Germline RET sequence variation I852M and occult medullary thyroid cancer: harmless polymorphism or causative mutation?
Germline RET sequence variation I852M and occult medullary thyroid cancer: harmless polymorphism or causative mutation?
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DOI：
10.1111/j.1365-2265.2011.04158.x
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发表时间：
2011-12-01
影响因子：
3.2
通讯作者：
Dralle, Henning
中科院分区：
文献类型：
--
作者：
Machens, Andreas;Spitschak, Alf;Dralle, Henning
目的转染期间重排（RET）基因分析被广泛用于识别甲状腺髓样癌（MTC）风险携带者，但偶尔也会发现包括RET I852 M在内的新序列“临床意义未知的变异体”。本研究旨在阐明RET I852 M是否代表一种无害的多态性或致病性突变。设计I852 M突变细胞体外功能特征支持的临床研究。患者和测量基因型-表型相关性，包括来自三代高加索人I852 M RET家族的五种激酶。结果在64例患者中发现一种淋巴结阴性的隐匿性MTC，1岁的索引患者，基础和刺激峰值降钙素水平分别升高190和13307 ng/l。她4岁的孙子没有C细胞疾病的组织病理学证据，尽管他的血清降钙素水平在5个月内从基础水平的3.2 ng/l增加到6.3 ng/l，在五肽胃泌素刺激后从17.2 ng/l增加到24.5 ng/l。他的母亲和两个11岁和1.5岁的兄弟姐妹，也携带该基因，具有正常的基础和刺激降钙素水平，因此没有接受手术。体外转染的NIH 3 T3细胞的功能表征（细胞增殖率;细胞活力;非贴壁依赖性细胞生长;细胞迁移;和侵袭）表明，I852 M突变细胞具有类似于美国甲状腺协会（ATA）A类V804 M突变体的转化和迁移活性。I852 M突变体表现出较弱的增殖能力比快速增殖的ATA C类C634 R突变体，并揭示了较弱的迁移活动相比，积极增长的ATA D类A883 F mutants.Conclusions I852 M序列变异代表真正的RET突变，属于弱激活RET种系突变的ATA A类。
Objective Rearranged during transfection (RET) gene analysis, widely used to identify carriers at risk of medullary thyroid cancer (MTC), occasionally uncovers novel sequence 'variants of unknown clinical significance' including RET I852M. This study aimed to clarify whether RET I852M represents a harmless polymorphism or a pathogenic mutation.Design Clinical investigation supported by functional characterization of I852M mutant cells in vitro.Patients and Measurements Genotype-phenotype correlation including five kindreds from a three-generational Caucasian I852M RET family.Results A node-negative occult MTC was found in the 64-yearold index patient who had increased basal and stimulated peak calcitonin levels of 190 and 13 307 ng/l, respectively. Her 4-year-old grandson had no histopathological evidence of C-cell disease although his serum calcitonin levels had increased within 5 months from 3.2 to 6.3 ng/l basally and from 17.2 to 24.5 ng/l after pentagastrin stimulation. His mother and two 11- and 1.5-year-old siblings, also carrying the gene, had normal basal and stimulated calcitonin levels and hence did not undergo surgery. Functional characterization of transfected NIH3T3 cells in vitro (cell proliferation rate; cell viability; anchorage-independent cell growth; cell migration; and invasion) indicated that I852M mutant cells have transforming and migratory activities similar to American Thyroid Association (ATA) class A V804M mutants. I852M mutants demonstrated a weaker proliferative potential than fast-proliferating ATA class C C634R mutants and revealed a weaker migratory activity compared with aggressively growing ATA class D A883F mutants.Conclusions I852M sequence variations represent genuine RET mutations, falling into ATA class A of weakly activating RET germline mutations.