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 singlestrand break (SSB) as well as exhibiting a defect in p53 accumulation. These findings suggested the role of ATR gene alterations in HL lymphomagenesis.

ATM and ATR signaling at a glance

“…In particular, in ATM, distinct mutations have been found that cause different human malignancies, including lung cancer, breast cancer, colon cancer, lymphocytic leukemia, pancreatic cancer, and head and neck cancer, among others (Ding et al, 2008;Goldgar et al, 2011;Guarini et al, 2012;Roberts et al, 2012;Seshagiri et al, 2012) (see poster). Homozygous loss-of-function mutations or deletion of ATR or Chk1 have not yet been reported; however, there are sporadic studies that show mutations in ATR or Chk1 in certain cancer types (Kim et al, 2007;Lewis et al, 2007;Liu et al, 2008;Menoyo et al, 2001;Zighelboim et al, 2009) (see poster), suggesting that the ATRChk1 axis cannot be generalized as a canonical tumor suppressor pathway.…”

Chromosomal Instability in Hodgkin Lymphoma: An In-Depth Review and Perspectives

“…ATR kinases play an important role in maintaining genome integrity during DNA replication through the phosphorylation and activation of Chk1 and regulation of the DNA damage response. Only one study [ 78 ] has examined ATR gene alterations in eight HL cell lines and in seven clinical cases. Alterations of ATR were detected in six of the eight HL cell lines and in three of the seven clinical cases, most of which displayed a delay/abrogation in the repair of DNA double-strand breaks (DSBs) and single-strand breaks (SSB), as well as a defect in p53 accumulation.…”

Precise detection of genomic imbalances at single-cell resolution reveals intra-patient heterogeneity in Hodgkin’s lymphoma

“…Noteworthy, most clonal alterations detected were gains in highly recurrent genomic locations containing driver genes such as PD-L1/PD-L2 and REL , while subclonal alterations in examined cases were mainly losses in regions containing tumor suppressors ( TNFAIP3 and CDKN1A ) and genes associated with DNA repair ( ATR ). ATR has already been proposed to have a role in lymphomagenesis in HL as deletions and insertions in the gene have been shown to cause a delay/abrogation in double-strand break and single-strand break repair and defects in the accumulation of p53 14 . Late mutations in cancer genes involved in maintenance of genome integrity through DNA damage response and repair have already been observed also in other cancer types, and it has been proposed that such mutations may provide advantages to emerging subclones later in evolution 15 .…”