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課題背景：腎透明細胞癌(ccRCC)是腎癌中最常見的病理類型，其發(fā)生和發(fā)展與VHL抑癌基因突變失活密切相關。最近在ccRCC樣本中一個針對3500個基因的大規(guī)模外顯子重測序發(fā)現(xiàn)了幾個新的癌癥基因，包括UTX，JARID1C 和SETD2。這些基因編碼的酶類，可以去甲基化(UTX, JARID1C)或甲基化(SETD2)組蛋白H3中的關鍵賴氨酸殘基。這些組蛋白H3賴氨酸殘基的甲基化修飾調控染色質的結構并提示與轉錄控制有關。然而，這些突變加起來也只存在于少于15%的ccRCC樣本中，這提示存在其他的，尚未發(fā)現(xiàn)的癌癥基因。由英、美、法、德、新加坡和荷蘭組成的國際研究小組在一系列ccRCC樣本中進行外顯子組測序，并發(fā)現(xiàn)染色質重構復合物基因PBRM1，是第二類主要的ccRCC癌癥基因，該基因在41% (92/227)的檢測病例中存在截短突變（truncating mutations，轉譯后形成截短的蛋白）。該項研究成果發(fā)表在2011年1月的Nature雜志上。 所用關鍵技術：外顯子組測序。上海天昊目前也正在積極地開展和承接外顯子組測序業(yè)務，希望藉此能幫助醫(yī)學領域研究者一起找出更多疾病的常見變異，一起完善醫(yī)學遺傳學研究的拼圖。 課題結果和討論，意義：本研究通過外顯子組測序發(fā)現(xiàn)了ccRCC的一個常見突變，這些數(shù)據(jù)進一步闡釋了ccRCC的體細胞遺傳結構，并強調染色質畸變的顯著生物學作用。該項發(fā)現(xiàn)被譽為腎癌研究20年來最重要的突破之一，將幫助研究人員了解腎癌的發(fā)展機理，并有助于催生轉化醫(yī)學和臨床診斷的可能。 參考文獻：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. |
