University of Hawaii Cancer Center, University of Hawaii, 701 Ilalo Street, Honolulu, Hawaii, 96813, USA.
Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio, 44195, USA.
J Cancer Res Clin Oncol. 2021 Jan;147(1):183-194. doi: 10.1007/s00432-020-03401-9. Epub 2020 Sep 29.
BRAF, a major driver of thyroid cancer, evaluated in the context of thyroid hormones and human relaxin.
Immunohistochemical expressions of BRAF, TSH, TSH receptor (TSHR), T4, T3 receptor (T3R), RLNH2, and its receptor, RXFP1, were evaluated in thyroid tumors from a retrospective U.S. population of 481 cancer cases diagnosed in 1983-2004.
BRAF was expressed in 52% of all thyroid tumors; expression of other markers ranged from 25% for T4 to 98% for RLNH2. Tumors predominantly exhibited hypothyroid-like conditions characterized by elevated TSH and TSHR and reduced T4. BRAF prevalence was significantly higher in tumors expressing TSH, TSHR, T3R, and RXFP1 and lower in tumors expressing T4. The proportion of BRAF mutation in classic papillary tumors significantly increased from 56 to 72% over the 21-year period of diagnoses, while expression of RXFP1, TSH, TSHR, and T3R decreased in non-tumor. Racial/ethnic differences were observed in thyroid hormone marker expression. Non-tumor expression of TSH, TSHR, and T3R were each associated with shorter overall survival, but did not remain significant after adjustment for demographic and clinical factors.
Our study provides the first evidence of the potential interaction of BRAF mutation, relaxin, and thyroid hormones in thyroid carcinogenesis. Moreover, our results suggest that hypothyroidism, influenced by RLNH2 activity, may underlie the development of the majority of thyroid cancers and mediate the role of BRAF in thyroid carcinogenesis. BRAF mutation is increasing in papillary thyroid cancers and may be contributing to the rising incidence of this malignancy.
BRAF 是甲状腺癌的主要驱动因素，本研究评估了其与甲状腺激素和人松弛素的关系。
在 1983 年至 2004 年期间诊断的 481 例美国癌症病例的回顾性人群中，评估了甲状腺肿瘤中 BRAF、促甲状腺激素（TSH）、TSH 受体（TSHR）、T4、T3 受体（T3R）、RLNH2 及其受体 RXFP1 的免疫组织化学表达。
所有甲状腺肿瘤中 BRAF 的表达率为 52%；其他标志物的表达率从 T4 的 25%到 RLNH2 的 98%不等。肿瘤主要表现为甲状腺功能减退样状态，表现为 TSH 和 TSHR 升高，T4 降低。在表达 TSH、TSHR、T3R 和 RXFP1 的肿瘤中，BRAF 的患病率显著较高，而在表达 T4 的肿瘤中则较低。在 21 年的诊断期间，经典乳头状肿瘤中 BRAF 突变的比例从 56%显著增加到 72%，而非肿瘤中 RXFP1、TSH、TSHR 和 T3R 的表达则降低。在甲状腺激素标志物表达方面观察到种族/民族差异。非肿瘤中 TSH、TSHR 和 T3R 的表达均与总生存期较短相关，但在调整人口统计学和临床因素后，这些因素不再具有显著性。
本研究首次提供了 BRAF 突变、松弛素和甲状腺激素在甲状腺癌发生中的潜在相互作用的证据。此外，我们的结果表明，RLNH2 活性影响的甲状腺功能减退症可能是大多数甲状腺癌发展的基础，并介导 BRAF 在甲状腺癌发生中的作用。BRAF 突变在甲状腺乳头状癌中呈增加趋势，可能导致这种恶性肿瘤的发病率上升。
