Uchino S, Noguchi S, Sato M, Yamashita H, Yamashita H, Watanabe S, Murakami T, Toda M, Ohshima A, Futata T, Mizukoshi T, Koike E, Takatsu K, Terao K, Wakiya S, Nagatomo M, Adachi M
Noguchi Thyroid Clinic and Hospital Foundation, Oita, Japan.
Cancer Res. 2000 Oct 1;60(19):5553-7.
Hyperparathyroidism is the first manifestation in a majority of multiple endocrine neoplasia (MEN1) patients. To discriminate between sporadic and hereditary parathyroid tumors and characterize MEN1 somatic mutations, we examined MEN1 gene mutations in patients who had undergone surgery for sporadic parathyroid tumors. DNA was extracted from fresh frozen parathyroid tumor specimens from 112 patients as well as from peripheral blood leukocytes from 64 of the 112 patients. Sequence analysis was performed to examine exons 2-10 of the MEN1 gene for mutations. Loss of heterozygosity (LOH) was also examined by an analysis of codon 418 and 541, which lie within a polymorphic region of MEN1. Somatic MEN1 mutations were found in 25 of the 112 patients (22%). Two patients had two point mutations (508del33 and Y341X and 363insT and 1767delT, respectively). A total of 27 mutations were characterized, 20 of which have not been reported previously. There were 7 nonsense mutations, 10 frameshift mutations, 2 splice site deletions, 5 missense mutations, and 3 in-frame mutations. Nineteen mutations (70%) predicted truncation of the menin protein. Germ-line MEN1 mutations were found in 3 of 64 patients (5%) who had no family history of endocrine tumors associated with MEN1, and these patients were identified as MEN1 gene probands. LOH at the MEN1 locus was detected in three parathyroid tumors showing germ-line mutation. LOH was significantly frequent in parathyroid tumors with somatic MEN1 mutations (15 of 22 tumors, 68%) but not in those without germ-line or somatic MEN1 mutations (14 of 51 tumors, 28%; P = 0.0011). Our findings suggest that alterations of both alleles of the MEN1 gene may be associated not only with endocrine tumors of affected MEN1 patients but also with sporadic parathyroid tumors. Germ-line MEN1 gene analysis can distinguish heritable from nonheritable parathyroid tumors, and MEN1 gene evaluation of patients with apparently sporadic parathyroid tumor is recommended before parathyroid surgery.
甲状旁腺功能亢进是大多数多发性内分泌腺瘤病1型（MEN1）患者的首发表现。为了区分散发性和遗传性甲状旁腺肿瘤，并对MEN1体细胞突变进行特征分析，我们检测了接受散发性甲状旁腺肿瘤手术患者的MEN1基因突变。从112例患者的新鲜冷冻甲状旁腺肿瘤标本以及112例患者中64例的外周血白细胞中提取DNA。进行序列分析以检测MEN1基因第2至10外显子的突变。还通过对位于MEN1多态性区域内的密码子418和541进行分析来检测杂合性缺失（LOH）。在112例患者中有25例（22%）发现了体细胞MEN1突变。两名患者分别有两个点突变（508del33和Y341X以及363insT和1767delT）。共鉴定出27种突变，其中20种此前未见报道。有7种无义突变、10种移码突变、2种剪接位点缺失、5种错义突变和3种框内突变。19种突变（70%）预测会导致menin蛋白截短。在64例无MEN1相关内分泌肿瘤家族史的患者中有3例（5%）发现了种系MEN1突变，这些患者被确定为MEN1基因先证者。在3例显示种系突变的甲状旁腺肿瘤中检测到MEN1基因座的LOH。LOH在有体细胞MEN1突变的甲状旁腺肿瘤中显著常见（22例肿瘤中有15例，68%），而在无种系或体细胞MEN1突变的肿瘤中则不常见（51例肿瘤中有14例，28%；P = 0.0011）。我们的研究结果表明，MEN1基因两个等位基因的改变可能不仅与受影响的MEN1患者的内分泌肿瘤有关，还与散发性甲状旁腺肿瘤有关。种系MEN1基因分析可以区分遗传性和非遗传性甲状旁腺肿瘤，建议在甲状旁腺手术前对明显为散发性甲状旁腺肿瘤的患者进行MEN1基因评估。
