Institute of Pathology and Molecular Pathology, Bundeswehrkrankenhaus Ulm, Ulm, Germany.
Bundeswehr Institute of Radiobiology, Munich, Germany.
J Pathol Clin Res. 2018 Jul;4(3):175-183. doi: 10.1002/cjp2.102. Epub 2018 May 26.
Childhood radiation exposure has been associated with increased papillary thyroid carcinoma (PTC) risk. The role of anaplastic lymphoma kinase (ALK) gene rearrangements in radiation-related PTC remains unclear, but STRN-ALK fusions have recently been detected in PTCs from radiation exposed persons after Chernobyl using targeted next-generation sequencing and RNA-seq. We investigated ALK and RET gene rearrangements as well as known driver point mutations in PTC tumours from 77 radiation-exposed patients (mean age at surgery 22.4 years) and PTC tumours from 19 non-exposed individuals after the Chernobyl accident. ALK rearrangements were detected by fluorescence in situ hybridisation (FISH) and confirmed with immunohistochemistry (IHC); point mutations in the BRAF and RAS genes were detected by DNA pyrosequencing. Among the 77 tumours from exposed persons, we identified 7 ALK rearrangements and none in the unexposed group. When combining ALK and RET rearrangements, we found 24 in the exposed (31.2%) compared to two (10.5%) in the unexposed group. Odds ratios increased significantly in a dose-dependent manner up to 6.2 (95%CI: 1.1, 34.7; p = 0.039) at Iodine-131 thyroid doses >500 mGy. In total, 27 cases carried point mutations of BRAF or RAS genes, yet logistic regression analysis failed to identify significant dose association. To our knowledge we are the first to describe ALK rearrangements in post-Chernobyl PTC samples using routine methods such as FISH and IHC. Our findings further support the hypothesis that gene rearrangements, but not oncogenic driver mutations, are associated with ionising radiation-related tumour risk. IHC may represent an effective method for ALK-screening in PTCs with known radiation aetiology, which is of clinical value since oncogenic ALK activation might represent a valuable target for small molecule inhibitors.
儿童时期的辐射暴露与甲状腺乳头状癌（PTC）风险增加有关。在与辐射相关的 PTC 中，间变性淋巴瘤激酶（ALK）基因重排的作用尚不清楚，但最近在切尔诺贝利事故后使用靶向下一代测序和 RNA-seq 检测到暴露于辐射的人 PTC 中的 STRN-ALK 融合。我们研究了 PTC 肿瘤中的 ALK 和 RET 基因重排以及已知的驱动点突变，这些 PTC 肿瘤来自 77 名辐射暴露患者（手术时的平均年龄为 22.4 岁）和切尔诺贝利事故后 19 名非暴露个体的 PTC 肿瘤。通过荧光原位杂交（FISH）检测 ALK 重排，并通过免疫组织化学（IHC）进行确认；通过 DNA 焦磷酸测序检测 BRAF 和 RAS 基因中的点突变。在 77 名暴露者的肿瘤中，我们发现了 7 种 ALK 重排，而未暴露组中没有发现。当将 ALK 和 RET 重排结合起来时，我们发现暴露组中有 24 例（31.2%），而未暴露组中有 2 例（10.5%）。在碘-131 甲状腺剂量大于 500 mGy 时，风险比呈剂量依赖性显著增加，最高达 6.2（95%CI：1.1，34.7；p=0.039）。总共 27 例携带 BRAF 或 RAS 基因的点突变，但逻辑回归分析未能确定显著的剂量关联。据我们所知，我们是第一个使用 FISH 和 IHC 等常规方法描述切尔诺贝利后 PTC 样本中 ALK 重排的人。我们的发现进一步支持了这样一种假设，即基因重排，而不是致癌驱动突变，与电离辐射相关的肿瘤风险有关。IHC 可能代表了一种有效的 ALK 筛选方法，用于已知辐射病因的 PTC，这具有临床价值，因为致癌性 ALK 激活可能是小分子抑制剂的一个有价值的靶点。
