Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer
Convergent structural alterations define SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeler as a central tumor suppressive complex in pancreatic cancer
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DOI：
10.1073/pnas.1114817109
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发表时间：
2012-01-31
影响因子：
11.1
通讯作者：
Pollack, Jonathan R.
中科院分区：
文献类型：
--
作者：
Shain, A. Hunter;Giacomini, Craig P.;Pollack, Jonathan R.
确定胰腺癌的分子遗传改变可能为这种致命疾病的治疗提供独特的见解。为了实现这一目标，我们在这里报告了一种整合的DNA微阵列和基于测序的胰腺癌基因组分析。值得注意的是，在新发现的改变中，基因组缺失、突变和重排经常针对编码开关/蔗糖不可发酵（SWI/SNF）染色质重塑复合体组分的基因，包括所有三个假定的DNA结合亚基（ARID1A、ARID1B和PBRM1）和两个酶亚基（SMARCA2和SMARCA4）。尽管每个SWI/SNF亚基的改变发生频率一般，就像基因组景观中的突变“山丘”，但它们共同影响了至少三分之一的胰腺癌，将SWI/SNF定义为一个主要的突变“山丘”。与肿瘤抑制作用一致，SMARCA4在SMARCA4缺失的胰腺癌细胞系中重新表达可降低细胞生长并促进衰老，而在SWI/ snf完整的细胞系中过表达则没有这种作用。此外，表达谱分析显示，SWI/SNF可能拮抗Polycomb抑制复合体2，暗示这可能是抑制肿瘤的一种机制。我们的研究结果表明，SWI/SNF是胰腺癌的中心肿瘤抑制复合物。
Defining the molecular genetic alterations underlying pancreatic cancer may provide unique therapeutic insight for this deadly disease. Toward this goal, we report here an integrative DNA microarray and sequencing-based analysis of pancreatic cancer genomes. Notable among the alterations newly identified, genomic deletions, mutations, and rearrangements recurrently targeted genes encoding components of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex, including all three putative DNA binding subunits (ARID1A, ARID1B, and PBRM1) and both enzymatic subunits (SMARCA2 and SMARCA4). Whereas alterations of each individual SWI/SNF subunit occurred at modest-frequency, as mutational "hills" in the genomic landscape, together they affected at least one-third of all pancreatic cancers, defining SWI/SNF as a major mutational "mountain." Consistent with a tumor-suppressive role, re-expression of SMARCA4 in SMARCA4-deficient pancreatic cancer cell lines reduced cell growth and promoted senescence, whereas its overexpression in a SWI/SNF-intact line had no such effect. In addition, expression profiling analyses revealed that SWI/SNF likely antagonizes Polycomb repressive complex 2, implicating this as one possible mechanism of tumor suppression. Our findings reveal SWI/SNF to be a central tumor suppressive complex in pancreatic cancer.