Nakamura T, Yana I, Kobayashi T, Shin E, Karakawa K, Fujita S, Miya A, Mori T, Nishisho I, Takai S
Department of Medical Genetics, Osaka University Medical School.
Jpn J Cancer Res. 1992 Dec;83(12):1293-8. doi: 10.1111/j.1349-7006.1992.tb02761.x.
Anaplastic carcinoma of the thyroid gland, which is one of the most aggressive, malignant tumors in humans, is considered to originate from preexisting differentiated thyroid cancer. To define the genetic alterations associated with such progression, we examined nine cases of anaplastic thyroid carcinoma for mutation in exons 4-9 of the p53 tumor suppressor gene. Preliminary screening for mutation by RNase protection analysis demonstrated that two out of nine anaplastic carcinomas contained sequence alterations in the p53 gene. Subsequent DNA sequencing identified the mutated nucleotides in these two cases; one was a nonsense mutation at codon 165, and the other was a single-base deletion at codon 176 resulting in the creation of a stop codon downstream due to frameshift. The fact that no mutations were detected in coexisting foci of papillary carcinomas from the same patients shows that these mutations of the p53 gene occurred after development of papillary carcinomas. These results suggest that p53 gene mutation triggers the progression from differentiated into anaplastic carcinoma in the human thyroid gland.
甲状腺未分化癌是人类最具侵袭性的恶性肿瘤之一，被认为起源于先前存在的分化型甲状腺癌。为了确定与这种进展相关的基因改变，我们检测了9例甲状腺未分化癌中p53肿瘤抑制基因外显子4至9的突变情况。通过核糖核酸酶保护分析进行突变初步筛查显示，9例未分化癌中有2例p53基因存在序列改变。随后的DNA测序确定了这2例中的突变核苷酸；其中1例是密码子165处的无义突变，另一例是密码子176处的单碱基缺失，由于移码导致下游产生一个终止密码子。同一患者共存的乳头状癌灶未检测到突变，这一事实表明p53基因的这些突变发生在乳头状癌发生之后。这些结果提示p53基因突变触发了人类甲状腺中从分化型癌向未分化癌的进展。
