PT - JOURNAL ARTICLE AU - Keenan Hartert AU - Saber Tadros AU - Alyssa Bouska AU - Dalia Moore AU - Tayla Heavican AU - Christine Pak AU - Chih Long Liu AU - Andrew Gentles AU - Elena Hartmann AU - Robert Kridel AU - Karin Ekstrom Smedby AU - Gunnar Juliusson AU - David Klinkebiel AU - Richard Rosenquist AU - Randy Gascoyne AU - Andreas Rosenwald AU - Martin Bast AU - Julie Vose AU - Matthew Lunning AU - Timothy Greiner AU - Scott Rodig AU - Javeed Iqbal AU - Ash Alizadeh AU - Michael R. Green TI - DNA copy number gains of <em>TCF4</em> (E2-2) are associated with poor outcome and the activated B-cell-like subtype of diffuse large B-cell lymphoma AID - 10.1101/170605 DP - 2017 Jan 01 TA - bioRxiv PG - 170605 4099 - http://biorxiv.org/content/early/2017/07/31/170605.short 4100 - http://biorxiv.org/content/early/2017/07/31/170605.full 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.