ATR alterations in Hodgkin's lymphoma

Abstract

Hodgkin's lymphoma (HL) is characterized by the presence of neoplastic Hodgkin and Reed-Sternberg cells (HRSC) in a background of inflammatory cells. Free radicals and oxidative stress generated in the inflammatory lesions could cause DNA damage, thus providing a basis for lymphomagenesis. Ataxia-telangiectasia mutated (ATM) and Rad3-related (ATR) genes are responsive genes for DNA damage, therefore the potential involvement of the ATR gene in HL pathogenesis was examined in 8 HL cell lines and 7 clinical cases. ATR alterations were detected in 6 out of 8 HL lines. Most aberrant transcripts observed were heterozygous deletions, which may have resulted from aberrant splicing. ATR aberrant transcripts were also detected in 3 out of 7 clinical cases. Three alterations, del exon 4, deletion exon 29-34 and insertion of 137 bp in exon 46/47 were commonly observed in both cell lines and clinical samples. HL cells with ATR alterations except del exon 4 showed a delay/abrogation in repair for DNA double-strand breaks (DSBs) and single-strand break (SSB) as well as exhibiting a defect in p53 accumulation. These findings suggested the role of ATR gene alterations in HL lymphomagenesis.