Cell-of-origin chromatin organization shapes the mutational landscape of cancer.
Cell-of-origin chromatin organization shapes the mutational landscape of cancer.
复制标题
细胞源染色质组织塑造了癌症的突变景观。
DOI：
10.1038/nature14221
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发表时间：
2015-02-19
期刊：
影响因子：
64.8
通讯作者：
Sunyaev, Shamil R.
中科院分区：
文献类型：
--
作者：
Polak, Paz;Karlic, Rosa;Koren, Amnon;Thurman, Robert;Sandstrom, Richard;Lawrence, Michael S.;Reynolds, Alex;Rynes, Eric;Vlahovicek, Kristian;Stamatoyannopoulos, John A.;Sunyaev, Shamil R.
癌症是一种由体细胞突变增强的疾病。癌症突变并不是沿着基因组均匀分布的。相反，不同的基因组区域在体细胞突变的局部密度上变化高达5倍，这对癌症基因组学的统计方法提出了一个基本问题。表观基因组组织已被认为是癌症突变景观的主要决定因素。然而，体细胞诱变和表观基因组特征都是高度细胞类型特异性的。我们研究了不同癌症类型的多个样本中突变的分布，并将其与细胞类型特异性表观基因组特征进行了比较。在这里，我们表明，染色质的可及性和修改，连同复制时间，解释高达86%的变异率沿着癌症基因组。绝大多数情况下，局部体细胞突变密度的最佳预测因子是源自相应恶性肿瘤起源的最可能细胞类型的表观基因组特征。此外，我们发现，细胞的起源染色质的功能是更强的癌症突变谱的决定因素比同源癌细胞系的染色质功能。我们进一步表明，癌症起源的细胞类型可以根据其基因组沿着的突变分布来准确地确定。因此，癌症基因组的DNA序列包含关于其起源细胞的身份和表观基因组特征的丰富信息。
Cancer is a disease potentiated by mutations in somatic cells. Cancer mutations are not distributed uniformly along the genome. Instead, different genomic regions vary by up to 5-fold in the local density of somatic mutations, posing a fundamental problem for statistical methods of cancer genomics. Epigenomic organization has been proposed as a major determinant of the cancer mutational landscape. However, both somatic mutagenesis and epigenomic features are highly cell-type-specific. We investigated the distribution of mutations in multiple samples of diverse cancer types and compared them to cell-type-specific epigenomic features. Here, we show that chromatin accessibility and modification, together with replication timing, explain up to 86% of the variance in mutation rates along cancer genomes. Overwhelmingly, the best predictors of local somatic mutation density are epigenomic features derived from the most likely cell type of origin of the corresponding malignancy. Moreover, we find that cell-of-origin chromatin features are much stronger determinants of cancer mutation profiles than chromatin features of cognate cancer cell lines. We show further that the cell type of origin of a cancer can be accurately determined based on the distribution of mutations along its genome. Thus, DNA sequence of a cancer genome encompasses a wealth of information about the identity and epigenomic features of its cell of origin.
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影响因子：
64.8
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30.8
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64.8
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Berger, Michael F.;Hodis, Eran;Heffernan, Timothy P.;Deribe, Yonathan Lissanu;Lawrence, Michael S.;Protopopov, Alexei;Ivanova, Elena;Watson, Ian R.;Nickerson, Elizabeth;Ghosh, Papia;Zhang, Hailei;Zeid, Rhamy;Ren, Xiaojia;Cibulskis, Kristian;Sivachenko, Andrey Y.;Wagle, Nikhil;Sucker, Antje;Sougnez, Carrie;Onofrio, Robert;Ambrogio, Lauren;Auclair, Daniel;Fennell, Timothy;Carter, Scott L.;Drier, Yotam;Stojanov, Petar;Singer, Meredith A.;Voet, Douglas;Jing, Rui;Saksena, Gordon;Barretina, Jordi;Ramos, Alex H.;Pugh, Trevor J.;Stransky, Nicolas;Parkin, Melissa;Winckler, Wendy;Mahan, Scott;Ardlie, Kristin;Baldwin, Jennifer;Wargo, Jennifer;Schadendorf, Dirk;Meyerson, Matthew;Gabriel, Stacey B.;Golub, Todd R.;Wagner, Stephan N.;Lander, Eric S.;Getz, Gad;Chin, Lynda;Garraway, Levi A.
通讯作者：
Garraway, Levi A.
影响因子：
30.8
作者：
Dulak, Austin M.;Stojanov, Petar;Peng, Shouyong;Lawrence, Michael S.;Fox, Cameron;Stewart, Chip;Bandla, Santhoshi;Imamura, Yu;Schumacher, Steven E.;Shefler, Erica;McKenna, Aaron;Carter, Scott L.;Cibulskis, Kristian;Sivachenko, Andrey;Saksena, Gordon;Voet, Douglas;Ramos, Alex H.;Auclair, Daniel;Thompson, Kristin;Sougnez, Carrie;Onofrio, Robert C.;Guiducci, Candace;Beroukhim, Rameen;Zhou, Zhongren;Lin, Lin;Lin, Jules;Reddy, Rishindra;Chang, Andrew;Landrenau, Rodney;Pennathur, Arjun;Ogino, Shuji;Luketich, James D.;Golub, Todd R.;Gabriel, Stacey B.;Lander, Eric S.;Beer, David G.;Godfrey, Tony E.;Getz, Gad;Bass, Adam J.
通讯作者：
Bass, Adam J.