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首页> 外文期刊>Radiation and Environmental Biophysics >Differential effects of genes of the Rb1 signalling pathway on osteosarcoma incidence and latency in alpha-particle irradiated mice
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Differential effects of genes of the Rb1 signalling pathway on osteosarcoma incidence and latency in alpha-particle irradiated mice

机译：Rb1信号通路基因对α粒子辐照小鼠骨肉瘤发生率和潜伏期的差异影响

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Osteosarcoma is the most frequent secondary malignancy following radiotherapy of patients with bilateral retinoblastoma. This suggests that the Rb1 tumour suppressor gene might confer genetic susceptibility towards radiation-induced osteosarcoma. To define the contribution of the Rb1 pathway in the multistep process of radiation carcinogenesis, we evaluated somatic allelic changes affecting the Rb1 gene itself as well as its upstream regulator p16 in murine osteosarcoma induced by 227Th incorporation. To distinguish between the contribution of germline predisposition and the effect of a 2-hit allelic loss, two mouse models harbouring heterozygote germline Rb1 and p16 defects were tested for the incidence and latency of osteosarcoma following irradiation. We could show that all tumours arising in BALB/c × CBA/CA hybrid mice (wild-type for Rb1 and for p16) carried a somatic allelic loss of either the Rb1 gene (76.5%) or the p16 gene (59%). In none of the tumours, we found concordant retention of heterozygosity at both loci. Heterozygote knock-out mice for Rb1 exhibit a significant increase in the incidence of osteosarcoma following 227Th incorporation (22/24 in Rb1+/− vs. 2/18 in Rb1+/+, p = 4 × 10−5), without affecting tumour latency. In contrast, heterozygote knock-out mice for p16 had no significant change in tumour incidence, but a pronounced reduction of latency (LT50% = 355 days in p16+/− vs. 445 days in p16+/+, p = 8 × 10−3). These data suggest that Rb1 germline defects influence early steps of radiation osteosarcomagenesis, whereas alterations in p16 mainly affect later stages of tumour promotion and growth.
机译：骨肉瘤是放疗双侧视网膜母细胞瘤患者后最常见的继发性恶性肿瘤。这表明Rb1抑癌基因可能赋予对辐射诱发的骨肉瘤的遗传易感性。为了确定Rb1途径在放射致癌作用的多步过程中的作用，我们评估了掺入 227 Th引起的鼠骨肉瘤中影响Rb1基因本身及其上游调节因子p16的体细胞等位基因变化。为了区分种系易感性的贡献和2次击中的等位基因缺失的影响，测试了两个携带杂合子种系Rb1和p16缺陷的小鼠模型照射后骨肉瘤的发生率和潜伏期。我们可以证明，在BALB / c×CBA / CA杂种小鼠中出现的所有肿瘤（Rb1和p16均为野生型）均携带Rb1基因（76.5％）或p16基因（59％）的体细胞等位基因缺失。在所有肿瘤中，我们均未发现两个基因座均杂合性一致。掺入 227 Th后，杂合子敲除Rb1小鼠的骨肉瘤发病率显着增加（Rb1 +/-中为22/24，Rb1 + / +中为2/18，p = 4×10 −5 ），而不会影响肿瘤潜伏期。相比之下，p16杂合子敲除小鼠的肿瘤发生率无明显变化，但潜伏期显着减少（p16 +/-中的LT 50％ = 355天，而p16 + / +中的445天，p = 8×10 −3 ）。这些数据表明Rb1种系缺陷影响放射骨肉瘤形成的早期步骤，而p16的改变主要影响肿瘤促进和生长的后期阶段。

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