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甲状腺乳头状癌(papillary thyroid cancer,PTC)起源于滤泡上皮细胞,是最常见的内分泌恶性肿瘤,占甲状腺恶性肿瘤的80%~85%[1]。PTC是相对惰性的恶性肿瘤,经过规范化的初始治疗如手术、放射性碘(radioactive iodine,RAI)治疗和TSH抑制后,患者的5年生存期可高达97%[2]。BRAFV600E基因是PTC中最常见的突变基因,人群中发生率为27.3%~90.2%[3]。有研究发现,BRAFV600E突变与PTC的临床病理特征如年龄、性别、肿瘤大小及淋巴结转移等有关,并可独立预测肿瘤的复发率和病死率[2, 4]。然而,也有相关文献报道BRAFV600E突变与PTC的临床病理特征没有关联[5]。本研究通过分析BRAFV600E突变与PTC临床病理特征之间的关系,检测甲状腺全切或近全切术后接受2次RAI治疗患者的刺激性甲状腺球蛋白(stimulated thyroglobulin,s-Tg)水平及其变化趋势,以此来评价BRAFV600E突变对RAI治疗的临床参考价值。
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由表1可知,2647例PTC患者BRAFV600E基因突变率为84.2%(2230/2647);BRAFV600E基因突变与患者的年龄、淋巴结转移相关,突变组的平均年龄的比例高于野生组(P=0.022);突变组的淋巴结转移比例高于野生组(48.39%对41.97%,P=0.016)。但是,BRAFV600E突变组与野生组的性别、PTC病灶长径间的差异均无统计学意义(P>0.05)。
组别 年龄(岁) 性别
[例(%)]肿瘤长径
[例(%)]淋巴结转移
[例(%)]中央区淋巴结
转移[例(%)]侧颈区淋巴结
转移[例(%)]男 女 ≤1 cm >1 cm 是 否 是 否 是 否 突变组
(n=2230)45.29±11.51 519
(23.27)1711
(76.73)1201
(53.86)1029
(46.14)1079
(48.39)1151
(51.61)897
(40.22)1333
(59.78)588
(26.37)1642
(73.63)野生组
(n=417)43.43±12.53 80
(19.18)337
(80.82)238
(57.07)179
(42.93)175
(41.97)242
(58.03)144
(34.53)273
(65.47)122
(29.26)295
(70.74)检验值 t=5.28 χ2=3.36 χ2=1.47 χ2=5.81 χ2=4.77 χ2=1.49 P值 0.022 0.067 0.226 0.016 0.029 0.222 表 1 2组甲状腺乳头状癌患者临床资料的比较
Table 1. Comparison of papillary thyroid cancer patients' clinical data between two groups
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由表2可知,在接受2次RAI治疗的86例PTC患者中,第1次RAI治疗前,2组间s-Tg水平差异无统计学意义;第2次RAI治疗前,BRAFV600E突变组的s-Tg水平明显高于野生组(P=0.003)。与突变组相比,野生组2次RAI治疗后s-Tg水平的差值(Δs-Tg)明显下降(P=0.006)。
组别 s-Tg1(ng/mL) s-Tg 2(ng/mL) Δs-Tg(ng/mL) 131I 剂量(×109 Bq) 突变组(n=57) 62.76±77.13 61.16±90.95 −1.61±37.18 4.15±0.81 野生组(n=29) 42.57±56.37 18.56±37.77 −24.00±30.00 4.06±0.74 检验值 Z=−1.24 Z=−2.41 t=−2.81 t=0.52 P值 0.172 0.003 0.006 0.607 注:表中,s-Tg1:第1次RAI治疗前的s-Tg;s-Tg2:第2次RAI治疗前的s-Tg;Δs-Tg:s-Tg1与s-Tg2的差值。PTC:甲状腺乳头状癌;RAI:放射性碘;s-Tg:刺激性甲状腺球蛋白 表 2 2组PTC患者在首次RAI治疗后s-Tg水平及变化趋势的比较
Table 2. Comparison of s-Tg level and change trend of papillary thyroid cancer patients after first radioactive iodine therapy between two groups
BRAFV600E 突变与甲状腺乳头状癌淋巴结转移的关系及对放射性碘治疗后s-Tg的影响
The association between BRAFV600E mutation and lymph node metastasis of papillary thyroid cancer and its effect on stimulated thyroglobulin radioactive iodine
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摘要:
目的 探讨BRAFV600E突变与甲状腺乳头状癌(PTC)淋巴结转移的关系,以及其对PTC患者放射性碘(RAI)治疗后刺激性甲状腺球蛋白(s-Tg)水平的影响。 方法 回顾性分析2013年1月至2018年12月于郑州大学附属肿瘤医院行甲状腺全切或近全切手术且病理证实为PTC并行BRAF基因检测的2647例患者[男性599例、女性2048例,年龄8~84(45.00±11.70)岁]的临床病理资料。根据BRAFV600E基因是否突变,将患者分为突变组(2230例)和野生组(417例),分析2组间年龄、性别、肿瘤长径和淋巴结转移的差异。选取接受过2次RAI治疗的PTC患者86例[男性28例、女性58例,年龄13~77(42.72±15.69)岁)],同样分为突变组(57例)和野生组(29例),分析2组间在行RAI治疗前后的s-Tg水平差异。采用χ2检验、两独立样本t检验和Mann-Whiney U秩和检验比较2组患者的临床资料;采用配对t检验评价s-Tg水平与BRAFV600E突变之间的关系。 结果 2647例PTC患者的BRAFV600E突变率为84.2%(2230/2647)。突变组的年龄和淋巴结转移的患者比例均高于野生组[(45.29±11.51)岁对(43.43±12.53)岁,t=5.28,P=0.022;48.39%对41.97%,χ2=5.81,P=0.016]。在接受2次RAI治疗的86例PTC患者中,第2次RAI治疗前,突变组的s-Tg水平明显高于野生组[(61.16±90.95) ng/mL对(18.56±37.77) ng/mL,Z=−2.41,P=0.003];与突变组相比,野生组患者第1次和第2次RAI治疗前的s-Tg水平差值明显下降[(−1.61±37.18) ng/mL对(−24.00±30.00) ng/mL,t=−2.81,P=0.006]。 结论 BRAFV600E突变的PTC患者出现淋巴结转移的风险较高,初始RAI治疗后生化指标s-Tg改善较差。 -
关键词:
- 甲状腺癌,乳头状 /
- BRAFV600E突变 /
- 淋巴结转移 /
- 碘放射性同位素;放射疗法 /
- 刺激性甲状腺球蛋白
Abstract:Objective To evaluate the association between BRAFV600E mutation and the lymph node metastasis (LNM) of papillary thyroid cancer (PTC). The effect of BRAFV600E mutation on stimulated thyroglobulin (s-Tg) after radioactive iodine (RAI) remnant ablation treatment was also evaluated. Methods The clinicopathological data of 2647 PTC patients (599 males; 2048 females; age range: 8–84 (45.00±11.70) years) who underwent near total or total thyroidectomy at Henan CancerHospital Affiliated to Zhengzhou University, from January 2013 to December 2018 were retrospectivelycollected and analyzed. The BRAFV600E status of the primary tumor was then identified. The patients were subsequently divided into the BRAFV600E mutation group (2230 cases) and the BRAFV600E wild group (417 cases), and differences in age, gender, tumor size, and lymph node metastasis between these two groups were analyzed. A total of 86 PTC patients (males 28; females 58; age range: 13–77 (42.72±15.69) years) who had received two RAI treatments were filtered from the groups and evaluated further in terms of differences in s-Tg level. The basic data of the two groups were compared via the chi-squared, two independent samples Student's t, and Mann-Whitney U rank-sum tests. Paired t test was used to evaluate the relationship between s-Tg and BRAFV600E mutation. Results The overall prevalence of BRAFV600E mutation in this study was 84.2% (2230/2647). The mean age and proportion of LNM were significantly higher in the mutation group than in the non-mutation group [(45.29±11.51) years vs. (43.43±12.53) years, t=5.28, P=0.022; 48.39% vs. 41.97%, χ2=5.81, P=0.016]. Among the 86 PTC patients who received RAI two RAI treatments, s-Tg levels were slightly higher in the mutation group [(61.16±90.95) ng/mL vs. (18.56±37.77) ng/mL, Z=−2.41, P=0.003], while significantly sharp decreased of s-Tg in wild group [(−1.61±37.18) ng/mL vs. (−24.00±30.00) ng/mL, t=−2.81, P=0.006] undergoing the first RAI remnant ablation. High s-Tg levels were present in the mutation group after the initial treatment. Conclusion PTC patients with the BRAFV600E mutation are at higher risk of developing LNM in PTC and show poor improvement in biochemical indicators after initial treatment. -
表 1 2组甲状腺乳头状癌患者临床资料的比较
Table 1. Comparison of papillary thyroid cancer patients' clinical data between two groups
组别 年龄(岁) 性别
[例(%)]肿瘤长径
[例(%)]淋巴结转移
[例(%)]中央区淋巴结
转移[例(%)]侧颈区淋巴结
转移[例(%)]男 女 ≤1 cm >1 cm 是 否 是 否 是 否 突变组
(n=2230)45.29±11.51 519
(23.27)1711
(76.73)1201
(53.86)1029
(46.14)1079
(48.39)1151
(51.61)897
(40.22)1333
(59.78)588
(26.37)1642
(73.63)野生组
(n=417)43.43±12.53 80
(19.18)337
(80.82)238
(57.07)179
(42.93)175
(41.97)242
(58.03)144
(34.53)273
(65.47)122
(29.26)295
(70.74)检验值 t=5.28 χ2=3.36 χ2=1.47 χ2=5.81 χ2=4.77 χ2=1.49 P值 0.022 0.067 0.226 0.016 0.029 0.222 表 2 2组PTC患者在首次RAI治疗后s-Tg水平及变化趋势的比较
Table 2. Comparison of s-Tg level and change trend of papillary thyroid cancer patients after first radioactive iodine therapy between two groups
组别 s-Tg1(ng/mL) s-Tg 2(ng/mL) Δs-Tg(ng/mL) 131I 剂量(×109 Bq) 突变组(n=57) 62.76±77.13 61.16±90.95 −1.61±37.18 4.15±0.81 野生组(n=29) 42.57±56.37 18.56±37.77 −24.00±30.00 4.06±0.74 检验值 Z=−1.24 Z=−2.41 t=−2.81 t=0.52 P值 0.172 0.003 0.006 0.607 注:表中,s-Tg1:第1次RAI治疗前的s-Tg;s-Tg2:第2次RAI治疗前的s-Tg;Δs-Tg:s-Tg1与s-Tg2的差值。PTC:甲状腺乳头状癌;RAI:放射性碘;s-Tg:刺激性甲状腺球蛋白 -
[1] Huang ML, Yan CJ, Xiao JJ, et al. Relevance and clinicopathologic relationship of BRAF V600E, TERT and NRAS mutations for papillary thyroid carcinoma patients in northwest China[J/OL]. Diagn Pathol, 2019, 14(1): 74[2019-08-07]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626378. DOI: 10.1186/s13000-019-0849-6. [2] Xing MZ, Alzahrani AS, Carson KA, et al. Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer[J]. JAMA, 2013, 309(14): 1493−1501. DOI: 10.1001/jama.2013.3190. [3] Pessôa-Pereira D, Medeiros MFDS, Lima VMS, et al. Association between BRAF (V600E) mutation and clinicopathological features of papillary thyroid carcinoma: a Brazilian single-centre case series[J]. Arch Endocrinol Metab, 2019, 63(2): 97−106. DOI: 10.20945/2359-3997000000120. [4] Xing MZ, Westra WH, Tufano RP, et al. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer[J]. J Clin Endocrinol Metab, 2005, 90(12): 6373−6379. DOI: 10.1210/jc.2005-0987. [5] Trovisco V, Soares P, Preto A, et al. Type and prevalence of BRAF mutations are closely associated with papillary thyroid carcinoma histotype and patients' age but not with tumour aggressiveness[J]. Virchows Arch, 2005, 446(6): 589−595. DOI: 10.1007/s00428-005-1236-0. [6] Elisei R, Viola D, Torregrossa L, et al. The BRAFV600E mutation is an independent, poor prognostic factor for the outcome of patients with low-risk intrathyroid papillary thyroid carcinoma: single-institution results from a large cohort study[J]. J Clin Endocrinol Metab, 2012, 97(12): 4390−4398. DOI: 10.1210/jc.2012-1775. [7] Haugen BR, Alexander EK, Bible KC, et al. 2015 American thyroid association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American thyroid association guidelines task force on thyroid nodules and differentiated thyroid cancer[J]. Thyroid, 2016, 26(1): 1−133. DOI: 10.1089/thy.2015.0020. [8] 王维娜, 曹燕珍, 陈海霞, 等. 甲状腺乳头状癌BRAF V600E基因突变与临床病理特征相关性研究[J]. 新疆医科大学学报, 2018, 41(1): 79−82. DOI: 10.3969/j.issn.1009-5551.2018.01.019.
Wang WN, Cao YZ, Chen HX, et al. Correlation between BRAF V600E mutation and clinicopathologic features of papillary thyroid carcinoma[J]. J Xinjiang Med Univ, 2018, 41(1): 79−82. DOI: 10.3969/j.issn.1009-5551.2018.01.019.[9] Guan HX, Ji MJ, Bao R, et al. Association of high iodine intake with the T1799A BRAF mutation in papillary thyroid cancer[J]. J Clin Endocrinol Metab, 2009, 94(5): 1612−1617. DOI: 10.1210/jc.2008-2390. [10] Seo JY, Choi JR, Moon HJ, et al. Clinical implication of highly sensitive detection of the BRAFV600E mutation in fine-needle aspirations according to the thyroid Bethesda system in patients with conventional papillary thyroid carcinoma[J]. Ann Otol Rhinol Laryngol, 2015, 124(5): 392−399. DOI: 10.1177/0003489414560433. [11] Giordano D, Frasoldati A, Kasperbauer JL, et al. Lateral neck recurrence from papillary thyroid carcinoma: predictive factors and prognostic significance[J]. Laryngoscope, 2015, 125(9): 2226−2231. DOI: 10.1002/lary.25094. [12] Palona I, Namba H, Mitsutake N, et al. BRAFV600E promotes invasiveness of thyroid cancer cells through nuclear factor κB activation[J]. Endocrinology, 2006, 147(12): 5699−5707. DOI: 10.1210/en.2006-0400. [13] Zhou DH, Li Z, Bai XF. BRAFV600E and RET/PTC promote proliferation and migration of papillary thyroid carcinoma cells in vitro by regulating nuclear factor-κB[J]. Med Sci Monit, 2017, 23: 5321−5329. DOI: 10.12659/msm.904928. [14] Revilla G, Corcoy R, Moral A, et al. Cross-talk between inflammatory mediators and the epithelial mesenchymal transition process in the development of thyroid carcinoma[J/OL]. Int J Mol Sci, 2019, 20(10): 2466[2019-08-07]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6566886. DOI: 10.3390/ijms20102466. [15] Sun Y, Yu S, Liu YY, et al. Expression of miRNAs in papillary thyroid carcinomas is associated with BRAF mutation and clinicopathological features in Chinese patients[J]. Int J Endocrinol, 2013, 2013: 128735. DOI: 10.1155/2013/128735. [16] Li BL, Lu Y, Yu LH, et al. miR-221/222 promote cancer stem-like cell properties and tumor growth of breast cancer via targeting PTEN and sustained Akt/NF-κB/COX-2 activation[J]. Chem Biol Interact, 2017, 277: 33−42. DOI: 10.1016/j.cbi.2017.08.014. [17] Galardi S, Mercatelli N, Farace MG, et al. NF-κB and c-Jun induce the expression of the oncogenic miR-221 and miR-222 in prostate carcinoma and glioblastoma cells[J]. Nucleic Acids Res, 2011, 39(9): 3892−3902. DOI: 10.1093/nar/gkr006. [18] Algeciras-Schimnich A. Thyroglobulin measurement in the management of patients with differentiated thyroid cancer[J]. Crit Rev Clin Lab Sci, 2018, 55(3): 205−218. DOI: 10.1080/10408363.2018.1450830. [19] 杨珂, 梁智勇, 孟超, 等. 甲状腺乳头状癌BRAFV600E基因突变与远处转移灶摄碘能力的相关性研究[J]. 中华核医学与分子影像杂志, 2014, 34(4): 287−291. DOI: 10.3760/cma.j.issn.2095-2848.2014.04.005.
Yang K, Liang ZY, Meng C, et al. Relationship between BRAFV600E mutation and radioactive iodine uptake in distant metastases from papillary thyroid cancer[J]. Chin J Nucl Med Mol Imaging, 2014, 34(4): 287−291. DOI: 10.3760/cma.j.issn.2095-2848.2014.04.005.[20] Durante C, Puxeddu E, Ferretti E, et al. BRAF mutations in papillary thyroid carcinomas inhibit genes involved in iodine metabolism[J]. J Clin Endocrinol Metab, 2007, 92(7): 2840−2843. DOI: 10.1210/jc.2006-2707. [21] Bastos AU, Oler G, Nozima BH, et al. BRAF V600E and decreased NIS and TPO expression are associated with aggressiveness of a subgroup of papillary thyroid microcarcinoma[J]. Eur J Endocrinol, 2015, 173(4): 525−540. DOI: 10.1530/EJE-15-0254. [22] Kotlarek M, Kubiak A, Czetwertynska M, et al. The rs2910164 genetic variant of miR-146a-3p is associated with increased overall mortality in patients with follicular variant papillary thyroid carcinoma[J/OL]. Int J Mol Sci, 2018, 19(3): 655[2019-08-07]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877516. DOI: 10.3390/ijms19030655.. [23] Chou CK, Liu RT, Kang HY. MicroRNA-146b: a novel biomarker and therapeutic target for human papillary thyroid cancer[J/OL]. Int J Mol Sci, 2017, 18(3): 636[2019-08-07]. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372649. DOI: 10.3390/ijms18030636.. [24] Gómez-Pérez AM, Cornejo Pareja IM, Garcia Alemán J, et al. New molecular biomarkers in differentiated thyroid carcinoma: impact of miR-146, miR-221 and miR-222 levels in the evolution of the disease[J]. Clin Endocrinol (Oxf), 2019, 91(1): 187−194. DOI: 10.1111/cen.13972.