Clonal evolution in breast cancer revealed by single nucleus genome sequencing.
Clonal evolution in breast cancer revealed by single nucleus genome sequencing.
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DOI：
10.1038/nature13600
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发表时间：
2014-08-14
期刊：
影响因子：
64.8
通讯作者：
Navin, Nicholas E.
中科院分区：
文献类型：
--
作者：
Wang, Yong;Waters, Jill;Leung, Marco L.;Unruh, Anna;Roh, Whijae;Shi, Xiuqing;Chen, Ken;Scheet, Paul;Vattathil, Selina;Liang, Han;Multani, Asha;Zhang, Hong;Zhao, Rui;Michor, Franziska;Meric-Bernstam, Funda;Navin, Nicholas E.
乳腺肿瘤队列的测序研究已经确定了许多普遍的突变，但对肿瘤内基因组多样性的了解有限。在这里，我们开发了一种全基因组和外显子组单细胞测序方法，称为Nuc-Seq，利用G2/M核实现91%的平均覆盖宽度。我们应用这种方法对雌激素受体阳性乳腺癌和三阴性导管癌的单个正常细胞核和肿瘤细胞核进行测序。同时，我们进行了单核拷贝数分析。我们的数据表明，非整倍体重排发生在肿瘤进化的早期，并随着肿瘤块的克隆扩大保持高度稳定。而点突变则逐渐进化，产生了广泛的克隆多样性。通过靶向单分子测序显示，许多不同的突变在肿瘤肿块中以低频率（<10%）发生。通过数学建模，我们发现三阴性肿瘤细胞的突变率增加（13.3倍），而ER+肿瘤细胞则没有。这些发现对乳腺癌化疗耐药的诊断、治疗和演变具有重要意义。
Sequencing studies of breast tumor cohorts have identified many prevalent mutations, but provide limited insight into the genomic diversity within tumors. Here, we developed a whole-genome and exome single cell sequencing approach called Nuc-Seq that utilizes G2/M nuclei to achieve 91% mean coverage breadth. We applied this method to sequence single normal and tumor nuclei from an estrogen-receptor positive breast cancer and a triple-negative ductal carcinoma. In parallel, we performed single nuclei copy number profiling. Our data show that aneuploid rearrangements occurred early in tumor evolution and remained highly stable as the tumor masses clonally expanded. In contrast, point mutations evolved gradually, generating extensive clonal diversity. Many of the diverse mutations were shown to occur at low frequencies (<10%) in the tumor mass by targeted single-molecule sequencing. Using mathematical modeling we found that the triple-negative tumor cells had an increased mutation rate (13.3X) while the ER+ tumor cells did not. These findings have important implications for the diagnosis, therapeutic treatment and evolution of chemoresistance in breast cancer.
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影响因子：
64.8
作者：
Ellis, Matthew J.;Ding, Li;Shen, Dong;Luo, Jingqin;Suman, Vera J.;Wallis, John W.;Van Tine, Brian A.;Hoog, Jeremy;Goiffon, Reece J.;Goldstein, Theodore C.;Ng, Sam;Lin, Li;Crowder, Robert;Snider, Jacqueline;Ballman, Karla;Weber, Jason;Chen, Ken;Koboldt, Daniel C.;Kandoth, Cyriac;Schierding, William S.;McMichael, Joshua F.;Miller, Christopher A.;Lu, Charles;Harris, Christopher C.;McLellan, Michael D.;Wendl, Michael C.;DeSchryver, Katherine;Allred, D. Craig;Esserman, Laura;Unzeitig, Gary;Margenthaler, Julie;Babiera, G. V.;Marcom, P. Kelly;Guenther, J. M.;Leitch, Marilyn;Hunt, Kelly;Olson, John;Tao, Yu;Maher, Christopher A.;Fulton, Lucinda L.;Fulton, Robert S.;Harrison, Michelle;Oberkfell, Ben;Du, Feiyu;Demeter, Ryan;Vickery, Tammi L.;Elhammali, Adnan;Piwnica-Worms, Helen;McDonald, Sandra;Watson, Mark;Dooling, David J.;Ota, David;Chang, Li-Wei;Bose, Ron;Ley, Timothy J.;Piwnica-Worms, David;Stuart, Joshua M.;Wilson, Richard K.;Mardis, Elaine R.
通讯作者：
Mardis, Elaine R.
影响因子：
64.8
作者：
Greaves, Mel;Maley, Carlo C.
通讯作者：
Maley, Carlo C.
DOI：
10.1038/nrc1299
发表时间：
2004-03
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.7
作者：
Dichosa, Armand E. K.;Fitzsimons, Michael S.;Han, Cliff S.
通讯作者：
Han, Cliff S.
DOI：
10.1073/pnas.0607057103
发表时间：
2006-11-28
影响因子：
11.1
作者：
Bielas, Jason H.;Loeb, Keith R.;Loeb, Lawrence A.
通讯作者：
Loeb, Lawrence A.