Departments of Genetics and Pathology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.
Cancer Res. 2010 Jun 1;70(11):4287-91. doi: 10.1158/0008-5472.CAN-10-0120. Epub 2010 May 25.
Sporadic clear cell renal cell carcinoma (cRCC) is genetically characterized by the recurrent loss of the short arm of chromosome 3, with a hotspot for copy number loss in the 3p21 region. We applied a method called "gene identification by nonsense-mediated mRNA decay inhibition" to a panel of 10 cRCC cell lines with 3p21 copy number loss to identify biallelic inactivated genes located at 3p21. This revealed inactivation of the histone methyltransferase gene SETD2, located on 3p21.31, as a common event in cRCC cells. SETD2 is nonredundantly responsible for trimethylation of the histone mark H3K36. Consistent with this function, we observed loss or a decrease of H3K36me3 in 7 out of the 10 cRCC cell lines. Identification of missense mutations in 2 out of 10 primary cRCC tumor samples added support to the involvement of loss of SETD2 function in the development of cRCC tumors.
散发性透明细胞肾细胞癌（cRCC）在遗传学上的特征是 3 号染色体短臂反复缺失，3p21 区域的拷贝数缺失热点。我们应用一种称为“通过无义介导的 mRNA 衰减抑制进行基因鉴定”的方法，对 10 个具有 3p21 拷贝数缺失的 cRCC 细胞系进行分析，以鉴定位于 3p21 上的双等位基因失活基因。这揭示了位于 3p21.31 上的组蛋白甲基转移酶基因 SETD2 的失活是 cRCC 细胞中的常见事件。SETD2 非冗余地负责组蛋白标记 H3K36 的三甲基化。与这一功能一致，我们在 10 个 cRCC 细胞系中的 7 个中观察到 H3K36me3 的缺失或减少。在 10 个原发性 cRCC 肿瘤样本中的 2 个中鉴定出错义突变，进一步支持 SETD2 功能丧失在 cRCC 肿瘤发生中的作用。
