Endocrine Division, Serviço de Endocrinologia, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Endocr Relat Cancer. 2010 Oct 5;17(4):953-63. doi: 10.1677/ERC-09-0312. Print 2010 Dec.
The possible role of RET variants in modifying the natural course of medullary thyroid carcinoma (MTC) is still a matter of debate. Here, we investigate whether the RET variants L769L, S836S, and G691S/S904S influence disease presentation in hereditary or sporadic MTC patients. One hundred and two patients with hereditary MTC and 81 patients with sporadic MTC attending our institution were evaluated. The frequencies of RET polymorphisms in hereditary MTC were as follows: L769L, 17.3%; S836S, 7.95%; and S904S/G691S, 18.2%. No associations were observed between these polymorphisms and pheochromocytoma, hyperparathyroidism, lymph node, or distant metastasis. However, patients harboring the S836S variant were younger than those without this allele (17±8.2 vs 28.6±14.4 years, P=0.01), suggesting that these patients had metastases at a young age. Accordingly, the cumulative frequency of local and/or distant metastases as estimated by Kaplan-Meier curves showed that lymph node and distant metastases occurred earlier in patients harboring the S836S variant (P=0.003 and P=0.026 respectively). The S836S allele frequency was higher in sporadic MTC patients than in controls (10.5 vs 3.1%, P=0.01). Individuals harboring the S836S variant were younger (38.6±13.3 vs 48.5±16.7 years, P=0.02) and showed a higher percentage of lymph node and distant metastases (P=0.02 and P=0.04 respectively). Kaplan-Meier estimates of lymph node and distant metastases yielded distinct curves for patients with or without the S836S allele (P=0.002 and P=0.001 respectively). Additional analyses using a COX regression model showed that the S836S variant was independently associated with metastatic disease (hazard ratio 2.82 (95% confidence interval 1.51-5.26), P=0.001). In conclusion, the RET S836S variant is associated with early onset and increased risk for metastatic disease in patients with hereditary or sporadic MTC.
RET 变异体在修饰甲状腺髓样癌 (MTC) 自然病程中的可能作用仍存在争议。在这里，我们研究了 RET 变异体 L769L、S836S 和 G691S/S904S 是否会影响遗传性或散发性 MTC 患者的疾病表现。我们评估了 102 例遗传性 MTC 患者和 81 例散发性 MTC 患者。遗传性 MTC 中 RET 多态性的频率如下：L769L，17.3%；S836S，7.95%；S904S/G691S，18.2%。这些多态性与嗜铬细胞瘤、甲状旁腺功能亢进、淋巴结或远处转移之间均无关联。然而，携带 S836S 变异体的患者比不携带该等位基因的患者年轻（17±8.2 岁 vs 28.6±14.4 岁，P=0.01），这表明这些患者在年轻时就发生了转移。因此，通过 Kaplan-Meier 曲线估计的局部和/或远处转移的累积频率表明，携带 S836S 变异体的患者发生淋巴结和远处转移的时间更早（P=0.003 和 P=0.026）。S836S 等位基因频率在散发性 MTC 患者中高于对照组（10.5%比 3.1%，P=0.01）。携带 S836S 变异体的个体更年轻（38.6±13.3 岁 vs 48.5±16.7 岁，P=0.02），且淋巴结和远处转移的比例更高（P=0.02 和 P=0.04）。携带或不携带 S836S 等位基因的患者的 Kaplan-Meier 估计淋巴结和远处转移曲线明显不同（P=0.002 和 P=0.001）。使用 COX 回归模型进行的进一步分析表明，S836S 变异体与遗传性或散发性 MTC 患者的转移性疾病独立相关（风险比 2.82（95%置信区间 1.51-5.26），P=0.001）。总之，RET S836S 变异体与遗传性或散发性 MTC 患者的疾病早期发生和转移风险增加有关。
