Oligonucleotide‐based array CGH analysis of diffuse large B‐cell lymphomas identifies gain of 7q22 as the most common genomic alteration

Abstract

While 40–50% of patients with diffuse large B‐cell lymphoma (DLBCL) respond well to therapy, for the remainder, this malignancy is rapidly fatal. The varied clinical response is likely due to the underlying molecular heterogeneity in DLBCL. Gene expression analyses have revealed clinically relevant subtypes and potential signaling pathways for therapeutic targeting. Nevertheless, there is a need to identify genes that have a critical function in DLBCL in order to broaden the number of therapeutic targets to treat this heterogeneous malignancy. We analyzed 60 nodal and extranodal DLBCLs and 28 DLBCL cell lines using Agilent Human Genome 44K or 105K CGH oligonucleotide arrays (Agilent Technologies). Slides were scanned with an Agilent Scanner, and the data were analyzed with Agilent Feature Extraction, Agilent CGH Analytics, and Nexus Copy Number software (Biodiscovery, Inc.). 60% of cases exhibited a gain in chromosomal material from 7q22. Patients whose malignancies exhibited this particular abnormality showed an increased survival of approximately 30% compared with those that did not. The smallest common region of gain consisted of a 150 kb stretch of DNA that contains a gene that encodes the zinc finger transcription factor protein ZKSCAN1. ZKSCAN1 protein expression was increased in cases that exhibited gains of 7q22. ZKSCAN1 has previously been implicated in the regulation of cell proliferation. It also appears to be regulated by the serine/threonine kinase ataxia‐telangiectasia mutated (ATM). ATM is activated in response to genotoxic insults and regulates proteins involved in the DNA damage checkpoint, cell cycle arrest, DNA repair, and apoptosis. Thus, ZKSCAN1 may play a key role in regulating the proliferation and/or survival of lymphoma cells in DLBCLs that exhibit a gain of 7q22.