Eng C, Mulligan L M, Healey C S, Houghton C, Frilling A, Raue F, Thomas G A, Ponder B A
Cancer Research Campaign Human Cancer Genetics Research Group, University of Cambridge, Addenbrooke's Hospital, United Kingdom.
Cancer Res. 1996 May 1;56(9):2167-70.
Mutations in the RET proto-oncogene are associated with the pathogenesis of medullary thyroid carcinoma (MTC). In an attempt to understand this process, we examined microdissected subpopulations from MTC and multiple metastases from these tumors. Approximately 80% of sporadic MTC's had at least one subpopulation with the RET codon 918 mutation, which is a mutation previously detected in sporadic MTC as a somatic mutation and in multiple endocrine neoplasia type 2B as a germline mutation. However, the distribution of this mutation was nonhomogeneous, occurring only in subpopulations in most tumors and among subsets of multiple metastases, thus implying that although the codon 918 mutation could be an early event, it is not necessarily an early or essential event in tumorigenesis. This heterogeneity suggests either that the codon 918 mutation can arise as an event in progression within a metastatic clone or within a single tumor, or that MTC can be of polyclonal origin. Of significance, one of two multiple endocrine neoplasia type 2A MTCs carried a somatic mutation at codon 918, in addition to the RET mutation present in the germline. We found no correlation between the presence of other somatic genetic events, such as loss of heterozygosity on chromosome arms 1p and 22q, and RET mutation status in the various subpopulations of MTC.
RET原癌基因的突变与甲状腺髓样癌（MTC）的发病机制相关。为了理解这一过程，我们检查了从MTC及其多处转移灶中显微切割得到的亚群。大约80%的散发性MTC至少有一个亚群存在RET密码子918突变，该突变先前在散发性MTC中作为体细胞突变被检测到，在2B型多发性内分泌腺瘤病中作为种系突变被检测到。然而，这种突变的分布并不均匀，仅在大多数肿瘤的亚群以及多处转移灶的子集中出现，因此这意味着尽管密码子918突变可能是一个早期事件，但它不一定是肿瘤发生过程中的早期或必要事件。这种异质性表明，要么密码子918突变可作为转移克隆内或单个肿瘤进展过程中的一个事件出现，要么MTC可能起源于多克隆。值得注意的是，在两个2A型多发性内分泌腺瘤病的MTC中，除了种系中存在的RET突变外，有一个还携带密码子918的体细胞突变。我们发现，在MTC的各个亚群中，其他体细胞遗传事件（如1号染色体臂和22号染色体臂杂合性缺失）的存在与RET突变状态之间没有相关性。
