Characteristics of molecular abnormalities in thyroid cancers from atomic bomb survivors

原子弹爆炸幸存者乳头状甲状腺癌（PTC）中RET/PTC重排：尽管RT-PCR在89.5%的PTC中明显表达微管蛋白mRNA，但在任何病例中均未检测到RET/PTC1或PTC3。PTC中RET的FISH分析：我们首次证实了RET癌基因扩增，该病例来自于接受131I内照射治疗的既往甲状腺癌的原子弹幸存者。在辐射诱导的乳头状甲状腺癌和低分化甲状腺癌中也观察到RET扩增，提示在甲状腺癌发生过程中参与了基因组不稳定性。原子弹幸存者甲状腺滤泡上皮的基因组不稳定性：53BP1病灶形成水平在癌症中明显高于正常滤泡细胞。在癌细胞中，这些53BP1病灶与上游的pATM和下游的p53分子共定位。在肿瘤周围的滤泡上皮中也可检测到低水平的53BP1灶形成，提示甲状腺癌发生的初始阶段。原子弹爆炸幸存者PTC中BRAF突变：14.9%的PTC中检测到热点点突变BRAF T1799A，其他为野生型。原子弹辐射与BRAF突变之间没有明显的关联。PTC中RET扩增与基因组不稳定性：PTC中RET扩增仅在辐射诱导和高分级病例中发现。在甲状腺癌变过程中，滤泡性腺瘤中可见53BP1病灶形成，其表达改变为异常型，并发生间变性。因此，基因组不稳定性可能在早期就被诱导，并随着肿瘤发生的进展而加速。53BP1在辐射诱导的PTC中的表达类型为异常型，提示RET扩增涉及基因组不稳定性增加。

RET/PTC rearrangement in papillary thyroid cancers (PTC) from A-bomb survivors : Although the expression of tubulin mRNA was evident in 89.5% of PTC by RT-PCR, neither RET/PTC1 nor PTC3 was detected in any cases.FISH analysis for RET in PTC : We firstly demonstrated amplification of RET oncogene in a case of anaplastic thyroid cancer from A-bomb survivors who received internal irradiation therapy with 131I for previous thyroid cancer. RET amplification was also observed in radiation-induced papillary thyroid cancers and poorly differentiated thyroid cancers, suggesting the involvement of genomic instability during thyroid carcinogenesis.Genomic instability in thyroid follicular epithelium from A-bomb survivors: The level of 53BP1 focus formation was significantly higher in cancers than normal follicular cells. These 53BP1 foci co-localized with upper stream pATM and downstream p53 molecules in cancer cells. A low level of 53BP1 foci formation could be detected also in follicular epithelium surrounding tumor, suggesting an initial stage during thyroid carcinogenesis.BRAF mutation in PTC from A-bomb survivors : A hot spot point mutation BRAF T1799A was detected in 14.9% of PTC, while others were wild type. No significant association was revealed between A-bomb radiation and BRAF mutation.RET amplification in PTC and genomic instability : RET amplification in PTC was only found in radiation-induced and high grade cases. During thyroid carcinogenesis, 53BP1 foci formation could be observed in follicular adenoma, and its expression altered into abnormal type with anaplastic transformation. Thus, genomic instability might be induced at the early stage and accelerated with progression of tumorigenesis. The type of 53BP1 expression in radiation-induced PTC was abnormal type, suggesting involvement of increased genomic instability in RET amplification.