scholarly journals Tumour gene expression signature in primary melanoma predicts long-term outcomes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Manik Garg ◽  
Dominique-Laurent Couturier ◽  
Jérémie Nsengimana ◽  
Nuno A. Fonseca ◽  
Matthew Wongchenko ◽  
...  
Keyword(s):  
Immune Cell ◽  
Primary Melanoma ◽  
Gene Expression Signature ◽  
Gene Signature ◽  
Prognostic Information ◽  
Regional Lymph Nodes ◽  
Machine Learning Classification ◽  
Expression Signature ◽  
Risk Of Death ◽  
Signature Genes

AbstractAdjuvant systemic therapies are now routinely used following resection of stage III melanoma, however accurate prognostic information is needed to better stratify patients. We use differential expression analyses of primary tumours from 204 RNA-sequenced melanomas within a large adjuvant trial, identifying a 121 metastasis-associated gene signature. This signature strongly associated with progression-free (HR = 1.63, p = 5.24 × 10−5) and overall survival (HR = 1.61, p = 1.67 × 10−4), was validated in 175 regional lymph nodes metastasis as well as two externally ascertained datasets. The machine learning classification models trained using the signature genes performed significantly better in predicting metastases than models trained with clinical covariates (pAUROC = 7.03 × 10−4), or published prognostic signatures (pAUROC < 0.05). The signature score negatively correlated with measures of immune cell infiltration (ρ = −0.75, p < 2.2 × 10−16), with a higher score representing reduced lymphocyte infiltration and a higher 5-year risk of death in stage II melanoma. Our expression signature identifies melanoma patients at higher risk of metastases and warrants further evaluation in adjuvant clinical trials.

scholarly journals Tumour gene expression signature in primary melanoma predicts long-term outcomes: A prospective multicentre study

2020 ◽  
Author(s):  
Manik Garg ◽  
Dominique-Laurent Couturier ◽  
Jérémie Nsengimana ◽  
Nuno A. Fonseca ◽  
Matthew Wongchenko ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Cell ◽  
Primary Melanoma ◽  
Gene Expression Signature ◽  
Stage Ii ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Expression Signature ◽  
Expression Score

AbstractPurposePredicting outcomes after resection of primary melanoma remains crude, primarily based on tumour thickness. We explored gene expression signatures for their ability to better predict outcomes.MethodsDifferential expression analysis of 194 primary melanomas resected from patients who either developed distant metastasis (n=89) or did not (n=105) was performed. We identified 121 metastasis-associated genes that were included in our prognostic signature, “Cam_121”. Several machine learning classification models were trained using nested leave- one-out cross validation (LOOCV) to test the signature’s capacity to predict metastases, as well as regression models to predict survival. The prognostic accuracy was externally validated in two independent datasets.ResultsCam_121 performed significantly better in predicting distant metastases than any of the models trained with the clinical covariates alone (pAccuracy=4.92×10−3), as well as those trained with two published prognostic signatures. Cam_121 expression score was strongly associated with progression-free survival (HR=1.7, p=3.44×10−6), overall survival (HR=1.73, p=7.71×10−6) and melanoma-specific survival (HR=1.59, p=0.02). Cam_121 expression score also negatively correlated with measures of immune cell infiltration (ρ=−0.73, p<2.2×10−16), with a higher score representing reduced tumour lymphocytic infiltration and a higher absolute 5-year risk of death in stage II melanoma.ConclusionsThe Cam_121 primary melanoma gene expression signature outperformed currently available alternatives in predicting the risk of distant recurrence. The signature confirmed (using unbiased approaches) the central prognostic importance of immune cell infiltration in long-term patient outcomes and could be used to identify stage II melanoma patients at highest risk of metastases and poor survival who might benefit most from adjuvant therapies.Translational relevancePredicting outcomes after resection of primary melanoma is currently based on traditional histopathological staging, however survival outcomes within these disease stages varies markedly. Since adjuvant systemic therapies are now being used routinely, accurate prognostic information is needed to better risk stratify patients and avoid unnecessary use of high cost, potentially harmful drugs, as well as to inform future adjuvant strategies. The Cam_121 gene expression signature appears to have this capability and warrants evaluation in prospective clinical trials.

The Expression Signature of M3 AML Suggests Direct and Indirect Effects of PML-RARA on Target Genes.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 719-719 ◽  
Author(s):  
Jacqueline E. Payton ◽  
Nicole R. Grieselhuber ◽  
Li-Wei Chang ◽  
Mark A. Murakami ◽  
Wenlin Yuan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Cell Lines ◽  
Binding Sites ◽  
Expression Profiles ◽  
Gene Expression Signature ◽  
Myeloid Cell ◽  
Expression Signature ◽  
Signature Genes ◽  
Cell Fractions

Abstract In order to better understand the pathogenesis of acute promyelocytic leukemia (APL, FAB M3), we sought to determine its gene expression signature by comparing the expression profiles of 14 APL samples to that of other AML subtypes (M0, M1, M2, M4, n=62) and to fractionated normal whole bone marrow cells (CD34 cells, promyelocytes, PMNs, n=5 each). We used ANOVA and SAM (Significance Analysis of Microarrays) to select genes that were highly expressed in APL cells and that displayed low to no expression in other AML subtypes. The APL signature was then further refined by filtering genes whose expression in APL was not significantly different from that of normal promyelocytes, yielding 1121 annotated genes that reliably distinguish APL from the other FAB subtypes using unsupervised hierarchical clustering, both in training and validation datasets. Fold change differences in expression between M3 and other AML FAB classes were striking, for example: GABRE 35.4, HGF 21.3, ANXA8 21.3, PTPRG 16.9, PTGDS 12.1, PPARG 11.1, STAB1 9.8. A large proportion of the APL versus other FAB dysregulome was recapitulated when we compared APL expression to that of the normal pattern of myeloid development. We identified 733 annotated genes with significantly different expression in APL versus normal myeloid cell fractions. These dysregulated genes were assigned to 4 classes: persistently expressed CD34 cell-specific genes, repressed promyelocyte-specific genes, prematurely expressed neutrophil-specific genes and genes with high expression in APL and low/no expression in normal myeloid cell fractions. Expression differences in several of the most dysregulated genes were validated by qRT-PCR. We then examined the expression of the APL signature genes in myeloid cell lines and tumors from a murine APL model. The bona fide M3 signature was not apparent in resting NB4 cells (which contain t(15;17), and which express PML-RARA), nor in PR-9 cells following Zn induction of PML-RARA expression, suggesting that neither cell line accurately models the gene expression signature of primary APL cells. Most of the nodal genes of the mCG-PML-RARA murine APL dysregulome (Yuan, et al, 2007) are similarly dysregulated in human M3 cells; however, the human and mouse dysregulomes do not completely coincide. Finally, we have begun investigating which APL signature genes are direct transcriptional targets of PML-RARA. The promoters of the APL signature genes were analyzed for the presence of known PML-RARA binding sites using multiple computational methods. The analyses demonstrated that several transcription factors (EBF3, TWIST1, SIX3, PPARG) have putative retinoic acid response elements (RAREs) in their upstream regulatory regions. Additionally, we examined the promoters of some of the most upregulated genes (HGF, PTGDS, STAB1) for known consensus sites of these transcription factors, and found that all have putative binding sites for at least one. These results suggest that PML-RARA may initiate a transcriptional cascade that relies not only on its own activity, but also on the actions of downstream transcription factors. In summary, our studies indicate that primary APL cells have a gene expression signature that is consistent and highly reproducible, but different from commonly used human APL cell lines and a mouse model of APL. The molecular mechanisms that govern this unique signature are currently under investigation.

scholarly journals Loss of CITED1, an MITF regulator, drives a phenotype switch in vitro and can predict clinical outcome in primary melanoma tumours

2014 ◽  
Author(s):  
Jill Howlin ◽  
Helena Cirenajwis ◽  
Barbara. Lettiero ◽  
Johan Staaf ◽  
Martin Lauss ◽  
...  
Keyword(s):  
Target Genes ◽  
Molecular Subtype ◽  
Primary Melanoma ◽  
Gene Expression Signature ◽  
Reciprocal Relationship ◽  
Signature Genes ◽  
Phenotype Switch ◽  
Mrna And Protein Expression ◽  
Whole Genome Expression

CITED1 is a non-DNA binding transcriptional co-regulator whose expression can distinguish the ‘proliferative’ from ‘invasive’ signature in the phenotype-switching model of melanoma. We have found that, in addition to other 'proliferative' signature genes, CITED1 expression is repressed by TGFβ while the ‘invasive’ signature genes are upregulated. In agreement, CITED1 positively correlates with MITF expression and can discriminate the MITF-high/pigmentation tumor molecular subtype in a large cohort (120) of melanoma cell lines. Interestingly, CITED1 overexpression significantly suppressed MITF promoter activation, mRNA and protein expression levels while MITF was transiently upregulated following siRNA mediated CITED1 silencing. Conversely, MITF siRNA silencing resulted in CITED1 downregulation indicating a reciprocal relationship. Whole genome expression analysis identified a phenotype shift induced by CITED1 silencing and driven mainly by expression of MITF and a cohort of MITF target genes that were significantly altered. Concomitantly, we found changes in the cell-cycle profile that manifest as transient G1 accumulation, increased expression of CDKN1A and a reduction in cell viability. Additionally, we could predict survival outcome by classifying primary melanoma tumors using our in vitro derived ‘CITED1-silenced’ gene expression signature. We hypothesize that CITED1 acts a regulator of MITF, functioning to maintain MITF levels in a range compatible with tumourigenesis.

Identification of a gene expression signature predictive of clinical benefit in patients with advanced mucosal melanoma (MCM) treated with immune checkpoint blockade.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9546-9546
Author(s):  
Suthee Rapisuwon ◽  
Alexander Noor Shoushtari ◽  
Lee S. Gottesdiener ◽  
Douglas Buckner Johnson ◽  
Daniel Ying Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Checkpoint ◽  
Chemokine Receptors ◽  
Tumor Response ◽  
Gene Expression Signature ◽  
Gene Signature ◽  
Anatomical Location ◽  
Expression Signature ◽  
Response Data ◽  
Treg Development

9546 Background: MCM is a rare melanoma subtype (only 1% of melanomas in the US). MCM has a lower tumor mutational burden than cutaneous melanoma (CM). While some patients (pts) with MCM respond to immune checkpoint inhibitor (ICI) therapy, predictive markers of response have not been established. We analyzed a cohort of MCM from pts treated with ICI to identify gene expression signatures associated with tumor response and clinical outcome. Methods: Fifty-eight MCM specimens were collected from 3 institutions. RNA was extracted from FFPE tissue slides and analyzed by NanoString 770 Immune Profiling Panel. Gene expression profiles were linked to anatomical location and disease outcome after ICI therapy: response as defined by RECIST v1.1 and median overall survival (mOS). Results: Fifty-one pts were treated with ICI - anti-CTLA-4 (n = 9), anti-PD1 (n = 38), or both (n = 5) ) and had tumor response evaluation. Three were without response data, 2 were without disease recurrence after surgery, 2 did not receive ICI. Among 51 pts with response data, seven were without long-term follow-up (1CR, 2PR, 3SD). The overall response rate (ORR) was 40.3%, similar to the prior study (Shoushtari et al, Cancer 2016). A signature involving differential expression of 87 immunoregulatory genes correlated with tumor response: ORR: 75% (12/16) signature high vs. 33.3% (7/21) signature low (p = 0.02, high vs. low) vs. 14.3% (2/14) signature average (p < 0.01; high vs. average). mOS for the whole population was 12.4 months. Pts with increased gene signature expression had superior mOS: signature-high: Not reached, signature-low: 8.2 months, (HR: 0.2; 95%CI: 0.07-0.55, p < 0.01). Transcript pathway analysis of the gene signature showed association with chemokine receptors, interleukin-10 signaling, and Treg development. Conclusions: We have identified a gene expression signature that involves chemokine receptors, IL-10 signaling, and Treg development gene sets, that appears to predict for tumor response and mOS in pts with advanced MCM treated with ICI. Further validation of these gene signatures is underway.

Identification of a Novel Gene Expression Signature in Mantle Cell Lymphoma from the Fondazione Italiana Linfomi (FIL)-MCL-0208 Trial: A Focus on the B Cell Receptor Pathway

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 701-701
Author(s):  
Riccardo Bomben ◽  
Simone Ferrero ◽  
Michele Dal Bo ◽  
Tiziana D'Agaro ◽  
Alessandro Re ◽  
...  
Keyword(s):  
Gene Expression ◽  
Board Of Directors ◽  
Cell Lines ◽  
Gene Expression Signature ◽  
Gene Signature ◽  
Advisory Committees ◽  
Expression Signature ◽  
Qrt Pcr ◽  
Mantle Cell ◽  
Bcr Signaling

Abstract Background. The aggressive clinical behavior of mantle cell lymphoma (MCL) is attributed to specific genetic and molecular mechanisms involved in its pathogenesis, mainly the t(11;14)(q13;q32) traslocation and cyclin D1 (CCND1) overexpression. Nevertheless, evidence of a certain degree of clinical/biological heterogeneity has been disclosed by gene expression profile (GEP) and (immuno)genetic/immunohistochemistry studies. Aim. To use a GEP approach to identify MCL subsets with peculiar clinical/biological features in the context of MCL patients treated homogeneously with an autologous transplantation-based program. Methods. The study was based on a cohort of 42 MCL cases enrolled in the Fondazione Italiana Linfomi (FIL)-MCL-0208 randomized Italian clinical trial. Purified clonal CD19+ MCL cells were obtained by high-speed cell sorting of peripheral blood MCL samples. GEP experiments were performed in 30 cases, with Agilent platform. Bioinformatics analyses were performed by Gene Springs and Gene Set Enrichment Analysis (GSEA) software. Gene signature validations were performed by quantitative real time PCR (QRT-PCR). Results. i)Unsupervised and supervised analyses. Unsupervised analysis by principal component analysis (PCA) was able to divide the cohort in two main subgroups named PCA1 (12 cases) and PCA2 (18 cases). Supervised analysis by segregating cases according to the PCA1 and PCA2 classification defined a gene expression signature of 710 gene (234 up-regulated) that highlighted a constitutive overexpression of genes of the BCR signaling pathway. Consistently,GSEA showed a significant enrichment of genes belonging to 3 gene sets related to BCR signaling. ii) Identification of a "PCA2-type" gene signature. By merging the list of differentially expressed genes according to supervised analysis of GEP data and the gene list related to BCR signaling according to GSEA, a group of 9 genes, all overexpressed in PCA2 cases, i.e. AKT3, BLNK, BTK, CD79B, PIK3CD, SYK, BCL2, CD72, FCGR2B, was obtained. Among these genes, a subgroup of 6 genes, i.e. AKT3, BLNK, BTK, CD79B, PIK3CD, SYK, was selected for the direct involvement in the BCR pathway, and utilized for further validations. iii) Generation of a 6-gene prediction model. The selected 6 genes were then utilized to generate a prediction model by using 20 cases as training sub-cohort and the remaining 10 cases as validation cohort. By this approach, 9/10 cases of the validation cohort were correctly assigned according to the PCA2/PCA1 classification. The model was re-tested by QRT-PCR in 24 cases used in the GEP (16 for training and 8 for validation), and again, 7/8 cases of the validation sub-cohort were correctly classified. QRT-PCR was then utilized to classify further 12 cases (7 cases defined as PCA2) not employed for GEP analysis. Overall, in the 42 cases, 23 cases were considered as PCA2 with the GEP/QRT-PCR approach. iv) Clinical/biological correlations. No association was found between the 6-gene signature and IGHV status (22/30 unmutated IGHV cases) or between the signature and the overexpression of SOX11 (17/30 cases over the median value). In addition, no association was found with the presence of the main recurrent mutations of the ATM, BIRC3, CCND1, KMTD2, NOTCH1, TP53, TRAF2, WHSC1 genes. Finally, an "ad-interim" analysis of progression free survivals (PFS) (Cortelazzo et al EHA, 2015) suggested a trend for a shorter PFS (2-years PFS 45% vs 72%, p=0.08) for cases classified as PCA2 by the GEP/QRT-PCR approach. v) 6-gene signature and sensitivity to the BCR inhibitor ibrutinib. The finding that PCA2 cases overexpressed BCR-related genes and had a more aggressive clinical course prompted us to investigate the 6-gene signature in the context of ibrutinib sensitive/resistant MCL cell lines. To do this, the proliferation rate of the MCL cell lines REC1, JEKO1, UPN1, GRANTA, JVM2, Z138 was investigated either in presence or in absence of ibrutinib 10 nanoM for 7 days. REC1, JEKO1 were selected as responsive by showing ≥80% inhibition upon ibrutinib. Of note, responsive cell lines showed higher expression levels of the 6-gene signature then the resistant counterpart, as evaluated by QRT-PCR. Conclusions. A novel 6-gene expression signature related to the BCR pathway has been found to characterize MCL cells with peculiar clinical/biological features and sensitivity to BCR inhibitors. Disclosures Luminari: Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Tumor-Infiltrating Lymphocyte Grade in Primary Melanomas Is Independently Associated With Melanoma-Specific Survival in the Population-Based Genes, Environment and Melanoma Study

2013 ◽  
Vol 31 (33) ◽  
pp. 4252-4259 ◽  
Author(s):  
Nancy E. Thomas ◽  
Klaus J. Busam ◽  
Lynn From ◽  
Anne Kricker ◽  
Bruce K. Armstrong ◽  
...  
Keyword(s):  
Primary Melanoma ◽  
Tumor Infiltrating Lymphocytes ◽  
Population Level ◽  
Tumor Stage ◽  
Population Based ◽  
Breslow Thickness ◽  
Prognostic Information ◽  
Histologic Subtype ◽  
Risk Of Death ◽  
Ajcc Staging

Purpose Although most hospital-based studies suggest more favorable survival with tumor-infiltrating lymphocytes (TILs) present in primary melanomas, it is uncertain whether TILs provide prognostic information beyond existing melanoma staging definitions. We addressed the issue in an international population-based study of patients with single and multiple primary melanomas. Patients and Methods On the basis of the Genes, Environment and Melanoma (GEM) study, we conducted follow-up of 2,845 patients diagnosed from 1998 to 2003 with 3,330 invasive primary melanomas centrally reviewed for TIL grade (absent, nonbrisk, or brisk). The odds of TIL grades associated with clinicopathologic features and survival by TIL grade were examined. Results Independent predictors (P < .05) for nonbrisk TIL grade were site, histologic subtype, and Breslow thickness, and for brisk TIL grade, they were age, site, Breslow thickness, and radial growth phase. Nonbrisk and brisk TIL grades were each associated with lower American Joint Committee on Cancer (AJCC) tumor stage compared with TIL absence (Ptrend < .001). Death as a result of melanoma was 30% less with nonbrisk TIL grade (hazard ratio [HR], 0.7; 95% CI, 0.5 to 1.0) and 50% less with brisk TIL grade (HR, 0.5; 95% CI, 0.3 to 0.9) relative to TIL absence, adjusted for age, sex, site, and AJCC tumor stage. Conclusion At the population level, higher TIL grade of primary melanoma is associated with a lower risk of death as a result of melanoma independently of tumor characteristics currently used for AJCC tumor stage. We conclude that TIL grade deserves further prospective investigation to determine whether it should be included in future AJCC staging revisions.

scholarly journals A vaccine-induced gene expression signature correlates with protection against SIV and HIV in multiple trials

2019 ◽  
Vol 11 (507) ◽  
pp. eaaw4236 ◽  
Author(s):  
Philip K. Ehrenberg ◽  
Shida Shangguan ◽  
Biju Issac ◽  
Galit Alter ◽  
Aviva Geretz ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
Vaccine Trial ◽  
Gene Expression Signature ◽  
Gene Signature ◽  
Antibody Responses ◽  
Expression Signature ◽  
Transcriptional Signature ◽  
Correlates Of Protection ◽  
Immunodeficiency Virus

Current HIV vaccines are only partially efficacious, presenting an opportunity to identify correlates of protection and, thereby, potential insight into mechanisms that prevent HIV acquisition. Two independent preclinical challenge studies in nonhuman primates (NHPs) previously showed partial efficacy of a mosaic adenovirus 26 (Ad26)–based HIV-1 vaccine candidate. To investigate the basis of this protection, we performed whole transcriptomics profiling by RNA sequencing (RNA-seq) in sorted lymphocytes from peripheral blood samples taken during these studies at different time points after vaccination but before challenge. We observed a transcriptional signature in B cells that associated with protection from acquisition of simian immunodeficiency virus (SIV) or the simian-human immunodeficiency virus (SHIV) in both studies. Strong antibody responses were elicited, and genes from the signature for which expression was enriched specifically associated with higher magnitude of functional antibody responses. The same gene expression signature also associated with protection in RV144 in the only human HIV vaccine trial to date that has shown efficacy and in two additional NHP studies that evaluated similar canarypox-based vaccine regimens. A composite gene expression score derived from the gene signature was one of the top-ranked correlates of protection in the NHP vaccine studies. This study aims to bridge preclinical and clinical data with the identification of a gene signature in B cells that is associated with protection from SIV and HIV infection by providing a new approach for evaluating future vaccine candidates.

scholarly journals A Gene Expression Signature to Predict Nucleotide Excision Repair Defects and Novel Therapeutic Approaches

2021 ◽  
Vol 22 (9) ◽  
pp. 5008
Author(s):  
Rongbin Wei ◽  
Hui Dai ◽  
Jing Zhang ◽  
David J. H. Shih ◽  
Yulong Liang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nucleotide Excision Repair ◽  
Cell Lines ◽  
Excision Repair ◽  
Gene Expression Signature ◽  
Gene Signature ◽  
Expression Signature ◽  
Nucleotide Excision ◽  
Functionally Impaired ◽  
Synthetically Lethal

Nucleotide excision repair (NER) resolves DNA adducts, such as those caused by ultraviolet light. Deficient NER (dNER) results in a higher mutation rate that can predispose to cancer development and premature ageing phenotypes. Here, we used isogenic dNER model cell lines to establish a gene expression signature that can accurately predict functional NER capacity in both cell lines and patient samples. Critically, none of the identified NER deficient cell lines harbored mutations in any NER genes, suggesting that the prevalence of NER defects may currently be underestimated. Identification of compounds that induce the dNER gene expression signature led to the discovery that NER can be functionally impaired by GSK3 inhibition, leading to synergy when combined with cisplatin treatment. Furthermore, we predicted and validated multiple novel drugs that are synthetically lethal with NER defects using the dNER gene signature as a drug discovery platform. Taken together, our work provides a dynamic predictor of NER function that may be applied for therapeutic stratification as well as development of novel biological insights in human tumors.

scholarly journals Loss of CITED1, an MITF regulator, drives a phenotype switch in vitro and can predict clinical outcome in primary melanoma tumours

2014 ◽  
Author(s):  
Jill Howlin ◽  
Helena Cirenajwis ◽  
Barbara. Lettiero ◽  
Johan Staaf ◽  
Martin Lauss ◽  
...  
Keyword(s):  
Target Genes ◽  
Molecular Subtype ◽  
Primary Melanoma ◽  
Gene Expression Signature ◽  
Reciprocal Relationship ◽  
Signature Genes ◽  
Phenotype Switch ◽  
Mrna And Protein Expression ◽  
Whole Genome Expression

CITED1 is a non-DNA binding transcriptional co-regulator whose expression can distinguish the ‘proliferative’ from ‘invasive’ signature in the phenotype-switching model of melanoma. We have found that CITED1 expression is repressed by TGFβ in addition to other ‘proliferative’ signature genes while the ‘invasive’ signature genes are upregulated. In agreement, CITED1 positively correlates with MITF expression and can discriminate the MITF-high/pigmentation tumor molecular subtype in a large cohort (120) of melanoma cell lines. Interestingly, CITED1 overexpression significantly suppressed MITF promoter activation, mRNA and protein expression levels while MITF was transiently upregulated following siRNA mediated CITED1 silencing. Conversely, MITF siRNA silencing resulted in CITED1 downregulation indicating a reciprocal relationship. Whole genome expression analysis identified a phenotype shift induced by CITED1 silencing and driven mainly by expression of MITF and a cohort of MITF target genes that were significantly altered. Concomitantly, we found changes in the cell-cycle profile that manifest as transient G1 accumulation, increased expression of CDKN1A and a reduction in cell viability. Additionally, we could predict survival outcome by classifying primary melanoma tumors using our in vitro derived ‘CITED1-silenced’ gene expression signature. We hypothesize that CITED1 acts a regulator of MITF, functioning to maintain MITF levels in a range compatible with tumourigenesis.

High BAALC expression associates with other molecular prognostic markers, poor outcome and a distinct gene expression signature in cytogenetically normal acute myeloid leukemia (CN AML): A Cancer and Leukemia Group B (CALGB) study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7013-7013
Author(s):  
C. Langer ◽  
A. S. Ruppert ◽  
M. D. Radmacher ◽  
S. P. Whitman ◽  
P. Paschka ◽  
...  
Keyword(s):  
Gene Expression ◽  
Molecular Markers ◽  
Prognostic Markers ◽  
De Novo ◽  
Gene Expression Signature ◽  
Prognostic Information ◽  
Expression Signature ◽  
Poor Outcome ◽  
Distinct Gene ◽  
Group B

7013 Background: High BAALC expression predicts poor outcome in CN AML patients (pts). Yet, little is known about BAALC's function or its relation to other prognostic markers. We evaluated BAALC expression in the context of molecular markers and clinical outcome in 172 de novo CN AML adults, aged <60 years (y) treated on similar CALGB protocols (9621 and 19808). Methods: BAALC expression was measured by quantitative real-time RT-PCR in pretreatment blood samples. Pts were grouped as high (n=86) or low BAALC (n=86) expressers using the median expression value, by protocol, as a cutoff. Gene expression profiling (Affymetrix U133 plus 2.0 GeneChip) was performed on high (n=26) and low (n=24) pts. Results: BAALC expression was associated with several molecular markers ( Table ). Complete remission (CR) rate was lower in high BAALC pts (79% v 90%), for whom achieving CR was almost 4 times less likely than for low BAALC pts (P=.02; odds ratio=0.27), after adjusting for age (P=.004), ERG expression (P=.05) and white blood cell count (WBC; P=.04). With a median follow-up of 4.3 y, high BAALC pts had shorter overall survival (OS) (P=.002; 3-y OS: 42% v 59%). In a multivariable model, high BAALC provided further adverse prognostic information (P=.06; hazard ratio=1.66) independent of FLT3 ITD (P<.001), WBC (P=.007) and NPM1 (P=.02). A gene expression signature was identified consisting of 312 probe sets differentially expressed (P<.001) between BAALC groups. High BAALC was associated with overexpression of, among other genes, PROM1, CD34 and KIT indicating a less differentiated phenotype in these pts. Conclusions: Although associated with other prognostic markers, high BAALC expression independently predicts outcome and is associated with a distinct gene expression profile, potentially identifying new therapeutic targets in this pt subset. No significant financial relationships to disclose. [Table: see text]

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