Cancer/Testis Genes in Multiple Myeloma: Expression Patterns and Vaccination Strategies Determined by Microarray Analysis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3401-3401
Author(s):  
Maud Condomines ◽  
Dirk Hose ◽  
Thierry Reme ◽  
Michael Hundemer ◽  
John De Vos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Tumor Escape ◽  
Event Free Survival ◽  
Chromosome X ◽  
Free Survival ◽  
Ct Antigens ◽  
Cancer Testis

Abstract Cancer-testis (CT) antigens are expressed in testis and malignant tumors, but rarely in non-gametogenic tissues. Due to this pattern, they represent attractive targets for cancer vaccination approaches. The aims of the present study were (1) to assess for the first time the expression of CT genes on a pangenomic basis in multiple myeloma (MM), (2) to provide selection strategies of CT antigens for clinical vaccination trials and (3) to assess the impact of CT gene expression on event-free survival. We report here the expression pattern of CT genes in purified MM cells (MMC) of 64 patients with newly-diagnosed MM, 12 patients with monoclonal gammopathy of unknown significance (MGUS), in normal plasma cell and B cell samples and in 20 MMC lines, using gene expression profiling (GEP). Out of 46 CT genes interrogated by the Affymetrix HG U133 Set arrays, 35 were expressed in MMC of at least one patient, according to the Affymetrix “present” call (frequency range: 2% – 66%). Of these, 24 CT genes were expressed in more than 5% of the MMC samples and 25 are located on chromosome X. MMC of 98% of the patients expressed at least one CT gene, 86% at least two, and 70% at least three CT genes. By using a set of 10 CT genes including KM-HN-1, MAGE-C1, MAGE-A3/6/12, MAGE-A5, MORC, DDX43, SPACA3, SSX-4, GAGE-1–8 and MAGE-C2, a combination of at least three CT genes - desirable to circumvent tumor escape mechanisms and immune tolerance - could be obtained in MMC of 67% of the patients. Thus, gene expression profiling can be used to select CT antigens as vaccination targets in individual patients. In a series of MMC from 111 patients treated with the same high-dose chemotherapy and autologous peripheral blood stem cell transplantation protocol and having a median two-year follow-up, we found that the expression of six CT genes, i.e. CTAG-1B, CTAG-2, MAGE-A1, MAGE-A2, MAGE-A3 and MAGE-A6 was associated with a shorter event-free survival (EFS). Furthermore, considering only the 25 CT genes encoded by chromosome X, a CT-Xhigh cluster comprising MMC of one third of the patients (35 of 111) could be defined using a binary hierarchical clustering based on Affymetrix call. Patients in the CT-Xhigh cluster had a shorter EFS (median 13 months) compared to patients in the CT-Xlow cluster (median 18 months, P = .003). The CT-Xhigh clsuter included more patients with a stage III disease (P = .004). These results confirm data from previous studies indicating that patients expressing some CT genes located on chromosome X have a poor outcome.

A New Molecular Classification of Multiple Myeloma Using Gene Expression Profiling and Fluorescence In Situ Hybridisation as Predictor for Event Free Survival.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 73-73 ◽  
Author(s):  
Dirk Hose ◽  
Jean-Francois Rossi ◽  
Carina Ittrich ◽  
John deVos ◽  
Axel Benner ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Molecular Classification ◽  
Differentially Expressed ◽  
Event Free Survival ◽  
Free Survival ◽  
Cytogenetic Aberrations

Abstract AIM was to establish a new molecular classification of Multiple Myeloma (MM) based on changes in global gene expression attributable to cytogenetic aberrations detected by interphase FISH (iFISH) in order to (i) predict event free survival (EFS) and (ii) investigate differentially expressed genes as basis for a group specific and risk adapted therapy. PATIENTS AND METHODS. Bone marrow aspirates of 105 newly diagnosed MM-patients (65 trial (TG) / 40 independent validation group (VG)) and 7 normal donors (ND) were CD138-purified by magnetic activated cell sorting. RNA was in-vitro transcribed and hybridised to Affymetrix HG U133 A+B GeneChip (TG) and HG U133 2.0 plus arrays (VG). CCND1 and CCND2 expression was verified by real time RT-PCR. iFISH was performed on purified MM-cells using probes for chromosomes 11q23, 11q13, 13q14, 17p13 and the IgH-translocations t(4;14) and t(11;14). Expression data were normalised (Bioconductor package gcrma) and nearest shrunken centroids (NSC) applied to calculate and cross validate a predictor on 40 patients of the TG with a comprehensive iFISH panel available combined with CCND overexpression. Differentially expressed genes were identified using empirical Bayes statistics for pairwise comparison. RESULTS. Overexpression of a D-type cyclin (D1 or D2) was found in 61/65 patients with MM compared to ND. CCND3 overexpression only appeared concomitantly with CCND2 overexpression. Four groups could be distinguished: (1.1) CCND1 (11q13) overexpression and trisomy 11q13, (1.2) CCND1 overexpression and translocations involving 11q13 i.e. t(11;14), (2.1) CCND2 overexpression without 11q13+, t(11;14), t(4;14), (2.2) CCND2 overexpression with t(4;14) and FGFR3 upregulation. A predictor of 6 to 566 genes correctly classifies all 40 patients of the TG (estimated cross validated error rate 0%). An independent VG of 40 patients was used. Genes with highest scores in NSC are: (1.1) CCND1, ribosomal proteins (e.g. RPL 28, 29), GPX1, CCRL2, (1.2) CCND1, TGIF, and NCAM (non-overexpression), (2.1) CCND2, (2.2) FGFR3, WHSC1, CCND2, IRTA2, SELL, and MAGED4. Distribution of clinical parameters (i.e. β2M, Durie Salmon stages, ISS) was not significantly different between the groups. The distribution of del(13)(q14q14) was (1.1) 31.5%, (1.2) 37.5%, (2.1) 37.5% and (2.2) 100%. (p<0.01). I.e. HGF, DKK1, VCAM, CD163 are differentially expressed between all 4 groups and ND (adjusted p<0.001). The groups defined by the predictor show a significantly different EFS after autologous stem cell transplantation according to the GMMG-HD3 protocol (median: (1.1) 18 / (1.2) not reached (no event) / (2.1) 22 / (2.2) 6 months; log-rank-test: p=0.004). CONCLUSION. CCND1 or CCND2 overexpression is nearly ubiquitous in MM and attributable to defined cytogenetic aberrations. Gene expression and iFISH allow a molecular classification of MM which can be predicted by gene expression profiling alone. Groups in the classification show a distinctive pattern in gene expression as well as a different EFS interpretable as risk stratification and indicator of therapeutic targets.

Ninety Percent Sustained Complete Response (CR) Rate Projected 4 Years after Onset of CR in Gene Expression Profiling (GEP)-Defined Low-Risk Multiple Myeloma (MM) Treated with Total Therapy 3 (TT3): Basis for GEP-Risk-Adapted TT4 and TT5

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 162-162 ◽  
Author(s):  
Bart Barlogie ◽  
Elias J. Anaissie ◽  
John D. Shaughnessy ◽  
Frits van Rhee ◽  
Mauricio Pineda-Roman ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Risk ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Complete Response ◽  
Low Risk ◽  
Event Free Survival ◽  
Free Survival ◽  
Response Onset ◽  
Dose Dense

Abstract We have previously reported on the remarkable activity of the TT3 program that incorporated both bortezomib (V) and thalidomide (T) into the up-front management of 303 patients. TT3 consisted of 2 cycles each of induction prior to and of dose-reduced consolidation therapy with VTD-PACE (cisplatin, doxorubicin, cyclophosphamide, etoposide) after melphalan 200mg/m2 (M200)-based tandem transplants, followed by maintenance therapy for 3 years with VTD and, in later stages, VRD (substituting T for lenalidomide, R). Characteristics included a median age of 59yr (range, 33–75yr), B2M &gt;=4mg/L in 37%, albumin &lt;3.5g/dL in 26%, ISS stages II and III in 33% and 21%, cytogenetic abnormalities (CA) in 33% and gene expression profiling (GEP)-defined high-risk MM in 15% of the 275 patients with such data. With a median follow-up of 39 months, 4-yr overall survival (OS) and event-free survival (EFS) estimates were 78% and 71%, respectively, including 84% and 77% among the 85% with GEP-defined low-risk MM contrasting with 43% and 33% in the remainder with high-risk MM (both p&lt;0.0001). Near-CR and CR, attained in 86% and 63%, were sustained at 4 years from response onset in 78% and 87%, which pertained to 83% and 90% with low-risk MM but to only 44% and 57% with high-risk MM (all p &lt;0.0001). These results were corroborated in a TT3 extension trial (TT3E) that enrolled 175 additional patients, comprising higher proportions of CA (42%) and GEP-defined high-risk MM (21%). Two-year estimates of OS and EFS are 85% and 85%, with 94% and 92% in low-risk patients versus 61% and 62% in high-risk MM (p=0.0001, p=0.0003); the 2-yr estimate of remaining in CR is 93% including 100% in low-risk and 77% in high-risk MM (p=0.01). Multivariate analysis of features linked to OS in TT3 included GEP-defined high-risk, CA, B2M and LDH elevation, collectively accounting for 41% of outcome variability by R2 statistics; the corresponding R2 values for EFS and n-CR duration were 38% and 39%. Compared to the predecessor trial, TT2, that evaluated the role of T in a randomized trial design in 668 patients, TT3 data were superior for OS (p=0.08), EFS (&lt;0.0001), n-CR duration (p&lt;0.0001) and CR duration (p=0.0002). In the low-risk subgroup, EFS (p=0.0001), n-CR duration (p&lt;0.0001) and CR duration (Figure 1a; p=0.0002) all were superior in TT3 versus TT2; whereas, in the high-risk MM group, outcomes remained poor also with TT3 despite superior EFS (Figure 1b; p=0.03). Based on these data, we have now started a GEP-risk-based algorithm of assigning separate therapies to good-risk (TT4) and poor-risk MM (TT5). As the TT3 results for low-risk are difficult to improve upon, TT4 randomizes patients between standard TT3 and TT3-LITE that employs only 1 cycle each of induction and consolidation (with anticipated further improvement in compliance) and 4-day-fractionated M50×4 to enable the addition of VTD and thus exploit synergistic drug interactions to occur. In order to sustain tolerable effective therapies for at least 3 years and prevent recurrence from previous drug-free or insufficiently effective phases in TT3, TT5 for high-risk MM employs less dose-intense and more dose-dense highly synergistic combination therapy, utilizing M10-VTD-PACE for induction, M80 (in 4 daily fractions of M20) plus VRD-PACE tandem transplants, separated by 2 cycles of M20 (in 4 daily fractions of M5) plus VTD-PACE, and followed by 2 years of monthly alternating R-VD and M-VD. Figure 1a: Superior CR duration with TT3 v TT2 in GEP-low-risk MM: Figure 1a:. Superior CR duration with TT3 v TT2 in GEP-low-risk MM: Figure 1b: Superior event-free survival with TT3 v TT2 in GEP-high-risk MM: Figure 1b:. Superior event-free survival with TT3 v TT2 in GEP-high-risk MM:

scholarly journals Gene Expression Profiling and Real-Time PCR Analyses Identify Novel Potential Cancer-Testis Antigens in Multiple Myeloma

2009 ◽  
Vol 183 (2) ◽  
pp. 832-840 ◽  
Author(s):  
Maud Condomines ◽  
Dirk Hose ◽  
Thierry Rème ◽  
Guilhem Requirand ◽  
Michael Hundemer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Gene Expression Profiling ◽  
Real Time ◽  
Real Time Pcr ◽  
Expression Profiling ◽  
Cancer Testis Antigens ◽  
Potential Cancer ◽  
Cancer Testis

Gene Expression Profiling Reveals Genes Predictive of Outcome In Infant Acute Lymphoblastic Leukemia (ALL) and Distinctive Age-Related Gene Expression Profiles ( 90 Days): A Children's Oncology Group Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 412-412
Author(s):  
Huining Kang ◽  
Carla S. Wilson ◽  
Richard C. Harvey ◽  
I-Ming Chen ◽  
Maurice H. Murphy ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Event Free Survival ◽  
Patient Age ◽  
Free Survival ◽  
Entire Cohort ◽  
Patient Âgé

Abstract Abstract 412 ALL arising in infants is a highly refractory disease. Overall event-free survival (EFS) remains poor and infants with MLL rearrangements (MLL-R) or those <90 days of age are known to have particularly poor outcomes. To identify genes predictive of event-free survival (EFS) that might serve as new diagnostic and therapeutic targets, we completed gene expression profiling (Affymetrix HG_U133Plus2) in 97 infant ALL cases registered to COG Clinical Trial P9407. Of these 97 infants, 78 were most recently uniformly treated on P9407 cohort 3. In the 97 cases, median age at diagnosis was 166 days (range 1–365) and increased age at diagnosis was significantly associated with improved EFS (P = 0.001). 89/97 infants had MLL-R, of which 49 had an AF4 partner gene (MLL-AF4 (AFF1)). Infants <90 days of age (P=.0001) and those with MLL-R (MLL-AF4, MLL-ENL (MLLT1), MLL-Other) had a significantly decreased EFS, while infants with MLL-AF9 (MLLT3) or cases lacking MLL-R had a significantly better EFS (P=0.014). From modeling expression profiles and multivariate analyses, a number of genes were identified that had a significant effect on EFS and were independent of patient age or MLL-R status, including: TACC2 and IRX2 (from modeling the entire cohort of 97 cases); RORA, IGJ, ZEB1, YES1 (cohort 3 modeled alone); and IRX1, IRX2, ST3GAL6, HLA-DQB1, STAB1, NEGR1, IRX5 (MLL-AF4 cases modeled alone). The significant effect of MEIS1 and KCNK12 expression on EFS was lost after consideration of MLL-R status, while the significance of many genes (particularly in the HOXA family) was not independent of patient age in multivariate analyses. Assessment of the expression levels of two genes alone at diagnosis: TACC2 and IRX2 in the entire cohort of 97 cases (P<0.0001; Fig. A), or, NEGRI and IRX2 in the MLL-AF4 cases (P<0.0001; Fig. B), were highly predictive of outcome on current treatment regimens. Distinctive and strikingly different gene expression profiles were also seen in infant ALL cases <90 days of age vs. >90 days of age (in the overall cohort and in the MLL-AF4 cases). Specifically evaluating the impact of patient age treated as a continuous variable revealed a striking transition in expression profiles at 90 days with a differential expression pattern involving many genes encoding histone-related, heat shock family, or immune response regulators (including HLA-DRB4, IL1R2, HSPA1A///1B). These distinctive profiles may reflect different transformed stem/precursor cells or susceptibilities to leukemic transformation at different patient ages, altered marrow microenvironments, or altered immune status; high expression of the heat shock proteins in particular among the youngest infants may reflect a more limited immune surveillance capacity. Given the rarity of infant ALL, this study represents one of the largest uniformly treated groups of infant leukemia to undergo gene expression profiling. In these studies we have identified genes that are highly predictive of outcome at diagnosis, in all infant ALL and in MLL-AF4 cases. Further analysis of these expression profiles, coupled with validation studies in other infant ALL cohorts, may allow for the identification of novel therapeutic targets among the genes discovered herein and ultimately for the development of more effective therapies. Disclosures: Felix: None: Patent not licensed.

Gene expression profiling for molecular classification of multiple myeloma in newly diagnosed patients

Blood ◽  
2010 ◽  
Vol 116 (14) ◽  
pp. 2543-2553 ◽  
Author(s):  
Annemiek Broyl ◽  
Dirk Hose ◽  
Henk Lokhorst ◽  
Yvonne de Knegt ◽  
Justine Peeters ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Plasma Cells ◽  
Medical Science ◽  
Protein Tyrosine Phosphatases ◽  
Molecular Classification ◽  
Newly Diagnosed ◽  
Expression Of Genes

Abstract To identify molecularly defined subgroups in multiple myeloma, gene expression profiling was performed on purified CD138+ plasma cells of 320 newly diagnosed myeloma patients included in the Dutch-Belgian/German HOVON-65/GMMG-HD4 trial. Hierarchical clustering identified 10 subgroups; 6 corresponded to clusters described in the University of Arkansas for Medical Science (UAMS) classification, CD-1 (n = 13, 4.1%), CD-2 (n = 34, 1.6%), MF (n = 32, 1.0%), MS (n = 33, 1.3%), proliferation-associated genes (n = 15, 4.7%), and hyperdiploid (n = 77, 24.1%). Moreover, the UAMS low percentage of bone disease cluster was identified as a subcluster of the MF cluster (n = 15, 4.7%). One subgroup (n = 39, 12.2%) showed a myeloid signature. Three novel subgroups were defined, including a subgroup of 37 patients (11.6%) characterized by high expression of genes involved in the nuclear factor kappa light-chain-enhancer of activated B cells pathway, which include TNFAIP3 and CD40. Another subgroup of 22 patients (6.9%) was characterized by distinct overexpression of cancer testis antigens without overexpression of proliferation genes. The third novel cluster of 9 patients (2.8%) showed up-regulation of protein tyrosine phosphatases PRL-3 and PTPRZ1 as well as SOCS3. To conclude, in addition to 7 clusters described in the UAMS classification, we identified 3 novel subsets of multiple myeloma that may represent unique diagnostic entities.

scholarly journals Erratum: Dose-dense and less dose-intense total therapy 5 for gene expression profiling-defined high-risk multiple myeloma

2016 ◽  
Vol 6 (9) ◽  
pp. e471-e471 ◽  
Author(s):  
Y Jethava ◽  
A Mitchell ◽  
M Zangari ◽  
S Waheed ◽  
C Schinke ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
High Risk ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Total Therapy ◽  
Dose Dense

Metaphase Cytogenetics Adds to Gene Expression Profiling in the Identification of High Risk Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 114-114
Author(s):  
Guido Tricot ◽  
Fenghuang Zhan ◽  
Bart Barlogie ◽  
Yongsheng Huang ◽  
Jeffrey Sawyer ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Prognostic Significance ◽  
Staging System ◽  
Treatment Modalities ◽  
Prognostic Impact ◽  
Newly Diagnosed ◽  
Prognostic Information

Abstract The International Staging System (ISS), based on B2-microglobulin and albumin levels at the time of diagnosis, has now generally been adopted as a new prognostic classification system for multiple myeloma (MM). While readily and widely applicable, ISS does not account for genetic disease features, such as metaphase (CA) and interphase fluorescence in situ hybridization (FISH) cytogenetic abnormalities, which when examined in the context of standard prognostic variables, confer higher hazards of relapse and disease-related death. Recently, gene expression profiling (GEP) uncovered the major prognostic significance for outcome of high expression of CKS1B, a gene mapping to an amplicon at chromosome 1q21. We have performed a comprehensive study of CA, FISH, GEP and ISS staging in 351 newly diagnosed MM patients, treated uniformly on Total Therapy 2. We have analyzed outcome based on a combination of high CKS1B by GEP and CA. GEP-based t(11;14) was prognostically favorable, irrespective of expression of CKS1B and, therefore, was removed from the group of patients with high CKS1B expression. After this adjustment, with the combination of both CA and high CKS1B (approximately 10% of all patients) conferred a very poor outcome with only 24% and 40% of such patients being event-free and/surviving at 3 years, compared with 72% and 84% for the others (p values : &lt;.0001). Such patients fared poorly, irrespective of their ISS stage. Similar prognostic information could be gained by combining CA with FISH-defined amplification of 1q21 and t(11;14). Because of their major prognostic impact, all newly diagnosed patients should be tested for these genetic markers. Novel treatment modalities are justified in the small subgroup of such poor prognosis patients, since they derive only a minor benefit from advances in MM therapy. CKS1B Q4 + CA (with no CCND1) vs. Others CKS1B Q4 + CA (with no CCND1) vs. Others

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