Summary There is substantial heterogeneity among primary prostate cancers, evident in the spectrum of molecular abnormalities and its variable clinical course. As part of The Cancer Genome Atlas (TCGA), we present a comprehensive molecular analysis of 333 primary prostate carcinomas. Our results revealed a molecular taxonomy in which 74% of these tumors fell into one of seven subtypes defined by specific gene fusions (ERG, ETV1/4, FLI1) or mutations (SPOP, FOXA1, IDH1). Epigenetic profiles showed substantial heterogeneity, including an IDH1-mutant subset with a methylator phenotype. Androgen receptor (AR) activity varied widely and in a subtype-specific manner with SPOP and FOXA1 mutant tumors having the highest levels of AR-induced transcripts. 25% of the prostate cancers had a presumed actionable lesion in the PI3K or MAPK signaling pathways, and DNA repair genes were inactivated in 19%. Our analysis reveals molecular heterogeneity among primary prostate cancers, as well as potentially actionable molecular defects.

The discovery that lymphocyte subpopulations participate in distinct components of the immune response focused attention onto the origins and function of lymphocytes more than 40 years ago. Studies in the 1960s and 1970s demonstrated that B and T lymphocytes were responsible primarily for the basic functions of antibody production and cell-mediated immune responses, respectively. The decades that followed have witnessed a continuum of unfolding complexities in B-cell development, subsets, and function that could not have been predicted. Some of the landmark discoveries that led to our current understanding of B lymphocytes as the source of protective innate and adaptive antibodies are highlighted in this essay. The phenotypic and functional diversity of B lymphocytes, their regulatory roles independent of antibody production, and the molecular events that make this lineage unique are also considered. Finally, perturbations in B-cell development that give rise to certain types of congenital immunodeficiency, leukemia/lymphoma, and autoimmune disease are discussed in the context of normal B-cell development and selection. Despite the significant advances that have been made at the cellular and molecular levels, there is much more to learn, and cross-disciplinary studies in hematology and immunology will continue to pave the way for new discoveries. IntroductionDespite a monotonous microscopic appearance that belies their remarkable developmental and functional heterogeneity, lymphocytes have stimulated the intellectual curiosity and challenged the experimental skills of investigators in many disciplines. We know them as T (thymus-derived) and B (bursal or bone marrowderived) lymphocytes, and the latter is the focus of this historical essay. A simple definition of B lymphocytes is a population of cells that express clonally diverse cell surface immunoglobulin (Ig) receptors recognizing specific antigenic epitopes. Their origin can be traced to the evolution of adaptive immunity in jawed vertebrates beginning more than 500 million years ago. 1 As shown in Figure 1, mammalian B-cell development encompasses a continuum of stages that begin in primary lymphoid tissue (eg, human fetal liver and fetal/adult marrow), with subsequent functional maturation in secondary lymphoid tissue (eg, human lymph nodes and spleen). The functional/protective end point is antibody production by terminally differentiated plasma cells. However, these B-cell development stages and their functional identities were essentially discovered in reverse chronologic order.The discovery of B cells did not originate in the identification of a cell, but rather the identification of a protein (ie, Ig or antibody). Identification of serum gammaglobulin as the source of antibodies 2 was a launching point for the eventual discovery of antibodyproducing cells. Plasma cells were suggested as a source of antibody production as early as 1948. 3 The 2 competing views of antibody formation, the "natural selection" theory and the "clonal selection" theory, were...

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Here we report stable gene transfer in cord blood-derived CD34 ؉ hematopoietic stem cells using a hyperactive nonviral Sleeping Beauty (SB) transposase (SB100X