Division of Endocrinology and Metabolism, Department of Medicine, Nippon Medical School, Tsukuba, Japan.
Clin Endocrinol (Oxf). 2012 Nov;77(5):707-14. doi: 10.1111/j.1365-2265.2012.04421.x.
Recently, TMEM127 was shown to be a new pheochromocytoma susceptibility gene; this is consistent with its function as a tumour suppressor gene (Journal of Clinical Endocrinology and Metabolism, 2009, 94, 2817). Most pheochromocytomas arise from the adrenal medulla, and in approximately half of the cases, the tumours are bilateral (Journal of Clinical Endocrinology and Metabolism, 2009, 94, 2817; Journal of the American Medical Association, 2004, 292, 943; Human Mutation, 2010, 31, 41; Science, 2009, 325, 1139). The aim of the present study was to determine whether TMEM127 mutations are involved in the pathogenesis of pheochromocytomas/paragangliomas in Japanese subjects.
For this study, 74 unrelated patients with pheochromocytoma/paraganglioma who tested negative for mutations and deletions in RET, VHL, SDHB and SDHD were recruited through a multi-institutional collaborative effort in Japan. The TMEM127 gene sequence was determined in their germline DNA, and tumour DNA was analysed for the loss of heterozygosity. In addition, their TMEM127 gene sequences were compared with sequences from 114 normal healthy, ethnically matched controls.
Among the 74 eligible patients, two unrelated patients (2·7%) with bilateral adrenal pheochromocytoma were found to have an identical germline TMEM127 mutation (c.116_119delTGTC, p.Ile41ArgfsX39) associated with 2q deletion loss of heterozygosity, which was also previously described in a Brazilian case (Journal of the American Medical Association, 2004, 292, 943). We also determined that none of the 114 normal healthy controls had this deletion mutation.
This is the first report showing that TMEM127 mutation plays a pathological role in pheochromocytoma in an Asian population. Although our surveillance is limited, the prevalence and the phenotype of this gene mutation appear to be similar to those reported in previous studies.
最近，TMEM127 被证明是一种新的嗜铬细胞瘤易感性基因；这与其作为肿瘤抑制基因的功能一致（《临床内分泌与代谢杂志》，2009 年，94 卷，2817 页）。大多数嗜铬细胞瘤起源于肾上腺髓质，大约一半的病例肿瘤是双侧的（《临床内分泌与代谢杂志》，2009 年，94 卷，2817 页；《美国医学会杂志》，2004 年，292 卷，943 页；《人类突变》，2010 年，31 卷，41 页；《科学》，2009 年，325 卷，1139 页）。本研究旨在确定 TMEM127 突变是否参与日本患者嗜铬细胞瘤/副神经节瘤的发病机制。
本研究中，通过日本多机构合作，招募了 74 名经 RET、VHL、SDHB 和 SDHD 基因突变和缺失检测呈阴性的嗜铬细胞瘤/副神经节瘤无关患者。对其生殖系 DNA 进行 TMEM127 基因序列测定，并分析肿瘤 DNA 的杂合性缺失。此外，还将他们的 TMEM127 基因序列与 114 名正常健康、种族匹配的对照者的序列进行了比较。
在 74 名合格患者中，发现两名无关联的双侧肾上腺嗜铬细胞瘤患者存在相同的生殖系 TMEM127 突变（c.116_119delTGTC，p.Ile41ArgfsX39），伴有 2q 缺失杂合性丢失，该突变也在巴西的一例病例中有所描述（《美国医学会杂志》，2004 年，292 卷，943 页）。我们还发现，114 名正常健康对照者均无此缺失突变。
这是首次报道 TMEM127 突变在亚洲人群嗜铬细胞瘤中发挥病理性作用。尽管我们的监测有限，但该基因突变的患病率和表型似乎与以前的研究报告相似。
