Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network.
Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network.
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DOI：
10.1158/1078-0432.ccr-12-3886
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发表时间：
2013-06-15
期刊：
影响因子：
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通讯作者：
ccRCC Cancer Genome Atlas (KIRC TCGA) Research Network investigators
中科院分区：
文献类型：
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作者：
Hakimi AA;Ostrovnaya I;Reva B;Schultz N;Chen YB;Gonen M;Liu H;Takeda S;Voss MH;Tickoo SK;Reuter VE;Russo P;Cheng EH;Sander C;Motzer RJ;Hsieh JJ;ccRCC Cancer Genome Atlas (KIRC TCGA) Research Network investigators
研究新发现的3p21染色体表观遗传肿瘤抑制因子PBRM1、SETD2和BAP1对609例透明细胞肾细胞癌（ccRCC）患者癌症特异性生存（CSS）的影响。对188名在纪念斯隆-凯特琳癌症中心（MSKCC）接受原发性ccRCC切除术的患者的3p肿瘤抑制子进行了选择测序，以询问基因型-表型关联。这些发现与来自421例原发性ccRCC患者的非重叠癌症基因组图谱（TCGA）队列的基因组和临床数据集分析进行了比较。3p21肿瘤抑制因子在MSKCC （PBRM1, 30.3%; SETD2, 7.4%; BAP1, 6.4%）和TCGA （PBRM1, 33.5%; SETD2, 11.6%; BAP1, 9.7%）队列中都经常发生突变。在两个队列中，BAP1突变与较差的CSS相关(MSKCC, p=0.002, HR 7.71 (2.08-28.6)；TCGA, p=0.002, HR 2.21(1.35-3.63))。在TCGA队列中，SETD2与较差的CSS相关（p=0.036, HR 1.68(1.04-2.73)）。相反，ccRCC中第二常见的基因突变PBRM1突变对CSS没有影响。染色体3p21位点包含三个经常突变的ccRCC肿瘤抑制基因。BAP1和SETD2突变（6-12%）与更严重的CSS相关，提示它们在疾病进展中的作用。PBRM1突变（30-34%）不影响CSS，暗示其在肿瘤起始中起主要作用。未来的努力应集中在治疗干预和进一步的临床，病理和分子对这类新型肿瘤抑制因子的研究。
To investigate the impact of newly identified chromosome 3p21 epigenetic tumor suppressors PBRM1, SETD2, and BAP1 on cancer specific survival (CSS) of 609 clear cell renal cell carcinoma (ccRCC) patients from two distinct cohorts. Select sequencing on 3p tumor suppressors of 188 patients who underwent resection of primary ccRCC at the Memorial Sloan-Kettering Cancer Center (MSKCC) was performed to interrogate the genotype-phenotype associations. These findings were compared to analyses of the genomic and clinical dataset from our non-overlapping The Cancer Genome Atlas (TCGA) cohort of 421 primary ccRCC patients. 3p21 tumor suppressors are frequently mutated in both the MSKCC (PBRM1, 30.3%; SETD2, 7.4%; BAP1, 6.4%) and the TCGA (PBRM1, 33.5%; SETD2, 11.6%; BAP1, 9.7%) cohorts. BAP1 mutations are associated with worse CSS in both cohorts (MSKCC, p=0.002, HR 7.71 (2.08–28.6); TCGA, p=0.002, HR 2.21 (1.35–3.63)). SETD2 are associated with worse CSS in the TCGA cohort (p=0.036, HR 1.68 (1.04–2.73)). On the contrary, PBRM1 mutations, the second most common gene mutations of ccRCC, have no impact on CSS. The chromosome 3p21 locus harbors three frequently mutated ccRCC tumor suppressor genes. BAP1 and SETD2 mutations (6–12%) are associated with worse CSS, suggesting their roles in disease progression. PBRM1 mutations (30–34%) do not impact CSS, implicating its principal role in the tumor initiation. Future efforts should focus on therapeutic interventions and further clinical, pathologic and molecular interrogation of this novel class of tumor suppressors.