Gimelli Stefania, Beri Silvana, Drabkin Harry A, Gambini Claudio, Gregorio Andrea, Fiorio Patrizia, Zuffardi Orsetta, Gemmill Robert M, Giorda Roberto, Gimelli Giorgio
Biologia Generale e Genetica Medica, Università di Pavia, Pavia, Italy.
Mol Cancer. 2009 Jul 30;8:52. doi: 10.1186/1476-4598-8-52.
RNF139/TRC8 is a potential tumor suppressor gene with similarity to PTCH, a tumor suppressor implicated in basal cell carcinomas and glioblastomas. TRC8 has the potential to act in a novel regulatory relationship linking the cholesterol/lipid biosynthetic pathway with cellular growth control and has been identified in families with hereditary renal (RCC) and thyroid cancers. Haploinsufficiency of TRC8 may facilitate development of clear cell-RCC in association with VHL mutations, and may increase risk for other tumor types. We report a paternally inherited balanced translocation t(8;22) in a proposita with dysgerminoma.
The translocation was characterized by FISH and the breakpoints cloned, sequenced, and compared. DNA isolated from normal and tumor cells was checked for abnormalities by array-CGH. Expression of genes TRC8 and TSN was tested both on dysgerminoma and in the proposita and her father.
The breakpoints of the translocation are located within the LCR-B low copy repeat on chromosome 22q11.21, containing the palindromic AT-rich repeat (PATRR) involved in recurrent and non-recurrent translocations, and in an AT-rich sequence inside intron 1 of the TRC8 tumor-suppressor gene at 8q24.13. TRC8 was strongly underexpressed in the dysgerminoma. Translin is underexpressed in the dysgerminoma compared to normal ovary.TRC8 is a target of Translin (TSN), a posttranscriptional regulator of genes transcribed by the transcription factor CREM-tau in postmeiotic male germ cells.
A role for TRC8 in dysgerminoma may relate to its interaction with Translin. We propose a model in which one copy of TRC8 is disrupted by a palindrome-mediated translocation followed by complete loss of expression through suppression, possibly mediated by miRNA.
RNF139/TRC8是一种潜在的肿瘤抑制基因，与PTCH相似，PTCH是一种与基底细胞癌和成胶质细胞瘤相关的肿瘤抑制因子。TRC8有可能以一种新的调节关系发挥作用，将胆固醇/脂质生物合成途径与细胞生长控制联系起来，并且已在遗传性肾癌（RCC）和甲状腺癌家族中被鉴定出来。TRC8单倍体不足可能与VHL突变相关，促进透明细胞-RCC的发展，并可能增加其他肿瘤类型的风险。我们报告了一名患有无性细胞瘤的先证者中存在父系遗传的平衡易位t(8;22)。
通过荧光原位杂交（FISH）对易位进行特征分析，并对断点进行克隆、测序和比较。通过阵列比较基因组杂交（array-CGH）检查从正常细胞和肿瘤细胞中分离的DNA是否存在异常。在无性细胞瘤以及先证者及其父亲中检测TRC8和TSN基因的表达。
易位的断点位于22q11.21染色体上的LCR-B低拷贝重复序列内，该序列包含参与反复和非反复易位的富含AT的回文重复序列（PATRR），以及位于8q24.13的TRC8肿瘤抑制基因内含子1内的富含AT的序列。TRC8在无性细胞瘤中强烈低表达。与正常卵巢相比，转脂蛋白在无性细胞瘤中低表达。TRC8是转脂蛋白（TSN）的靶标，TSN是减数分裂后雄性生殖细胞中转录因子CREM-tau转录的基因的转录后调节因子。
TRC8在无性细胞瘤中的作用可能与其与转脂蛋白的相互作用有关。我们提出了一个模型，其中TRC8的一个拷贝被回文介导的易位破坏，随后通过抑制导致表达完全丧失，可能由微小RNA（miRNA）介导。
