Biomedical subjects

Jan Delabie

Publications and source records attributed to Jan Delabie.

At least 19 recordsLinked to original sources

PubMed2006

Molecular diagnosis of Burkitt's lymphoma.

BACKGROUND: The distinction between Burkitt's lymphoma and diffuse large-B-cell lymphoma is crucial because these two types of lymphoma require different treatments. We examined whether gene-expression profiling could reliably distinguish Burkitt's lymphoma from diffuse large-B-cell lymphoma. METHODS: Tumor-biopsy specimens from 303 patients with aggressive lymphomas were profiled for gene expression and were also classified according to morphology, immunohistochemistry, and detection of the t(8;14) c-myc translocation. RESULTS: A classifier based on gene expression correctly identified all 25 pathologically verified cases of classic Burkitt's lymphoma. Burkitt's lymphoma was readily distinguished from diffuse large-B-cell lymphoma by the high level of expression of c-myc target genes, the expression of a subgroup of germinal-center B-cell genes, and the low level of expression of major-histocompatibility-complex class I genes and nuclear factor-kappaB target genes. Eight specimens with a pathological diagnosis of diffuse large-B-cell lymphoma had the typical gene-expression profile of Burkitt's lymphoma, suggesting they represent cases of Burkitt's lymphoma that are difficult to diagnose by current methods. Among 28 of the patients with a molecular diagnosis of Burkitt's lymphoma, the overall survival was superior among those who had received intensive chemotherapy regimens instead of lower-dose regimens. CONCLUSIONS: Gene-expression profiling is an accurate, quantitative method for distinguishing Burkitt's lymphoma from diffuse large-B-cell lymphoma.

Adolescent↗

PubMed2006

Peripheral T-cell lymphoma with involvement of the expanded mantle zone.

Peripheral T-cell lymphoma (PTCL) with a nodular architecture is rare. Recently, two variants have been described with infiltration of the B-cell follicle, one variant that localizes to the marginal zone with a so-called perifollicular growth pattern, and a variant that localizes to the germinal center. These lymphomas have a CD4+ phenotype and may express Bcl-6. We have studied five similar cases of PTCL with involvement of the B-cell follicle. However, our cases differ from the cases previously described by their predominant and frequently patchy involvement of the expanded mantle zone of the B-cell follicle at onset. Later biopsies in three of the cases show diffuse infiltration of the lymph node, without features of angioimmunoblastic TCL (AILT). All cases expressed Bcl-6 in addition to CD4. Cytogenetics was available in four of the cases but revealed no recurrent chromosomal aberrations or changes associated with other types of PTCL. No mutations of the BCL-6 gene were observed. Together, the cases seem to have an intermediately aggressive clinical behavior. Whether our cases are part of a spectrum of PTCLs that encompasses previously described variants with predominant marginal zone or germinal center infiltration or they represent a separate T-cell lymphoma type remains to be demonstrated by a study of more of such cases.

Adult↗

PubMed2006

Mutation and genomic deletion status of ataxia telangiectasia mutated (ATM) and p53 confer specific gene expression profiles in mantle cell lymphoma.

Although mantle cell lymphoma (MCL) frequently harbors inactivated ataxia telangiectasia mutated (ATM) and p53 alleles, little is known about the molecular phenotypes caused by these genetic changes. We identified point mutations and genomic deletions in these genes in a series of cyclin D1-positive MCL cases and correlated genotype with gene expression profiles and overall survival. Mutated and/or deleted ATM and p53 alleles were found in 56% (40/72) and 26% (21/82) of the cases examined, respectively. Although MCL patients with inactive p53 alleles showed a significant reduction in median overall survival, aberrant ATM status did not predict for survival. Nevertheless, specific gene expression signatures indicative of the mutation and genomic deletion status of each gene were identified that were different from wild-type cases. These signatures were comprised of a select group of genes related to apoptosis, stress responses, and cell cycle regulation that are relevant to ATM or p53 function. Importantly, we found the molecular signatures are different between cases with mutations and deletions, because the latter are characterized by loss of genes colocalized in the same chromosome region of ATM or p53. This information on molecular phenotypes may provide new areas of investigation for ATM function or may be exploited by designing specific therapies for MCL cases with p53 aberrations.

Apoptosis↗

PubMed2006

BCL2 expression is a prognostic marker for the activated B-cell-like type of diffuse large B-cell lymphoma.

BACKGROUND: The role of BCL2 as a predictor of survival in diffuse large B-cell lymphoma (DLBCL) is controversial. DLBCL is heterogeneous, and the expression of BCL2 is variable within the two major subgroups of DLBCL, germinal center B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL, as well as primary mediastinal DLBCL. PATIENTS AND METHODS: In this study, we investigated the correlation of BCL2 expression with survival in the two major subgroups of DLBCL, as well as the mechanisms of BCL2 expression. RESULTS: There was no significant correlation between BCL2 protein expression and overall survival within the GCB subgroup, but BCL2 expression had a significant adverse effect on overall survival within the ABC subgroup (P = .008). This correlation was also observed at the mRNA level (P < .04). The difference remained significant when the analyses were performed at different cutoff values. The t(14;18) was frequently observed in the GCB subgroup and was highly associated with BCL2 expression. Patients with ABC DLBCL did not exhibit t(14;18) but had a markedly higher frequency of chromosome 18q21 amplification, on which BCL2 resides. Thus, alternative mechanisms such as 18q21 amplification or activation of the nuclear factor-kappa B pathway, as reported previously, seem to be mainly responsible for the upregulation of BCL2 expression in the ABC subgroup. CONCLUSION: Treating all DLBCL as a single entity ignores the mechanistic differences in BCL2 upregulation and obscures the prognostic significance of BCL2 expression. Hence, the significance of BCL2 and other biomarkers should be assessed in the context of DLBCL subgroups in future studies.

Aged↗

PubMed2006

The expression of fibroblast growth factors and their receptors in Hodgkin's lymphoma.

The expression of fibroblast growth factors (FGF1 and FGF2) and their receptors has been reported in a variety of human neoplasms, including haematological neoplasia. Fibroblast growth factors can promote tumour growth directly, or indirectly through promoting the growth of vessels. In the present study, we evaluated the expression of FGF1 and FGF2 as well as FGF receptors 1-4 (FGFR1-FGFR4) in 39 cases of Hodgkin's lymphoma, including all subtypes, as well as Hodgkin's lymphoma cell lines. FGF1 and FGF2 and their receptors FGFR2-FGFR4, but not FGFR1, were found to be expressed by the malignant cells in the majority of cases. Interestingly, only FGFR3, but none of the FGFs or the other FGFRs, was expressed by the Hodgkin's lymphoma cell lines. This indicates that only FGFR3 is constitutively expressed by Hodgkin's lymphoma cells, whereas FGFs and the other FGFRs are induced in vivo. Culture of the Hodgkin's cell lines under conditions of hypoxic stress could induce vascular endothelial growth factor (VEGF) but not FGF expression. FGFs, in contrast to VEGF, might be expressed in response to paracrine stimuli. In situ hybridization did not reveal FGFR3 gene amplification or translocation as the cause of constitutive FGFR3 expression, as has been shown in a subset of multiple myeloma. FGFR3 might be expressed as part of the Hodgkin's cell phenotype. The demonstration of widespread expression of FGFs and some of their receptors in Hodgkin's lymphoma suggests that FGFs are important for sustaining growth of the lymphoma and suggests that anti-FGF antibodies could be used as an adjuvant treatment.

Cell Hypoxia↗

PubMed2006

Molecular cytogenetic analysis of leukemic mantle cell lymphoma with a cryptic t(11;14).

We report a case of leukemic mantle cell lymphoma of the blastoid variant with complex chromosomal rearrangements leading to the recombination of BCL1 from 11q13 and IGH from 14q32. G-banding analysis showed, in addition to multiple other chromosome abnormalities, a del(11)(q13) and addition of unknown material to chromosome arms 13p and 21p. The two latter rearrangements were revealed, by use of multicolor in situ hybridization (M-FISH) analysis, to be a der(13)(qter-->p11::14q32::11q13-->11q22::14q32-->14q11::11q22-->11qter) and a similar der(21)(qter-->p11::14q32::11q13-->11q23::14q32-->14q11::11q22-->11qter). FISH with locus-specific probes for BCL1 and IGH showed a fusion signal on both derivative chromosomes.

Chromosome Banding↗

PubMed2005

Loss of major histocompatibility class II expression in non-immune-privileged site diffuse large B-cell lymphoma is highly coordinated and not due to chromosomal deletions.

Decreased major histocompatibility class II (MHCII) expression is associated with poor survival in diffuse large B-cell lymphoma (DLBCL). Immune-privileged site DLBCL (IP-DLBCL) patients reportedly have frequent large deletions at the MHCII locus whereas the mechanism of decreased expression in non-IP-DLBCL is unknown. Gene expression profiling data were used for correlation analyses between expression levels of MHCII genes with each other and their transcriptional regulator, CIITA. Comparative genomic hybridization (CGH) assessed chromosomal alterations at MHCII-related loci. Finally, a map was created of expression of genes that are telomeric, within, or centromeric to the MHCII locus. Correlation coefficients among MHCII genes ranged from 0.73 to 0.92, whereas those between adjacent and intervening genes were lower (-0.12 to 0.49). Correlations between MHCII and CIITA expression were higher (0.53 to 0.60) than between CIITA and neighboring genes (-0.05 to 0.22). In 23 MHCII(-) cases, CGH detected 2 losses and 2 gains at MHCII loci. Expression of genes telomeric, within, and centromeric to MHCII loci were near normal in most MHCII(-) cases. Large deletions of the MHCII locus are uncommon in non-IP-DLBCL, implicating altered transcription as the operative mechanism for decreased expression.

Centromere↗

PubMed2005

Cyclin D1-negative mantle cell lymphoma: a clinicopathologic study based on gene expression profiling.

Cyclin D1 overexpression is believed to be essential in the pathogenesis of mantle cell lymphoma (MCL). Hence, the existence of cyclin D1-negative MCL has been controversial and difficult to substantiate. Our previous gene expression profiling study identified several cases that lacked cyclin D1 expression, but had a gene expression signature typical of MCL. Herein, we report the clinical, pathologic, and genetic features of 6 cases of cyclin D1-negative MCL. All 6 cases exhibited the characteristic morphologic features and the unique gene expression signature of MCL but lacked the t(11;14)(q13; q32) by fluorescence in situ hybridization (FISH) analysis. The tumor cells also failed to express cyclin D1 protein, but instead expressed either cyclin D2 (2 cases) or cyclin D3 (4 cases). There was good correlation between cyclin D protein expression and the corresponding mRNA expression levels by gene expression analysis. Using interphase FISH, we did not detect chromosomal translocations or amplifications involving CCND2 and CCND3 loci in these cases. Patients with cyclin D1-negative MCL were similar clinically to those with cyclin D1-positive MCL. In conclusion, cases of cyclin D1-negative MCL do exist and are part of the spectrum of MCL. Up-regulation of cyclin D2 or D3 may substitute for cyclin D1 in the pathogenesis of MCL.

Cyclin D1↗

PubMed2005

Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction.

Gene-expression profiling has identified 3 major subgroups of diffuse large B-cell lymphoma (DLBCL): germinal center B-cell-like (GCB), activated B-cell-like (ABC), and primary mediastinal DLBCL (PMBCL). Using comparative genomic hybridization (CGH), we investigated the genetic alterations of 224 cases of untreated DLBCL (87 GCB-DLBCL, 77 ABC-DLBCL, 19 PMBCL, and 41 unclassified DLBCL) previously characterized by gene-expression profiling. The DLBCL subgroups differed significantly in the frequency of particular chromosomal aberrations. ABC-DLBCL had frequent trisomy 3, gains of 3q and 18q21-q22, and losses of 6q21-q22, whereas GCB-DLBCL had frequent gains of 12q12, and PMBCL had gains of 9p21-pter and 2p14-p16. Parallel analysis of CGH alterations, locus-specific gene-expression profiles, and global gene-expression signatures revealed that DNA amplifications and gains had a substantial impact on the expression of genes in the involved chromosomal regions, and some genes were overexpressed in a DLBCL subgroup-specific fashion. Unexpectedly, specific chromosomal alterations were associated with significant changes in gene-expression signatures that reflect various aspects of lymphoma cell biology as well as the host response to the lymphoma. In addition, gains involving the chromosomal region 3p11-p12 provided prognostic information that was statistically independent of the previously defined gene-expression-based survival model, thereby improving its predictive power.

Chromosomes, Human↗

PubMed2005

New probabilistic graphical models for genetic regulatory networks studies.

This paper introduces two new probabilistic graphical models for reconstruction of genetic regulatory networks using DNA microarray data. One is an independence graph (IG) model with either a forward or a backward search algorithm and the other one is a Gaussian network (GN) model with a novel greedy search method. The performances of both models were evaluated on four MAPK pathways in yeast and three simulated data sets. Generally, an IG model provides a sparse graph but a GN model produces a dense graph where more information about gene-gene interactions may be preserved. The results of our proposed models were compared with several other commonly used models, and our models have shown to give superior performance. Additionally, we found the same common limitations in the prediction of genetic regulatory networks when using only DNA microarray data.

Algorithms↗

PubMed2005

CDK4 and MDM2 gene alterations mainly occur in highly proliferative and aggressive mantle cell lymphomas with wild-type INK4a/ARF locus.

Amplification of 12q13 locus occurs in some mantle cell lymphomas (MCL), potentially involving CDK4 and MDM2 genes. To determine the role of these genes in MCL, we have examined their gene status and expression and their relationship to INK4a/ARF and p53 gene aberrations in 69 tumors. Increased CDK4 gene copy number was detected in 4 of 19 (21%) highly proliferative blastoid variants and was associated with mRNA and protein overexpression. Three additional cases showed mRNA overexpression with no structural alterations of the gene. MDM2 gene overexpression was detected in three blastoid tumors (16%) with no relationship to gene copy gains. INK4a/ARF and p53 aberrations were observed in 13 and 12 tumors, respectively. Four of the seven lymphomas with CDK4 aberrations had concurrent inactivation of p53 gene, whereas only one case had a concomitant homozygous deletion of INK4a/ARF. No other gene alterations were found in the three cases with MDM2 overexpression. Patients with INK4a/ARF deletions or simultaneous aberrations of p53 and CDK4 had a significantly shorter median survival (17 months) than patients with isolated alterations of p53, MDM2, or CDK4 (32 months) and patients with no alterations in any of these genes (77 months). The prognostic impact of the concomitant oncogenic alterations of the p14ARF/p53 and p16INK4a/CDK4 pathways was independent of the proliferation of the tumors. These findings indicate that CDK4 and MDM2 gene alterations mainly occur in MCL with a wild-type INK4a/ARF locus and may contribute to the higher proliferation and more aggressive behavior of the tumors.

ADP-Ribosylation Factors↗

PubMed2005

Identification of a novel centrosome/microtubule-associated coiled-coil protein involved in cell-cycle progression and spindle organization.

Here we describe the identification of a novel vertebrate-specific centrosome/spindle pole-associated protein (CSPP) involved in cell-cycle regulation. The protein is predicted to have a tripartite domain structure, where the N- and C-terminal domains are linked through a coiled-coil mid-domain. Experimental analysis of the identified domains revealed that spindle association is dependent on the N-terminal and the coiled-coil mid domain. The expression of CSPP at the mRNA level was detected in all tested cell lines and in testis tissue. Ectopic expression of CSPP in HEK293T cells blocked cell-cycle progression in early G1 phase and in mitosis in a dose-dependent manner. Interestingly, mitosis-arrested cells contained aberrant spindles and showed impairment of chromosome congression. Inhibition of CSPP gene expression by small interfering RNAs induced cell-cycle arrest/delay in S phase. This phenotype was characterized by elevated levels of cyclin A, decreased levels of cyclin E and hyperphosphorylation of the S-phase checkpoint kinase Chk1. The activation of Chk1 may indicate a replication stress response due to an inappropriate G1/S-phase transition. Taken together, we demonstrate that CSPP is associated with centrosomes and microtubules and may play a role in the regulation of G(1)/S-phase progression and spindle assembly.

Amino Acid Sequence↗

PubMed2005

PU.1 protein expression has a positive linear association with protein expression of germinal centre B cell genes including BCL-6, CD10, CD20 and CD22: identification of PU.1 putative binding sites in the BCL-6 promotor.

The transcription factor PU.1 has been shown to be crucial for the early stages of B cell development but its function at later stages of B cell development is less well known. We observed previously that PU.1 is expressed uniformly throughout the mature pre-plasma cell B cell population, the only exception being a subpopulation of germinal centre (GC) cells which showed exceptionally high expression of PU.1. This suggested that PU.1 may also have a role in GC B cell biology. To test this hypothesis and to screen for possible genes regulated by PU.1, we first evaluated semi-quantitatively the possible co-expression of PU.1 with proteins known to be upregulated or downregulated during GC B cell development. Normal lymphoid tissues and 255 B cell non-Hodgkin lymphomas of putative GC B cell origin were evaluated. PU.1 expression was positively associated with CD10 (p < 0.0001), CD20 (p = 0.043), CD22 (p = 0.005), CD79a (p = 0.024) and Bcl-6 (p < 0.0001) and negatively associated with cytoplasmic immunoglobulin light-chain expression (p = 0.036) in diffuse large B cell lymphoma. Identical or nearly identical associations were found in follicular lymphoma. Since CD20 is known to be partly regulated by PU.1 and putative PU.1-binding sites have been described in the regulatory regions of the CD22, CD79a and CD10 genes, we looked for putative PU.1 binding sites in the BCL6 promotor. Four such putative PU.1 binding sites were identified. Further analysis by gel-shift electromobility essay showed that PU.1 protein binds to three of the four putative binding sites in the BCL6 promotor. PU.1 and Bcl-6 were also found to be upregulated in centroblasts in the normal GC, but jointly downregulated in a subpopulation of centrocytes. Our findings support the contention that PU.1 may also have an important role in GC B cell development.

Antigens, CD↗

PubMed2005

Validation of tissue microarray immunohistochemistry staining and interpretation in diffuse large B-cell lymphoma.

Tissue microarrays (TMAs) show concordance with whole tissue sections in the immunohistochemical evaluation of tumor cells. However, potential inter-institutional variability among observers and immunohistochemical staining methods has not been fully addressed. We selected 21 cases of diffuse large B-cell lymphoma (DLBCL) to process for TMAs. Immunohistochemical stains were performed in 3 laboratories, and reviewed independently by 3 hematopathologists at the 3 institutions. Stains were scored on a 4-point scale. Statistical analyses of variation in the scoring among observers and among different institutions' stains were performed. Stains for CD3, CD10, CD20, BCL-2, BCL-6, MIB-1, and FOX-P1 revealed little variation among observers, with an average 51-82% complete agreement and 82-100% agreement +/- 1 numerical score. The rate of concordance when evaluating most stains performed in different laboratories was also relatively good, with an average of 55-72% complete agreement and 70-97% agreement +/- 1 score. However, scoring of MUM-1 and p53 stains showed wider variation, with an average of only 37 and 30% complete agreement among observers, and 11 and 45% agreement when stains from different institutions were examined. Further statistical analyses were performed to compare the observers' scoring of their own institution's stains (self-review) vs. observers' scoring of other institutions' stains (non-self). The agreement rate for the p53 stain was significantly higher when based on self-review (average 58% complete agreement) compared with an agreement rate of only 10.5% when based on a review of stains performed in another laboratory, non-self review, P < 0.01. This difference in the self- vs. non-self review was not seen when data for MUM-1 were analysed. In conclusion, most phenotypic markers used in the analysis of DLBCL can be evaluated in TMAs with adequate agreement among observers and laboratories. These include CD3, CD20, CD10, BCL-2, BCL-6, MIB-1, and FOX-P1. However, some markers, such as p53 and MUM-1, are more prone to inter-institutional variation. Variations in interpretation can be partially overcome by self-adjusted/adapt tendency, as seen with p53. Especially with newly developed markers, such as MUM-1, the development of standardized techniques for staining and interpretation is critical to reduce inter-observer variability.

Analysis of Variance↗

PubMed2005

t(14;22)(q32;q11) in non-Hodgkin lymphoma and myeloid leukaemia: molecular cytogenetic investigations.

Two non-Hodgkin lymphomas (NHL), one chronic lymphocytic leukaemia/small lymphocytic lymphoma and one diffuse large B-cell lymphoma and three cases of myeloid leukaemia, two chronic (CML) and one acute (AML), showed, by G-banding analysis, apparently identical chromosomal translocations t(14;22)(q32;q11), in three of the cases as the sole abnormality. Fluorescence in situ hybridisation (FISH) analysis with locus-specific probes for ABL at 9q34 [bacterial artificial chromosomes (BACs) 835J22 and 1132H12], IGH at 14q32 [P1 artificial chromosome (PAC) 998D24] and IGL (PAC 1019H10) and BCR (BAC 74M14) at 22q11, as well as multicolour in situ hybridisation (M-FISH) analyses were performed. A three-way variant translocation of the classical t(9;22)(q34;q11), t(9;22;14)(q34;q11;q32), involving both BCR and ABL, was unravelled by the molecular cytogenetic investigations in the three myeloid leukaemia cases; a similar variant translocation has previously been reported in seven CML. The two cases of NHL (one NHL with a similar 14;22-translocation has been reported previously) had no involvement of BCR or ABL, but instead the IGH and IGL genes were shown to be juxtaposed by the t(14;22)(q32;q11). How such a rearrangement with recombination of IGH and IGL might elicit a pathogenetic effect is completely unknown.

Chromosomes, Human, Pair 14↗

PubMed2005

G-banding and molecular cytogenetic analyses of marginal zone lymphoma.

We analysed the acquired chromosomal aberrations of 22 marginal zone lymphoma (MZL) patients by various genome-wide cytogenetic techniques, such as G-banding, multicolour fluorescence in situ hybridisation (M-FISH), cross-species colour banding (RxFISH), and comparative genomic hybridisation (CGH), as well as FISH with locus-specific probes. Patients with an abnormal chromosome 3 (n = 11), the most frequently rearranged chromosome, showed a shorter median survival than patients with a normal chromosome 3 (n = 11, 74 months vs. 219 months, P < 0.03). Four of five patients with nodal MZL had chromosome 3 abnormalities and patients with nodal MZL had a shorter median survival than patients in the other morphological subgroups of MZL (P < 0.003). CGH analysis showed only gains of chromosome material, namely of chromosome regions 3p12-25, 3q12-21, 3q23-28, 12q13-15, 12q22-24, 19p13 and 19q13 in two to four cases each (20-40%). In two MZL, the novel unbalanced translocation der(13)t(3;13)(q24;p11) was detected as the sole karyotypic rearrangement, indicating that gain of 3q24-qter could be an important event in the pathogenesis of these lymphomas. Another two cases showed, in addition to other abnormalities, a t(4;14)(p13;q32). Both these lymphomas had involvement of the IGH gene at 14q32, and one of them also of the RHOH/TTF gene at 4p13, which encodes a new member of the RHO protein subfamily.

Adult↗

PubMed2004

Ephrin-A1 binding to CD4+ T lymphocytes stimulates migration and induces tyrosine phosphorylation of PYK2.

Eph receptors, the largest subfamily of receptor tyrosine kinases, and their ephrin ligands are important mediators of cell-cell communication regulating cell attachment, shape, and mobility. Here we demonstrate that CD4+ T lymphocytes express the EphA1 and EphA4 receptors and that these cells bind the ligand ephrin-A1. Further we show ephrin-A1 expression in vivo on high endothelial venule (HEV) endothelial cells. Ephrin-A1 binding to CD4+ T cells stimulates both stromal cell-derived factor 1alpha (SDF-1alpha)- and macrophage inflammatory protein 3beta (MIP3beta)-mediated chemotaxis. In line with the increased chemotactic response, increased actin polymerization is observed in particular with the combination of ephrin-A1 and SDF-1alpha. Signaling through EphA receptors induces intracellular tyrosine phosphorylation. In particular, proline-rich tyrosine kinase 2 (PYK2) is phosphorylated on tyrosine residues 402 and 580. Ephrin-A1-induced chemotaxis and intracellular tyrosine phosphorylation, including EphA1 and Pyk2, was inhibited by Tyrphostin-A9. In conclusion, ligand engagement of EphA receptors on CD4+ T cells stimulates chemotaxis, induces intracellular tyrosine phosphorylation, and affects actin polymerization. This, together with our finding that ephrin-A1 is expressed by HEV endothelial cells, suggests a role for Eph receptors in transendothelial migration.

Actins↗

PubMed2004

Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells.

BACKGROUND: Patients with follicular lymphoma may survive for periods of less than 1 year to more than 20 years after diagnosis. We used gene-expression profiles of tumor-biopsy specimens obtained at diagnosis to develop a molecular predictor of the length of survival. METHODS: Gene-expression profiling was performed on 191 biopsy specimens obtained from patients with untreated follicular lymphoma. Supervised methods were used to discover expression patterns associated with the length of survival in a training set of 95 specimens. A molecular predictor of survival was constructed from these genes and validated in an independent test set of 96 specimens. RESULTS: Individual genes that predicted the length of survival were grouped into gene-expression signatures on the basis of their expression in the training set, and two such signatures were used to construct a survival predictor. The two signatures allowed patients with specimens in the test set to be divided into four quartiles with widely disparate median lengths of survival (13.6, 11.1, 10.8, and 3.9 years), independently of clinical prognostic variables. Flow cytometry showed that these signatures reflected gene expression by nonmalignant tumor-infiltrating immune cells. CONCLUSIONS: The length of survival among patients with follicular lymphoma correlates with the molecular features of nonmalignant immune cells present in the tumor at diagnosis.

Adult↗