Ikaros is a critical target during simultaneous exposure to X‐rays and N‐ethyl‐N‐nitrosourea in mouse T‐cell lymphomagenesis. Issue 2 (26th June 2012)

• Record Type: Journal Article
• Authors: Hirano, Shinobu; Kakinuma, Shizuko; Amasaki, Yoshiko; Nishimura, Mayumi; Imaoka, Tatsuhiko; Fujimoto, Shinji; Hino, Okio; Shimada, Yoshiya
• Is Part Of: International journal of cancer. Volume 132:Issue 2(2013:Jan. 15)
• Page Start: 259
• Page End: 268
• Publication Date: 2012-06-26
• Subjects: Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.27668
• Languages: English
• ISSNs: 0020-7136

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>Cancer risk associated with radiation exposure is considered the result of concurrent exposure to other natural and manmade carcinogens. Available data on the molecular characteristics of cancer after simultaneous exposure to radiation and chemicals are insufficient. In our study, we used a mouse thymic lymphoma (TL) model that was synergistically induced by simultaneous exposure to X‐rays and <italic>N</italic>‐ethyl‐<italic>N</italic>‐nitrosourea (ENU) at subcarcinogenic doses and analyzed the mutation frequency and spectrum of the TL‐associated genes <italic>Ikaros</italic>, <italic>Notch1</italic>, <italic>p53</italic> and <italic>Kras</italic>. We found that the point mutation frequency in <italic>Ikaros</italic> was significantly increased to 47% for simultaneous exposure compared to 13 and 0% for X‐ray and ENU exposure alone, respectively. These mutations were mostly G:C > A:T at non‐CpG sites and T:A > C:G, both of which are characteristic of ENU mutagenesis. About half of the point mutations were accompanied by loss of heterozygosity (LOH), typical of X‐irradiation. The remaining half did not include LOH, which suggests that they were dominant‐negative mutations. In <italic>Notch1</italic>, the frequency of abnormalities was high (>58%) regardless of the treatment, suggesting that <italic>Notch1</italic> aberration may be important for T‐cell lymphomagenesis. The <italic>p53</italic> and <italic>Kras</italic> mutation frequencies were low for all treatments (<23%). Importantly, the frequency of TLs containing mutations in multiple genes, especially both <italic>Ikaros</italic> and <italic>Notch1</italic>, increased after simultaneous exposure. Thus, after simultaneous exposure, <italic>Ikaros</italic> is a critical target and is inactivated by ENU‐induced point mutations and/or X‐ray‐induced LOH in T‐cell lymphomagenesis. Furthermore, concomitant alterations of multiple tumor‐associated genes may contribute to enhanced lymphomagenesis after simultaneous exposure.</p> </abstract>