Dave, S. S. et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N. Engl. J. Med. 351, 2159-2169

University of Rochester, Rochester, New York, United States
New England Journal of Medicine (Impact Factor: 54.42). 12/2004; 351(21):2159-69. DOI: 10.1056/NEJMoa041869
Source: PubMed

ABSTRACT 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.
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.
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.
The length of survival among patients with follicular lymphoma correlates with the molecular features of nonmalignant immune cells present in the tumor at diagnosis.

  • Source
    • "The similarity between the gene expression profile (GEP) of CLL cells isolated from lymph nodes (Herishanu et al., 2011) and GEP of CLL cells after coculture with NLCs (Burger et al., 2009) suggest that NLCs are a valid model system for the CLL lymph node microenvironment . Comparable to NLCs in CLL are monocyte-derived lymphoma associated macrophages (LAM), which have prognostic significance in follicular lymphoma (Dave et al., 2004) and diffuse large B cell lymphoma (Lenz et al., 2008), suggesting that similar supportive molecular interactions exist between LAM and lymphoma cells. CXCR4 (Burger et al., 1999) and CXCR5 (Burkle et al., 2007) chemokine receptors are expressed at high levels on CLL cells, which allows CLL cells to sense and follow CXCL12 and CXCL13 chemokine gradients, established by tissue stromal cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic Lymphocytic Leukemia (CLL) is a prototype microenvironment-dependent B-cell malignancy, in which the neoplastic B cells co-evolve together with a supportive tissue microenvironment, which promotes leukemia cell survival, growth, and drug-resistance. Chemo-immunotherapy is an established treatment modality for CLL patients, resulting in high rates of responses and improved survival, especially in low-risk CLL. New, alternative treatments target B-cell receptor (BCR) signaling and the Chemokine (C-X-C motif) Receptor 4 (CXCR4)- Chemokine (C-X-C motif) Ligand 12 (CXCL12) axis, which are key pathways of CLL-microenvironment cross talk. The remarkable clinical efficacy of inhibitors targeting the BCR-associated kinases bruton’s tyrosine kinase (BTK) and phosphoinositide 3-kinase delta (PI3Kδ) challenge established therapeutic paradigms and corroborate the central role of BCR signaling in CLL pathogenesis. In this review, we discuss the cellular and molecular components of the CLL microenvironment. We also describe the emerging therapeutic options for CLL patients, with a focus on inhibitors of CXCR4-CXCL12 and BCR signaling.
    Pharmacology [?] Therapeutics 12/2014; 144(3). DOI:10.1016/j.pharmthera.2014.07.003 · 7.75 Impact Factor
  • Source
    • "Ranking methods include the t-statistic for difference in expression of good versus bad prognosis genes (Bell et al., 2011; Verhaak et al., 2013) and signed averaging of discretized or continuous expression values (Colman et al., 2010; Dave et al., 2004; Hallett et al., 2010; Kang et al., 2012;Rè me et al., 2013). Replacing lasso coefficients by their signs has been proposed for summarizing gene pathway activity (Eng et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Motivation: The successful translation of genomic signatures into clinical settings relies on good discrimination between patient sub-groups. Many sophisticated algorithms have been proposed in the statistics and machine learning literature, but in practice simpler algorithms are often used. However, few simple algorithms have been formally described or systematically investigated. Results: We give a precise definition of a popular simple method we refer to as mas-o-menos, which calculates prognostic scores for discrimination by summing standardized predictors, weighted by the signs of their marginal associations with the outcome. We study its behavior theoretically, in simulations and in an extensive analysis of 27 independent gene expression studies of bladder, breast and ovarian cancer, altogether totaling 3833 patients with survival outcomes. We find that despite its simplicity, mas-o-menos can achieve good discrimination performance. It performs no worse, and sometimes better, than popular and much more CPU-intensive methods for discrimination, including lasso and ridge regression.
    Bioinformatics 07/2014; 30(21). DOI:10.1093/bioinformatics/btu488 · 4.62 Impact Factor
  • Source
    • "Cytotoxic T lymphocytes were shown to have a tumor controlling potential, but, once they are present in the tumor microenvironment, they may be inhibited by regulatory T and/or B cells [21] [22] [23] [24] [25] or exhausted as shown in melanoma [26] and lymphoma [27]. Conversely, immune response signatures have identified tumor infiltrating T cells, monocytes, and dendritic cells as being predictive of survival of FL [28]. RT-PCR based gene expression profiling results were in agreement with these observations [29]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Growing evidence suggests that the patient's immune response may play a major role in the long-term efficacy of antibody therapies of follicular lymphoma (FL). Particular long-lasting recurrence free survivals have been observed after first line, single agent rituximab or after radioimmunotherapy (RIT). Rituximab maintenance, furthermore, has a major efficacy in prolonging recurrence free survival after chemotherapy. On the other hand, RIT as a single step treatment showed a remarkable capacity to induce complete and partial remissions when applied in recurrence and as initial treatment of FL or given for consolidation. These clinical results strongly suggest that RIT combined with rituximab maintenance could stabilize the high percentages of patients with CR and PR induced by RIT. While the precise mechanisms of the long-term efficacy of these 2 treatments are not elucidated, different observations suggest that the patient's T cell immune response could be decisive. With this review, we discuss the potential role of the patient's immune system under rituximab and RIT and argue that the T cell immunity might be particularly promoted when combining the 2 antibody treatments in the early therapy of FL.
    Clinical and Developmental Immunology 11/2013; 2013:875343. DOI:10.1155/2013/875343 · 2.93 Impact Factor
Show more