RT Journal Article SR Electronic T1 DNA copy number gains of TCF4 (E2-2) are associated with poor outcome and the activated B-cell-like subtype of diffuse large B-cell lymphoma JF bioRxiv FD Cold Spring Harbor Laboratory SP 170605 DO 10.1101/170605 A1 Keenan Hartert A1 Saber Tadros A1 Alyssa Bouska A1 Dalia Moore A1 Tayla Heavican A1 Christine Pak A1 Chih Long Liu A1 Andrew Gentles A1 Elena Hartmann A1 Robert Kridel A1 Karin Ekstrom Smedby A1 Gunnar Juliusson A1 David Klinkebiel A1 Richard Rosenquist A1 Randy Gascoyne A1 Andreas Rosenwald A1 Martin Bast A1 Julie Vose A1 Matthew Lunning A1 Timothy Greiner A1 Scott Rodig A1 Javeed Iqbal A1 Ash Alizadeh A1 Michael R. Green YR 2017 UL http://biorxiv.org/content/early/2017/07/31/170605.abstract AB Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma and can be classified into two prognostically distinct molecular subtypes based upon transcriptional profiling. The activated B-cell (ABC)-like subtype is associated with a poor clinical outcome, and chronic activation of B-cell receptor signaling. Although many genetic alterations have been identified that contribute to this phenotype, these only account for a minority of cases. We employed public high-resolution DNA copy number profiles from 673 tumors to define the landscape of somatic copy number alterations (SCNAs) in DLBCL. Using integrative analysis of gene-expression profiling data, we found DNA-binding transcription factors to be a significantly enriched targets of SCNAs in DLBCL. We extended upon this observation in an additional 2,506 tumors from 6 other histologies, and found SCNA of transcription factors to be pervasive across B-cell malignancies. Furthermore, co-segregating SCNAs targeting transcription factors were associated with adverse patient outcome and the ABC-like subtype of DLBCL. This included a novel target of DNA copy number gain, TCF4 (E2-2). Gains of TCF4 were associated with a transcriptional signature that included increased expression of B-cell receptor signaling components. In a validation cohort of 124 DLBCL tumors interrogated by targeted sequencing, we found that TCF4 DNA copy number gains significantly co-associate with somatic mutation of CD79B and MYD88. Together, these data suggest that SCNA of transcription factor genes are an important feature of B-cell malignancies, and these alterations may contribute to the ABC-like phenotype of DLBCL in tandem with other previously defined somatic alterations.