Cebrian Arancha, Lesueur Fabienne, Martin Sam, Leyland Jean, Ahmed Shahana, Luccarini Craig, Smith Paula L, Luben Robert, Whittaker Joanne, Pharoah Paul D, Dunning Alison M, Ponder Bruce A J
Cancer Research UK Human Cancer Genetics Research Group, Department of Oncology, University of Cambridge CB1 8RN, United Kingdom.
J Clin Endocrinol Metab. 2005 Nov;90(11):6268-74. doi: 10.1210/jc.2004-2449. Epub 2005 Aug 9.
Medullary thyroid carcinoma (MTC) is a characteristic tumor occurring in individuals with multiple endocrine neoplasia type 2 who carry germ-line mutations in RET (rearranged during transfection). However, most MTC occur in individuals without a family history.
The objective of this study was to explore the possibility that susceptibility in these cases results from low penetrance alleles of RET, its coreceptors, and ligands.
We carried out an association study in 135 sporadic MTC (sMTC) patients and 533 controls from the United Kingdom population.
We analyzed 33 polymorphisms in all nine genes involved in the glial cell line-derived neurotropic factor receptor-alpha (GFRalpha)-RET complex. This is the first association study in which all genes involved in this complex have been investigated for susceptibility to sMTC. We did not find any association between single nucleotide polymorphisms in the exonic regions of the GFRalpha2, GFRalpha3, GFRalpha4, glial cell line-derived neurotropic factor, neurturin, or persephin genes and risk of developing sMTC. We found a strong association between the disease and specific haplotypes of RET. We not only confirmed the previously described association with G691S and S904S (for heterozygotes: odds ratio, 1.85; range, 1.22-2.82; P = 0.004), but we found a novel protective effect associated with a specific haplotype (odds ratio, 0.39; range, 0.21-0.72; P = 0.005) revealing the existence of different genetic variants in the RET oncogene that either increase or decrease risk of sMTC.
甲状腺髓样癌（MTC）是一种发生于2型多发性内分泌腺瘤病患者的特征性肿瘤，这些患者携带RET（转染期间重排）的种系突变。然而，大多数MTC发生在无家族病史的个体中。
本研究的目的是探讨这些病例中的易感性是否源于RET及其共受体和配体的低外显率等位基因。
我们对来自英国人群的135例散发性MTC（sMTC）患者和533名对照进行了关联研究。
我们分析了参与胶质细胞系源性神经营养因子受体α（GFRalpha）-RET复合物的所有9个基因中的33个多态性。这是首次对该复合物中所有涉及的基因进行sMTC易感性研究的关联研究。我们未发现GFRalpha2、GFRalpha3、GFRalpha4、胶质细胞系源性神经营养因子、神经营养素或persephin基因外显子区域的单核苷酸多态性与发生sMTC的风险之间存在任何关联。我们发现疾病与RET的特定单倍型之间存在强关联。我们不仅证实了先前描述的与G691S和S904S的关联（杂合子：比值比，1.85；范围，1.22 - 2.82；P = 0.004），而且我们发现了一种与特定单倍型相关的新的保护作用（比值比，0.39；范围，0.21 - 0.72；P = 0.005），揭示了RET癌基因中存在增加或降低sMTC风险的不同遗传变异。
