{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T15:21:32Z","timestamp":1764688892312},"reference-count":49,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2012,6,26]],"date-time":"2012-06-26T00:00:00Z","timestamp":1340668800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Intl Journal of Cancer"],"published-print":{"date-parts":[[2013,1,15]]},"abstract":"<jats:title>Abstract<\/jats:title><jats: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\u2010rays and <jats:italic>N<\/jats:italic>\u2010ethyl\u2010<jats:italic>N<\/jats:italic>\u2010nitrosourea (ENU) at subcarcinogenic doses and analyzed the mutation frequency and spectrum of the TL\u2010associated genes <jats:italic>Ikaros<\/jats:italic>, <jats:italic>Notch1<\/jats:italic>, <jats:italic>p53<\/jats:italic> and <jats:italic>Kras<\/jats:italic>. We found that the point mutation frequency in <jats:italic>Ikaros<\/jats:italic> was significantly increased to 47% for simultaneous exposure compared to 13 and 0% for X\u2010ray and ENU exposure alone, respectively. These mutations were mostly G:C &gt; A:T at non\u2010CpG sites and T:A &gt; 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\u2010irradiation. The remaining half did not include LOH, which suggests that they were dominant\u2010negative mutations. In <jats:italic>Notch1<\/jats:italic>, the frequency of abnormalities was high (&gt;58%) regardless of the treatment, suggesting that <jats:italic>Notch1<\/jats:italic> aberration may be important for T\u2010cell lymphomagenesis. The <jats:italic>p53<\/jats:italic> and <jats:italic>Kras<\/jats:italic> mutation frequencies were low for all treatments (&lt;23%). Importantly, the frequency of TLs containing mutations in multiple genes, especially both <jats:italic>Ikaros<\/jats:italic> and <jats:italic>Notch1<\/jats:italic>, increased after simultaneous exposure. Thus, after simultaneous exposure, <jats:italic>Ikaros<\/jats:italic> is a critical target and is inactivated by ENU\u2010induced point mutations and\/or X\u2010ray\u2010induced LOH in T\u2010cell lymphomagenesis. Furthermore, concomitant alterations of multiple tumor\u2010associated genes may contribute to enhanced lymphomagenesis after simultaneous exposure.<\/jats:p>","DOI":"10.1002\/ijc.27668","type":"journal-article","created":{"date-parts":[[2012,6,9]],"date-time":"2012-06-09T06:15:18Z","timestamp":1339222518000},"page":"259-268","source":"Crossref","is-referenced-by-count":5,"title":["<i>Ikaros<\/i> is a critical target during simultaneous exposure to X\u2010rays and N\u2010ethyl\u2010N\u2010nitrosourea in mouse T\u2010cell 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