Genome Expression in Lymphoma, Leukemia and Multiple Myeloma

This study will use genomics-based technology, such as DNA microarrays, to more precisely diagnose subsets of lymphoma, leukemia and multiple myeloma patients. There have been many attempts to classify lymphoid cancers in ways that will be useful for clinical diagnosis and treatment. Although broad diagnostic categories have been reliably defined, patients within each category have distinct clinical courses, suggesting that these classifications could be further divided into molecular (genetic) subtypes. For example, 40 percent of patients with diffuse large B-cell lymphoma achieve long-term disease remissions following combination chemotherapy and are apparently cured, whereas the remaining 60 percent die from the disease. Similarly, some patients with follicular lymphoma develop aggressive disease within a few years of diagnosis, while others have stable disease over 10 to 20 years. Although the distinctions in clinical course of these diseases are recognized, there are no studies to determine the molecular (genetic) basis for this variability. This study will try to define new molecular diagnostic categories in these diseases and correlate them with clinical features, including treatment response, disease remission and overall survival following chemotherapy.

This retrospective study will use clinical data and tissue samples from participating centers in the Lymphoma/Leukemia Molecular Profiling Project LLMPP). New patients will not be recruited for this study.

Biopsy materials, including fresh frozen or OTC-embedded lymphoma biopsy material, viably frozen samples of peripheral blood cells from leukemia patients, and viably frozen samples of bone marrow aspirates from multiple myeloma patients will be collected from pathologists participating in the LLMPP. RNA and genomic DNA will be extracted from the tumor samples. A variety of technologies will be used to characterize the genome of the cancer cells, including lymphochip microarrays for array-based comparative genomic hybridization; Southern blotting and PCR for translocation of genes previously implicated in these malignancies; and PCR and DNA sequencing methods for analyzing base changes in the genome of the cancer cells. Clinical information from the initial diagnosis to disease relapse will be taken from existing databases and/or patient charts. Gene expression will be correlated with the clinical data. If a small number of genes is found to strongly predict clinical outcome, quantitative RT-PCR assays using the Taqman technology may be developed as an alternative to DNA microarray analysis.

Current diagnosis of the lymphoid malignancies relies upon the morphological appearance of the cancer cells supplemented by a few molecular markers. Within a diagnostic category, the clinical courses and responses of patients to therapy are variable, suggesting that the existing diagnostic categories may harbor more than one disease entity. Recent genomic technologies allow a comprehensive molecular analysis of the expression of the genome in cancer cells. DNA microarray analysis of gene expression in lymphomas revealed distinct molecular subtypes of diffuse large B-cell lymphoma and these new molecularly-defined lymphoma subtypes had divergent clinical outcomes. To extend our genomic analysis to all lymphoid malignancies, we have formed a consortium of cooperating institutions termed the Lymphoma/Leukemia Molecular Profiling Project (LLMPP). The clinical centers participating in the LLMPP will send lymphoma, leukemia and multiple myeloma samples to the NCI for gene expression profiling, array-based comparative genomic hybridization and cancer gene resequencing. Clinical data will also be sent for the patients in this study for the purpose of correlating gene expression measurements with clinical outcome. The goals of this effort are to define new molecular diagnostic categories in these diseases that are clinically relevant and to gain new insight into the molecular pathways that are active in these malignancies. The home institutions providing clinical data and tissue samples have obtained local approval by their clinical research committees for this study. No new patients will be enrolled or biopsied for this study.

• Lymphoma
• Leukemia
• Multiple Myeloma
• Lymphoid Malignancies

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• INCLUSION CRITERIA:

Diagnosis of lymphoid malignancy at one of the LLMPP participating institutions, including specimens originating at other clinical sites and submitted to LLMPP participating sites.

Informed consent for research studies performed on biopsy material or waiver of the requirement for informed consent by the clinical research review boards at the LLMPP institutions.

Sufficient frozen biopsy and/or FFPE material from initial biopsy and/or biopsies at relapse of disease to obtain adequate RNA and DNA for gene expression profiling and analysis of genomic alterations in the malignant cells.