课题背景：肾透明细胞癌(ccRCC)是肾癌中最常见的病理类型，其发生和发展与VHL抑癌基因突变失活密切相关。最近在ccRCC样本中一个针对3500个基因的大规模外显子重测序发现了几个新的癌症基因，包括UTX，JARID1C 和SETD2。这些基因编码的酶类，可以去甲基化(UTX, JARID1C)或甲基化(SETD2)组蛋白H3中的关键赖氨酸残基。这些组蛋白H3赖氨酸残基的甲基化修饰调控染色质的结构并提示与转录控制有关。然而，这些突变加起来也只存在于少于15%的ccRCC样本中，这提示存在其他的，尚未发现的癌症基因。由英、美、法、德、新加坡和荷兰组成的国际研究小组在一系列ccRCC样本中进行外显子组测序，并发现染色质重构复合物基因PBRM1，是第二类主要的ccRCC癌症基因，该基因在41% (92/227)的检测病例中存在截短突变（truncating mutations，转译后形成截短的蛋白）。该项研究成果发表在2011年1月的Nature杂志上。

所用关键技术：外显子组测序。上海天昊目前也正在积极地开展和承接外显子组测序业务，希望藉此能帮助医学领域研究者一起找出更多疾病的常见变异，一起完善医学遗传学研究的拼图。

课题结果和讨论，意义：本研究通过外显子组测序发现了ccRCC的一个常见突变，这些数据进一步阐释了ccRCC的体细胞遗传结构，并强调染色质畸变的显著生物学作用。该项发现被誉为肾癌研究20年来最重要的突破之一，将帮助研究人员了解肾癌的发展机理，并有助于催生转化医学和临床诊断的可能。

参考文献：Ignacio Varela, Patrick Tarpey, Keiran Raine, et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature. 469: 539–542 (2011).

Abstract The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. A recent large-scale screen of ~3,500 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (also known as KDM6A)1, JARID1C (also known as KDM5C) and SETD2 (ref. 2). These genes encode enzymes that demethylate (UTX, JARID1C) or methylate (SETD2) key lysine residues of histone H3. Modification of the methylation state of these lysine residues of histone H3 regulates chromatin structure and is implicated in transcriptional control3. However, together these mutations are present in fewer than 15% of ccRCC, suggesting the existence of additional, currently unidentified cancer genes. Here, we have sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodelling complex gene PBRM1 (ref. 4) as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology.