Cancer - Hematological Malignancies

Genomic approaches to hematologic malignancies

Ebert, BL & Golub TR, 2004. Blood 104(4): 923-32

Abstract

In the past several years, experiments using DNA microarrays have contributed to an increasingly refined molecular taxonomy of hematologic malignancies. In addition to the characterization of molecular profiles for known diagnostic classifications, studies have defined patterns of gene expression corresponding to specific molecular abnormalities, oncologic phenotypes, and clinical outcomes. Furthermore, novel subclasses with distinct molecular profiles and clinical behaviors have been identified. In some cases, specific cellular pathways have been highlighted that can be therapeutically targeted. The findings of microarray studies are beginning to enter clinical practice as novel diagnostic tests, and clinical trials are ongoing in which therapeutic agents are being used to target pathways that were identified by gene expression profiling. While the technology of DNA microarrays is becoming well established, genome-wide surveys of gene expression generate large data sets that can easily lead to spurious conclusions. Many challenges remain in the statistical interpretation of gene expression data and the biologic validation of findings. As data accumulate and analyses become more sophisticated, genomic technologies offer the potential to generate increasingly sophisticated insights into the complex molecular circuitry of hematologic malignancies. This review summarizes the current state of discovery and addresses key areas for future research.

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Comment

This well written article briefly discusses gene expression microarrays, then addresses their application to hematologic malignancies, acute myeloid leukemia, acute lymphoblastic leukemia, mixed-lineage leukemia and diffuse large B-cell lymphoma. The article has a limited number of visuals but very clearly addresses the issues in translating microarray technology from the bench to the bedside, including acquisition of clinical samples and analysis of the data.

Burkitt's Lymphoma -- The Message from Microarrays

Harris, NL & Horning, SJ, 2006. N. Eng. J. Med. 354(23):2495-2498

Intro. Paragraph

Two articles in this issue of the Journal, by Dave et al. and Hummel et al., report on the use of gene-expression microarray technology to improve the accuracy of the diagnosis of Burkitt's lymphoma. The two studies differ in many important ways, but both reach the same conclusion: the gene-expression profiling of cases classified as Burkitt's lymphoma by expert pathologists identifies a characteristic genetic signature that clearly distinguishes this tumor from cases of diffuse large-B-cell lymphoma. Furthermore, the microarray method seems to outperform the expert pathologists: 17 percent and 34 percent of cases with the gene-expression signature of Burkitt's lymphoma had been called diffuse large-B-cell lymphoma or unclassifiable high-grade B-cell lymphoma; 0.4 percent and 4 percent of cases without the Burkitt's signature had been called classic or atypical Burkitt's lymphoma; and 3 percent and 8 percent of cases diagnosed as diffuse large-B-cell lymphoma or unclassifiable high-grade B-cell lymphoma had a Burkitt's signature. . . .

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Molecular Diagnosis of Burkitt's Lymphoma

Dave, SS et al., 2006. N. Eng. J. Med. 354(23):2431-2442

Abstract

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-{kappa}B 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.

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A biologic definition of Burkitt's lymphoma from transcriptional and genomic profiling

Hummel, M et al., 2006. N. Eng. J. Med. 354(23):2419-2430

Abstract

Background The distinction between Burkitt's lymphoma and diffuse large-B-cell lymphoma is unclear. We used transcriptional and genomic profiling to define Burkitt's lymphoma more precisely and to distinguish subgroups in other types of mature aggressive B-cell lymphomas. Methods We performed gene-expression profiling using Affymetrix U133A GeneChips with RNA from 220 mature aggressive B-cell lymphomas, including a core group of 8 Burkitt's lymphomas that met all World Health Organization (WHO) criteria. A molecular signature for Burkitt's lymphoma was generated, and chromosomal abnormalities were detected with interphase fluorescence in situ hybridization and array-based comparative genomic hybridization. Results We used the molecular signature for Burkitt's lymphoma to identify 44 cases: 11 had the morphologic features of diffuse large-B-cell lymphomas, 4 were unclassifiable mature aggressive B-cell lymphomas, and 29 had a classic or atypical Burkitt's morphologic appearance. Also, five did not have a detectable IG-myc Burkitt's translocation, whereas the others contained an IG-myc fusion, mostly in simple karyotypes. Of the 176 lymphomas without the molecular signature for Burkitt's lymphoma, 155 were diffuse large-B-cell lymphomas. Of these 155 cases, 21 percent had a chromosomal breakpoint at the myc locus associated with complex chromosomal changes and an unfavorable clinical course. Conclusions Our molecular definition of Burkitt's lymphoma clarifies and extends the spectrum of the WHO criteria for Burkitt's lymphoma. In mature aggressive B-cell lymphomas without a gene signature for Burkitt's lymphoma, chromosomal breakpoints at the myc locus were associated with an adverse clinical outcome.

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