to have deletion (del) 7/7q (P =.07) by trend, were more likely to be NPM1 mut (P =.002) & to have FLT3 -ITD (P <.001) & had lower BAALC (P =.1) & lower EVI1 expression (P =.09) by trend.Pts grouped in cluster 3 (n=59) had lower WBC (P<.001), PB blasts (P<.001) & BM blasts (P<.001) at diagnosis & were less likely to have de novo AML (P<.001). They were more likely to have trisomy 8 (P =.05), del5/5q (P =.004), monosomal KT (P =.04), complex KT (P =.07) by trend & ELN adv risk (P =.04), were less likely to be NPM1 mut (P =.03) &FLT3 -ITD by trend (P =.08) & had lower ERG (P =.008) & higher miR-9 (P =.009) expression.Pts grouped in cluster 4 (n=49) had lower WBC (P =.03), higher PB blasts (P =.007) & BM blasts (P<.001) at diagnosis. They were less likely to have del5/5q (P =.008) &NPM1 mut (P <.001) & had lower miR-9 (P =.007) & higher BAALC (P<.001), ERG (P<.001) &MN1 (P<.001) expression.For the entire set of pts, belonging to one of the antigen expression clusters did not impact on outcome. However, when the ELN groups were regarded separately, within the ELN fav group, cluster 1 pts had a significantly shorter event free survival (EFS, P =.04, Figure 2A) & within the ELN int-I group, cluster 3 pts had a trend for better (P =.096) & cluster 4 pts for worse EFS (P =.087).In conclusion, the antigen expression patterns at diagnosis obtained by unsupervised cluster analysis associated with distinct biological & clinical features (Figure 2B): NPM1 mut were enriched in clusters 1 & 2. Cluster 1 was characterized by ELN fav risk, normal KT, de novo disease & lower BAALC, ERG, MN1 &miR-181a expression. Cluster 2 was characterized by a high incidence of FLT3-ITD. We found more pts with ELN adv risk, monosomal KT, secondary AML & low miR-9 expression in cluster 3 & higher miR-9 as well as lower BAALC, ERG &MN1 expression levels in cluster 4. Even though we did not observe a prognostic impact of the antigen expression patterns in the entire cohort, the patterns may help to refine the ELN risk classification for AML pts undergoing SCT. Assessing the diagnostic antigen expression patterns provides information on disease biology, clinical parameters and potentially disease aggressiveness in AML. [Display omitted] [Display omitted] DisclosuresFranke:BMS: Honoraria; MSD: Other: Travel Costs; Novartis: Other: Travel Costs. Niederwieser:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Racial/ethnic variation in a common genetic alteration in prostate cancer.

14 Background: The molecular basis of racial/ethnic differences in the detection and outcomes of the carcinoma of the prostate (CaP) needs to be better defined to improve biomarkers and identify appropriate therapeutic targets. ETS-related gene fusions in proto-oncogenes (ERG, ETV1) are among the most common early oncogenic alterations described in CaP. Studies have highlighted the racial/ethnic variation in ERG fusion and ERG oncoprotein expression frequencies showing: the highest frequencies in Caucasian (CA) men, the lowest frequencies in Asian men, and intermediate frequencies in African American (AA) men. These differences persisted when patients were carefully matched for age and clinico-pathologic features. Building on previous work, the current study was conducted to evaluate ERG expression frequencies in a large cohort of AA and CA CaP patients. Methods: Patients enrolled at the Walter Reed National Military Medical Center who consented to provide radical prostatectomy (RP) specimens to the CPDR Tissue Bank and Clinical Database were evaluated. The current study included 443 AA and 696 CA patients. ERG oncoprotein expression was detected by immunohistochemistry using the 9FY mouse monoclonal anti-ERG antibody and was correlated with clinico-pathologic features and CaP outcomes. Results: Lower frequencies of ERG in the index tumors of AA men as compared to CA men (28.4% vs. 51.5%, p &lt; 0.0001) were observed. Furthermore, AA men with higher grade CaP (Gleason 8-10) had even lower ERG frequency (16%), suggesting distinct molecular biologic features in aggressive CaP for AA men. A trend with age was observed for both racial groups, with younger CA showing higher ERG frequencies. At least one focus of ERG positive PIN was present in prostates with ERG positive tumors. In both CA and AA patients, a very low frequency (8%) of ERG expression was noted in anterior index tumors compared to posterior tumors. Conclusions: This study lends increasing support to differences of the most common early genomic alteration (ERG) between AA and CA CaP patients. The study also underscores the importance of identifying new or improving existing biomarkers with consideration of patient race/ethnicity.

Abstract C18: ERG-focused evaluations of prostate cancer of African American men and its potential impact on utility in biomarker development and in enhanced personalized medicine

Abstract Introduction: Prostate cancer incidence and associated mortality is highest in African American men in comparison to other ethnicities. The observed differences in incidence and disease aggressiveness at presentation support a potential role for different biochemical pathways of prostate carcinogenesis between African American and Caucasian men. Emerging observations of the ethnic differences of the ERG oncogenic activation, the most common prostate cancer genomic alteration described in Western countries, provides new insights into the ERG based stratification of prostate cancers in the context of the increasingly diverse ethnic patient populations in The United States. This rapidly advancing knowledge has potential to stratify prostate cancers by ERG typing in a given patient population that may eventually lead to new targeted treatments. Experimental procedures: For the comparative evaluation of ERG frequencies, ERG oncoprotein expression was analyzed in whole-mounted sections of 91 Caucasian American and 91 African American prostate cancer cases matched for age, Gleason score and pathologic stage. To evaluate the association of high grade tumors with ERG status prostate cancer specimens with a primary Gleason pattern of 4 or 5 or cumulative Gleason score of 8-10 from a total of 63 African American patients and 63 Caucasian American patients matched for age. For the comprehensive evaluation of ERG frequencies in African American patients we have examined 306 whole mounted prostate specimens representing hormone naïve cases with a minimum of two years of follow up after radical prostatectomy. ERG oncoprotein was evaluated by immunohistochemistry in all cases and the genomic rearrangement of the ERG gene was assessed in selected cases by FISH assy. Results: Markedly greater frequencies of ERG oncoprotein expression was noted in the index tumors of the Caucasian Americans (63.3%) compared to the African Americans (28.6%). The observed difference was even more pronounced in higher grade disease indicating significantly lower ERG frequencies among African American (16%) patients in comparison to Caucasian American men (49%). Comprehensive evaluation of ERG frequencies revealed that ERG positive tumors were more likely to be present in index tumors of younger African American men, whereas, ERG negative tumors were significantly associated with higher pathologic T stage when all tumors were assessed. Conclusions: ERG-based stratification defines molecular subtypes of prostate cancers. Association of ERG negative status with high grade tumors and poor prognostic features in African American patients warrants the development of informative marker panels that includes ERG to aid in diagnostic, prognostic and targeted therapy settings. The results of the present study underscore that typing prostate cancers for ERG significantly contributes to the understanding of causal alterations resulting in higher incidence and associated mortality among African American prostate cancer patients. Citation Format: Albert Dobi, Philip Rosen, James Farrell, Michael Degon, Denise Young, Sudhir Srivastava, Jacob Kagan, Gyorgy Petrovics, Jennifer Cullen, David G. McLeod, Isabell A. Sesterhenn, Shiv Srivastava. ERG-focused evaluations of prostate cancer of African American men and its potential impact on utility in biomarker development and in enhanced personalized medicine. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C18. doi:10.1158/1538-7755.DISP13-C18

ERG Overexpression Is Highly Associated With ERG Gene Amplifications In Patients With Myeloid Malignancies

BackgroundThe proto-oncogene ERG is located on chromosome 21q22 and overexpression of ERG was shown to have an adverse impact on outcome in cytogenetically normal AML (CN-AML). Acquired gain of chromosome 21 (+21) is a recurrent cytogenetic abnormality in AML, however, the pathogenetic impact remains elusive. Data indicate that +21 could be the underlying mechanism for altered expression of genes located in the respective regions, such as ERG, which might contribute to the pathogenesis in myeloid malignancies with +21. Aims1) To investigate a possible relationship between ERG copy numbers and variations in ERG mRNA expression levels in patients (pts) with myeloid malignancies. 2) Analysis of ERG expression in CN-AML to reveal a possible association between ERG overexpression and other relevant molecular markers and to ascertain the prognostic impact of ERGin context of these markers. MethodsERG mRNA expression and ERG copy numbers were analyzed using a hydrolysis probe based real-time PCR assay. 1) To address ERG expression in relation to +21 the following cohorts were analyzed: 62 AML pts with a complex karyotype including +21 (CK+21); 44 AML pts with a non-complex aberrant karyotype including +21 (AK+21); 19 pts with various myeloid malignancies (10 de novo AML, 3 MDS, 1 s-AML, 2 t-AML, 1 MDS/AML, 1 t-MDS, 1 MDS/MPN) all of them showing ERG amplification by interphase FISH and array CGH (ERG-Amp). In addition, 32 CK-AML and 330 CN-AML pts without +21 or ERGamplification were analyzed. Results were expressed as mean values±SEM. Expression levels/DNA copy numbers were compared by t-test. 2)ERG expression was assessed in a cohort of 330 patients (<65 years) with de novo CN-AML. Female/male ratio was 169/161. To distinguish low from high ERG expressers the median %ERG/ABL1 level was used. BAALC expression levels were analyzed accordingly. Expression levels were correlated with clinical outcome and with the presence of mutations (mut) in ASXL1 (n=330), CEBPA (n=330), DNMT3A (n=261), FLT3-TKD (n=330), IDH1R132 (n=328), IDH2R140 (n=328), IDH2R172 (n=328), NPM1 (n=330), NRAS (n=330), RUNX1 (n=329), TET2 (n=166), WT1 (n=329) and FLT3-ITD (n=330), and with MLL-PTD (n=330) and BAALCexpression (n=328). Results1) Analysis of pts with +21 or ERG-Amp revealed significantly higher expression levels of ERG in pts with +21 (AK+21 and CK+21 combined, 331 ± 28) and ERG-Amp (606 ± 127) as compared to pts with CN-AML (229 ± 10; p=0.001, p=0.008, respectively) or CK-AML (177 ± 36; p=0.001, p=0.004, respectively). Mean ERG expression was even higher in pts with ERG-Amp (606 ± 127) as compared to pts with +21 (331 ± 28, p=0.047). Quantification of ERG copy numbers on DNA level showed good correlation to ERG mRNA expression, with abundantly higher ERG DNA amount in +21 (3.25 ±0.14) and moreover in ERG-Amp (9.21 ±1.05) as compared to CN-AML and CK-AML (combined: 2.20 ± 0.05; p<0.001 and p<0.001, respectively). 2) In CN-AML, %ERG/ABL1 levels ranged from 0.078 to 1,016.027 (median: 188.904). High ERG expression was associated with lower age (mean: 48.7 vs. 52.4 years, p=0.002), higher white blood cell (WBC) count (mean: 64.8 vs. 44.4 x 109/L, p=0.019), FLT3-ITDmut/wt ratio≥0.5 (51/165, 30.9% vs. 24/165, 14.5%, p=0.001), IDH2R172mut (6/164, 3.7% vs. 0/164, 0.0%, p=0.030) and high BAALC expression (104/164, 63.4% vs. 59/164, 36.0%, p<0.001), as compared to low ERG expression. In contrast, NPM1mut (91/165, 55.2% vs. 118/165, 71.5%, p=0.003), IDH1R132mut (10/165, 6.1% vs. 29/163, 17.8%, p=0.001) and TET2mut (10/76, 13.2% vs. 22/90, 24.4%, p=0.077) were less frequent in high ERG expressers. Survival analysis revealed inferior overall survival (OS at 3 years: 52.2% vs. 68.7%, p=0.021) and event free survival (EFS at 3 years: 34.6% vs. 43.1%, p=0.052) for high ERG expressers as compared to low ERG expressers. In a multivariate analysis adjusted for age, WBC, BAALC expression, FLT3-ITDmut/wt ratio≥0.5, MLL-PTD and WT1mut, high ERG expression revealed a trend towards an adverse impact on OS (p=0.069), while no impact on EFS was observed. Conclusions1) Gain of chromosome 21 and especially amplification of chromosomal band 21q22 is a mechanism for ERG overexpression. This might indicate ERG as an important factor contributing to the pathogenesis and progression of myeloid malignancies with gain of chromosome 21. 2) In CN-AML, ERG overexpression is associated to several molecular markers and has a negative impact on OS and EFS. Disclosures:Weber:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Noel:MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Loss of CDKN1B/p27Kip1 expression is associated with ERG fusion-negative prostate cancer, but is unrelated to patient prognosis

The cyclin-dependent kinase inhibitor p27Kip1 has been suggested as a prognostic marker in prostate cancer. The aim of this study was to determine the clinical and prognostic role of p27 expression in hormone-naive prostate cancers. A tissue microarray containing samples from 4,699 prostate cancers with attached pathological, clinical follow-up and molecular data was analyzed for nuclear p27 expression by immunohistochemistry. p27 staining was negative in 18.6%, weak in 33.5%, moderate in 28.4% and strong in 19.5% of 3,701 interpretable cancer spots. Loss of p27 immunostaining was linked to tumors of low Gleason grade (P<0.0001) and ERG fusion-negative cancers (P<0.0001). p27 levels were not associated with other parameters, including tumor stage, nodal stage, preoperative prostate-specific antigen (PSA) levels, surgical margin status and cell proliferation (as measured by the Ki67 labeling index). p27 expression was also unrelated to clinical outcome in all cancers, as well as in the subsets of ERG fusion-positive and -negative cancers. Overall, the present data demonstrated that elevated p27 expression was often unrelated to prostate cancer phenotype. Furthermore, the lack of an effect of the p27 protein levels on PSA recurrence following radical prostatectomy indicated that factors other than p27 expression are likely to be the major determinants of prostate cancer recurrence. However, a subset of ERG-negative, low-grade tumors was frequently characterized by loss of p27, suggesting a role of this alteration for the development of these tumors.

Abstract 1920: Variation of ERG oncoprotein expression in prostate cancer patients with different ethnicities.

Abstract Introduction and Objectives: ERG gene fusions leading to ERG overexpression represent a highly prevalent oncogenic alteration (50-70%) in prostate cancer (CaP) patients of Caucasian ethnicity. We and others noted lower ERG frequency in CaP of African Americans (AA) in comparison to Caucasian Americans (CA). There is no study of ERG alterations in CaP patients from India. This study focused on comparative analysis of the frequency of ERG oncoprotein expression in CaP patients with Asian (India, Japan), African (AA) and Caucasian (CA) ethnicity. Materials and Methods: Coded archived FFPE tissue blocks from radical prostatectomy (RP) specimens of 51 patients from the Rajiv Gandhi Cancer Institute (RGCI), New Delhi, India, were analyzed for the presence of ERG oncoprotein by immunohistochemistry (IHC) using a highly specific ERG monoclonal antibody (ERG MAb, 9FY). From Japan, tissue microarray (TMA) derived from surgical specimens of 64 patients (160 cancer spots) with localized CaP was analyzed by the same anti-ERG MAb. A USA cohort of whole mount prostate specimens, minimizing sampling bias and allowing for assessment of ERG in multifocal tumor context, from 91 AA and 91 CA CaP patients (matched for age, Gleason score and pathologic stage) was analyzed by ERG IHC. Results: Of thirty evaluable specimens from India, ERG positive tumors were present in 8 cases (27%). Among 64 patients from Japan, 16 patients (25%) showed at least one positive cancer spot for ERG expression in the TMA. No correlation between ERG status and Gleason score or PSA failure was found. Systematic evaluation of whole mount prostatectomy specimens revealed that the frequency of ERG positive prostate tumors was significantly greater among CA than AA men when assessed in all tumor foci (41.9% vs. 23.9%, p&amp;lt;0.0001) or in index tumors (63.3% vs. 28.6%, p&amp;lt;0.0001). Conclusions: Frequency of ERG oncoprotein expression is much lower in CaP patients with Asian (25-27%) or African (28%) descent than in CaP patients with European descent (63%). This study underscores that typing of prostate tumors for ERG may enhance our understanding of biological differences between ethnic groups. This research in part was supported by the National Cancer Institute R01CA162383 (S. S.) and USU-CPDR funds. Citation Format: Gyorgy Petrovics, Sudhir Rawal, Molly Williams, Philip Rosen, David Pfister, Takahiro Inoue, Osamu Ogawa, Monica Colombo, Yongmei Chen, Denise Young, Albert Dobi, David G. McLeod, Isabell Sesterhenn, Shiv Srivastava. Variation of ERG oncoprotein expression in prostate cancer patients with different ethnicities. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1920. doi:10.1158/1538-7445.AM2013-1920

ERG protein expression reflects hormonal treatment response and is associated with Gleason score and prostate cancer specific mortality

BackgroundERG (ETSregulated gene) protein expression has been shown to reflect ERG genomic rearrangements in prostate cancer (PCA). However, ERG protein expression prognostic value has not been yet investigated. DesignERG protein expression was investigated in a cohort of 312 men with PCA diagnosed in transurethral resection of the prostate. ResultsERG expression was detected in 76/293 (25.9%) of patients. Overall ERG expression was associated with Gleason score (GS) (p<0.0001), tumour volume (p=0.04) and with cancer specific mortality (p=0.15). Low ERG intensity was significantly associated with higher GS (p=0.02) and marginally with cancer specific mortality (p=0.11). The association with caner specific mortality was more significant in patients without any hormonal manipulation (p=0.02). Multivariate Cox model using GS, tumour volume and ERG intensity to predict time to cancer specific death yielded a marginally significant effect for high versus low ERG protein expression (hazard ratio (HR)=0.36; 95% confidence interval (CI): 0.10–1.38; p=0.14) and a non-significant effect for GS >7 (HR=4.85; 95%CI: 0.48, 48.65; p=0.18). Men with ERG expression showed longer free progression time to castration resistant disease compared to men with no ERG expression (mean 11.39 versus 6.1months, p=0.08). ConclusionWe report significant association between ERG protein levels and each of GS, progression to castration resistant and cancer specific mortality. High ERG intensity was associated with lower GS, better overall survival and longer free progression times to castration resistant disease. ERG protein levels may have prognostic and therapeutic role in PCA and should be investigated in future studies.

Pediatric-inspired intensified therapy of adult T-ALL reveals the favorable outcome of NOTCH1/FBXW7 mutations, but not of low ERG/BAALC expression: a GRAALL study

AbstractDespite recent progress in the understanding of acute lymphoblastic leukemia (T-ALL) oncogenesis, few markers are sufficiently frequent in large subgroups to allow their use in therapeutic stratification. Low ERG and BAALC expression (E/Blow) and NOTCH1/FBXW7 (N/F) mutations have been proposed as powerful prognostic markers in large cohorts of adult T-ALL. We therefore compared the predictive prognostic value of N/F mutations versus E/Blow in 232 adult T-ALLs enrolled in the LALA-94 and Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocols. The outcome of T-ALLs treated in the pediatric-inspired GRAALL trials was significantly superior to the LALA-94 trial. Overall, 43% and 69% of adult T-ALL patients were classified as E/Blow and N/F mutated, respectively. Strikingly, the good prognosis of N/F mutated patients was stronger in more intensively treated, pediatric-inspired GRAALL patients. The E/B expression level did not influence the prognosis in any subgroup. N/F mutation status and the GRAALL trial were the only 2 independent factors that correlated with longer overall survival by multivariate analysis. This study demonstrates that the N/F mutational status and treatment protocol are major outcome determinants for adults with T-ALL, the benefit of pediatric inspired protocols being essentially restricted to the N/F mutated subgroup.

BAALC and ERG expression levels are associated with outcome and distinct gene and microRNA expression profiles in older patients with de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study

AbstractBAALC and ERG expression levels are prognostic markers in younger (< 60 years) cytogenetically normal acute myeloid leukemia (CN-AML) adults; their prognostic impact in older (≥ 60 years) patients requires further investigation. We evaluated pretreatment expression of BAALC and ERG in 158 de novo patients treated on cytarabine/daunorubicin-based protocols. The patients were also characterized for other established molecular prognosticators. Low BAALC and ERG expression levels were associated with better outcome in univariable and multivariable analyses. Expression levels of both BAALC and ERG were the only factors significantly associated with overall survival upon multivariable analysis. To gain biological insights, we derived gene expression signatures associated with BAALC and ERG expression in older CN-AML patients. Furthermore, we derived the first microRNA expression signatures associated with the expression of these 2 genes. In low BAALC expressers, genes associated with undifferentiated hematopoietic precursors and unfavorable outcome predictors were down-regulated, whereas HOX genes and HOX-gene–embedded microRNAs were up-regulated. Low ERG expressers presented with down-regulation of genes involved in the DNA-methylation machinery, and up-regulation of miR-148a, which targets DNMT3B. We conclude that in older CN-AML patients, low BAALC and ERG expression associates with better outcome and distinct gene and microRNA expression signatures that could aid in identifying new targets and novel therapeutic strategies for older patients.

Abstract 4963: ERG expression levels reflect functional status of androgen receptor in prostate cancer

Abstract Background: Expression of the ERG proto-oncogene, is activated in 50-70% of prostate tumors by androgen receptor (AR) mediated signals due to the fusion of AR regulated promoters (primarily TMPRSS2 and to a lesser extent SLC45A3 and NDRG1) to the ERG protein coding sequence. Our previous studies of quantitative expression levels of ERG or TMPRSS2-ERG fusion transcripts have noted that relatively low or no ERG expression in prostate tumors significantly associated with progressive disease. Here, we have tested the hypothesis that ERG expression levels in prostate tumor cells reflect AR transcriptional regulatory function in a given biological context of the tumor progression. Therefore, tumors with lower ERG may represent a subset with attenuated AR signaling. Experimental procedures: Expression of ERG and other AR regulated genes were evaluated in a GeneChip dataset obtained from a panel of laser capture micro-dissected well/moderately differentiated (WD) or poorly differentiated (PD) tumor cells derived from primary tumors of patients, who had no prior androgen ablation treatment. Results: ERG expression pattern was similar to that of other AR regulated genes. Low frequency of ERG expression was noted in PD tumor cells (30%) in comparison to WD tumor cells (80%), suggesting for subdued AR function in a significant fraction of tumors with genomic alterations of ERG. Conclusions: We developed a cumulative AR Function Index (ARFI) by integrating ERG into a panel of defined AR target genes, may have future potential in stratifying patients for targeted therapy on the basis of overall AR functional status in primary tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4963.

1429 IN VIVO READOUT OF ANDROGEN RECEPTOR (AR) FUNCTIONAL STATUS IN PRIMARY TUMORS FOR PATIENT STRATIFICATION

You have accessJournal of UrologyProstate Cancer: Basic Research VIII1 Apr 20101429 IN VIVO READOUT OF ANDROGEN RECEPTOR (AR) FUNCTIONAL STATUS IN PRIMARY TUMORS FOR PATIENT STRATIFICATION Gyorgy Petrovics, Bungo Furusato, Syed Shaheduzzaman, Yongmei Chen, Timothy Nydam, Lakshmi Ravindranath, Amina Ali, Maryanne Vahey, Isabell Sesterhenn, David McLeod, Albert Dobi, and Shiv Srivastava Gyorgy PetrovicsGyorgy Petrovics Rockville, MD More articles by this author , Bungo FurusatoBungo Furusato Washington, DC More articles by this author , Syed ShaheduzzamanSyed Shaheduzzaman Rockville, MD More articles by this author , Yongmei ChenYongmei Chen Rockville, MD More articles by this author , Timothy NydamTimothy Nydam Washington, DC More articles by this author , Lakshmi RavindranathLakshmi Ravindranath Rockville, MD More articles by this author , Amina AliAmina Ali Washington, DC More articles by this author , Maryanne VaheyMaryanne Vahey Silver Spring, MD More articles by this author , Isabell SesterhennIsabell Sesterhenn Washington, DC More articles by this author , David McLeodDavid McLeod Washington, DC More articles by this author , Albert DobiAlbert Dobi Rockville, MD More articles by this author , and Shiv SrivastavaShiv Srivastava Rockville, MD More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1122AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Expression of the ERG proto-oncogene is activated in 50-70% of prostate tumors by AR mediated signals due to the fusion of AR regulated promoters (primarily TMPRSS2 and to a lesser extent SLC45A3 and NDRG1) to the ERG protein coding sequence. Our previous studies of quantitative expression levels of ERG or TMPRSS2-ERG fusion transcripts have noted that relatively low or no ERG expression in prostate tumors significantly associated with progressive disease. Here, we have tested the hypothesis that ERG expression levels in prostate tumor cells reflect AR transcriptional regulatory function in a given biological context of the tumor progression. Therefore, tumors with lower ERG may represent a subset with attenuated AR signaling. METHODS From over 300 radical prostatectomy (RP) specimens archived in the CPDR Biospecimen Bank with 8-13 years follow-up, 40 frozen tissue specimens were selected for this study: 20 with well/moderately differentiated (WD) tumor and less aggressive clinical features, and 20 with poorly differentiated (PD) tumor and more aggressive clinical characteristics, all from patients with no prior androgen ablation treatment. Prostate epithelial cells with tumor and benign morphology were microdissected (LCM) and the extracted RNA was analyzed by GeneChip technology (Affymetrix) after linear amplification. A selected set of known androgen regulated genes was used as in vivo AR readout (androgen receptor function index = ARFI). Correlation of ERG with ARFI and with clinico-pathological parameters was analyzed by conventional statistical approaches. RESULTS Positive regulation of ERG in the TMPRSS2-ERG fusion context by functional androgen signaling was evident in the majority of human prostate tumors, while absence of ERG tightly correlated with deregulated expression of AR target genes. Overall, ERG expression pattern was similar to that of other AR regulated genes. Strikingly low frequency of ERG expression was noted in PD tumor cells (30%) in comparison to WD tumor cells (80%), suggesting for subdued AR function in a significant fraction of tumors with genomic alterations of ERG. CONCLUSIONS By integrating ERG into a panel of defined AR target genes, we developed a cumulative AR Function Index (ARFI), which if validated may have future potential in stratifying patients for targeted therapy on the basis of overall AR functional status in primary tumors. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e551 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Gyorgy Petrovics Rockville, MD More articles by this author Bungo Furusato Washington, DC More articles by this author Syed Shaheduzzaman Rockville, MD More articles by this author Yongmei Chen Rockville, MD More articles by this author Timothy Nydam Washington, DC More articles by this author Lakshmi Ravindranath Rockville, MD More articles by this author Amina Ali Washington, DC More articles by this author Maryanne Vahey Silver Spring, MD More articles by this author Isabell Sesterhenn Washington, DC More articles by this author David McLeod Washington, DC More articles by this author Albert Dobi Rockville, MD More articles by this author Shiv Srivastava Rockville, MD More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

Detection of ERG and MN1 Gene Expression in Adult Patients with De Novo Acute myeloid Leukemia(AML) by Real-Time Quantitative Polymerase Chain Reaction and Its Clinical Significance.

Abstract 4706 IntrodutionCurrent study found that certain genetic abnormalities are related to the prognosis of AML, such as ERG and MN1 gene expression. However, little is known about the clinical significance of ERG and MN1 expression level in Chinese patients with AML and and their correlation. Patients and methodsA real time quantitative reverse transcriptase polymerase chain reaction method was established for detecting ERG and MN1 gene expression levels in 87 de novo AML patients. ResultsThe median expression levels of ERG and MN1 in AML patient were statistically higher than that in normal control group (P<0.001). ERG gene expression had no correlation with MN1 gene expression (P=0.194) in AML patients. ERG and MN1 gene expressions were equally distributed among the FAB subtypes (P=0.850 and 0.870). Spearman's rank correlation showed that leukocyte counts and lactate dehydrogenase were significantly related to high ERG expression (P=0.005 and 0.032), but not significant correlation was found between hemoglobin and platelet counts. The ERG expression level of cases with middle and low risk group was lower than that of cases with high risk group (P<0.036). There was no significant difference of CR rates in high and low ERG and MN1 expression groups after chemical theropy (P=0.968 and 0.695). During the follow-up of one year, the cumulative relapse rates of high ERG expression groups was significantly higher than that of low ERG expression groups(P=0.039), and high ERG expression cases have a significantly worse OS than low ERG expression cases(P=0.005). ConclusionsThere isn't a linear correlation between ERG gene expression and MN1 gene expression in AML. Overexpression of ERG gene is a independent prognositic factor for AML. Quantification of the two gene expression together is not more effective to the judgement of prognosis in AML. Disclosures:No relevant conflicts of interest to declare.

NOTCH1/FBXW7 Mutations, but Not Low ERG/BAALC Expression, Identify a Major Subgroup of Adult T-ALL with a Favorable Outcome: a GRAALL Study.

Abstract 1568▪▪This icon denotes an abstract that is clinically relevant.Poster Board I-592Several somatic genetic abnormalities have been identified in T-ALL but therapeutic stratification still relies on clinical markers. NOTCH1 and/or FBXW7 (N/F) mutations both lead to activation of the NOTCH1 pathway and are amongst the most frequent mutations in T-ALL. We identified N/F mutations as a good prognostic marker, found in 70% of patients within the French LALA-94 and GRAALL-2003 prospective adult T-ALL trials, whereas the German GMALL group reported that low ERG and BAALC (E/B) transcript expression also predicts a highly favorable outcome in 41% of adult T-ALL (Baldus et al. J Clin Oncol. 2007 25(24):3739-45). In order to compare the predictive prognosis value of N/F mutations versus low E/B expression, we analyzed 189 adult T-ALL for both, including 107 previously reported cases and 82 unreported cases included within the ongoing GRAALL-2005 trial up to the first planned interim analysis.E/B were quantified by real time RT-PCR and the comparative cycle threshold (Ct) method was used to determine the relative expression levels for ERG and BAALC to ABL. T-ALL patients were classified as low E/B expressers (E/Blow) or high E/B expressers (E/Bhigh) as previously reported by Baldus et al. Despite the use of ABL rather than GPI as internal control, we observed the same incidence of E/Blow. 41% (n=77) of T-ALLs were classified as E/Blowand 59% (n=112) as E/Bhigh. 68% (n=128) of cases were mutated for NOTCH1 and/or FBXW7 (N/Fmut) and 32% (n=61) were germline for both (N/FGL). As expected E/Bhigh correlated with an immature phenotype (p<0.0001). There was no association between E/B expression level and F/Nmut (p=0.5) and no significant correlation for either N/F or E/B status with age and leucocytosis at diagnosis.There was no difference in overall survival (OS) and event free survival (EFS) between E/Bhigh and E/Blow (4-years OS: 57% v 55 %; 4-years EFS: 46% v 47%). In contrast, N/Fmut compared with N/FGL had a better OS (67% v 36%; P= .002) and EFS (56% v 32%; P=.008). When the LALA and GRAALL protocols were analyzed separately, N/Fmut retained their significant favorable outcome, including in the GRAALL-2003 and GRAALL-2005 trials, which give overall good results for T-ALL. E/B expression did not impact on prognosis in either the GRAALL trials (E/Bhigh OS =68% EFS= 64% v E/Blow OS= 62% EFS=50%) or the LALA trials (E/Bhigh OS =46% EFS= 30% v E/Blow OS= 39% EFS=29%) individually.Taken overall, our data demonstrate that N/Fmut, but not low E/B expression, identify a major subgroup (68%) of adult T-ALL with a highly favorable outcome that could justify individual therapeutic stratification for T-ALL. N/F mutation status is also better suited to individual patient stratification than the continuous spectrum of ERG and BAALC transcript expression. DisclosuresNo relevant conflicts of interest to declare.

Aberrant Gene Expression of BAALC and ERG in Older [≥60 Years (y)] De Novo Cytogenetically Normal Acute Myeloid Leukemia (CN-AML): A Cancer and Leukemia Group B (CALGB) Study.

Abstract 214BAALC &ERG are aberrantly expressed in younger (<60 y) adult CN-AML patients (pts), where expression levels of these genes are also associated with clinical outcome. Whether aberrant BAALC &ERG expression also occurs in older (≥60 y) CN-AML pts is unknown. To assess the BAALC &ERG expression levels in older CN-AML & their impact on outcome we studied pts ≥60 y (median age, 68 y; range 60–83) enrolled on cytarabine/daunorubicin-based protocols [CALGB 10201, 9720, 9420, 8923, 8525], with diagnostic blood samples available for quantitative RT-PCR analysis (n=158), that were also characterized for other molecular prognosticators (FLT3-ITD, FLT3-TKD, NPM1 &WT1 mutations). BAALC &ERG expression values were normalized to an internal control (ABL1), & the median gene expression value was used to define high & low expressers for BAALC &ERG. Gene (GEP) & microRNA (MEP) expression profiling were done using, respectively, Affymetrix U133 plus 2.0 & OSU CCC v4.0 arrays. At diagnosis, lower BAALC expression was associated with mutated NPM1 (P<.001) & low ERG expression (P<.001). Lower BAALC expressers had a higher complete remission rate (CR; 86% v 54%, P<.001) & longer disease-free (DFS; P=.006; 3y rates 19% v 12%) & overall survival (OS; P<.001; 3y 29% v 10%) than higher expressers. Lower ERG expression was associated with lower WBC (P=.005), % marrow (BM; P=.001) & blood (P<.001) blasts & absent FLT3-ITD (P<.001) & low BAALC expression (P<.001). Lower ERG expression also associated with longer DFS (P=.001; 3y 18% v 14%) & OS (P<.001; 3y 24% v 15%). In multivariable models (Table 1), low BAALC expression independently associated with CR & longer DFS. BAALC &ERG expression were the only factors associated with OS. Comparison of age-groups (60-69 y v ≥70 y; Table 2) showed BAALC expression had a stronger prognostic impact in ≥70 y pts; lower expression was associated with higher CR rates & longer DFS & OS. ERG expression had instead stronger prognostic impact in 60-69 y pts (Table 2); lower expression was associated with longer DFS & OS. GEP (482 probes) & MEP (22 probes) differentiated low from high BAALC expressers. Low BAALC expressers had down-regulation of stem cell markers (CD34, CD133) & unfavorable outcome predictors (HGF, MN1, CD200), & up-regulation of HOX genes &miR-10a &miR-10b. GEP (1554 probes) & MEP (11 probes) differentiating low from high ERG expressers showed low ERG expressers had down-regulation of DNMT3B & up-regulation of topoisomerase 1 (TOP1), which is associated with enhanced chemotherapy sensitivity. Among up-regulated microRNAs in low ERG expressers was miR-208a, which is predicted to target ERG. In conclusion, lower expression of both BAALC &ERG associated with better outcome in older CN-AML pts even in the context of other established prognostic molecular markers, but have different impact on age-groups. GEP & MEP provided novel information that may elucidate how differential expression levels of these genes contribute to leukemogenesis & aid in developing novel risk-adapted therapies.Table 1:Multivariable analyses for CR, DFS & OSVariables in the final modelCRDFSOSOR*PHR†PHR†PBAALC, low v high (median cut)4.32<.0010.64.030.49<.001‡ERG, low v high (median cut)----0.69.03WBC, each 50 unit increase0.68.02----NPM1, mutated v wild-type2.34.04----FLT3-ITD, any ITD v no ITD--1.79<.001‡--Age, each 10 year increase--0.65.047--*OR, odd ratio, >1 (<1) mean higher (lower) CR rate for the 1st category listed for the dichotomous variables & for the higher values of the continuous variables.†HR, hazard ratio, <1 (>1) indicate lower (higher) risk for an event for the first category listed for the dichotomous variables & for the higher values of the continuous variables. Variables considered in the models were those significant at α=0.20 in univariable analyses.‡Variable did not meet the proportional hazards assumption, a covariate was used to account for time dependence.Table 2:Age-Group comparison for CR, DFS & OSClinical endpointBAALC expressionERG expression60-69 y Pts (n=86)≥70 y Pts (n=72)60-69 y Pts (n=86)≥70 y Pts (n=72)LowHighPLowHighPLowHighPLowHighP% achieving CR8471.198837<.0018076.807153.15DFS, % in CR at 3 y1610.102314.03196<.0011725.48OS, % alive at 3 y2412.01358<.0012412.0062318.03The age-group clinical endpoints significantly associated with BAALC or ERG expression levels are denoted by bold type. Disclosures:No relevant conflicts of interest to declare.

Role of Multifocal Electroretinography in the Diagnosis of Idiopathic Macular Hole

To analyze the preoperative results of multifocal electroretinography (mfERG) in the fellow eyes of patients with idiopathic unilateral macular hole and to evaluate the usefulness of this method in predicting the likelihood of macular hole formation in the fellow eye. Over a period of 5 years, 80 eyes of 40 patients (mean age, 64.9 years) with unilateral idiopathic macular hole were examined. The diagnosis of idiopathic macular hole was confirmed by optical coherence tomography (OCT). The fellow eyes were intact in all cases. All patients underwent vitreoretinal surgery. Before the surgery, both eyes of the patients were examined by mfERG. During the follow-up period, the 40 fellow eyes were also observed by OCT, and the changes in the vitreofoveal attachment were investigated. The preoperative response densities and ring ratios of mfERG were analyzed in both eyes, and discriminant analysis was used to calculate the best separator function. Preoperative mfERGs demonstrated significantly lower mean response densities in the central area of the 40 eyes with macular hole than in the fellow eyes. During the follow-up period, macular hole was diagnosed in 13 fellow eyes by OCT. The preoperative values of the mfERGs in these eyes were significantly lower than in the other 27 cases. The mfERG ring ratios were significantly lower in the fellow eyes in which macular holes developed than in those that remained intact. The analysis of ERG in the fellow eyes of patients with macular hole seems clinically useful. The lower amplitude may forecast the propensity for subsequent development of a macular hole. Patients with low central ERG amplitude and lower ring ratios in the healthy fellow eyes should have stricter follow-up.