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Mutational signature in colorectal cancer caused by genotoxic pks(+)E. coli 期刊论文
NATURE, 2020, 580 (7802) : 269-+
作者:  Lin, Xi;  Li, Mingyue;  Wang, Niandong;  Wu, Yiran;  Luo, Zhipu;  Guo, Shimeng;  Han, Gye-Won;  Li, Shaobai;  Yue, Yang;  Wei, Xiaohu;  Xie, Xin;  Chen, Yong;  Zhao, Suwen;  Wu, Jian;  Lei, Ming;  Xu, Fei
收藏  |  浏览/下载:22/0  |  提交时间:2020/07/03

Various species of the intestinal microbiota have been associated with the development of colorectal cancer(1,2), but it has not been demonstrated that bacteria have a direct role in the occurrence of oncogenic mutations. Escherichia coli can carry the pathogenicity island pks, which encodes a set of enzymes that synthesize colibactin(3). This compound is believed to alkylate DNA on adenine residues(4,5) and induces double-strand breaks in cultured cells(3). Here we expose human intestinal organoids to genotoxic pks(+)E. coli by repeated luminal injection over five months. Whole-genome sequencing of clonal organoids before and after this exposure revealed a distinct mutational signature that was absent from organoids injected with isogenic pks-mutant bacteria. The same mutational signature was detected in a subset of 5,876 human cancer genomes from two independent cohorts, predominantly in colorectal cancer. Our study describes a distinct mutational signature in colorectal cancer and implies that the underlying mutational process results directly from past exposure to bacteria carrying the colibactin-producing pks pathogenicity island.


Organoids derived from human intestinal cells that are co-cultured with bacteria carrying the genotoxic pks(+) island develop a distinct mutational signature associated with colorectal cancer.


  
Oceanic forcing of penultimate deglacial and last interglacial sea-level rise 期刊论文
NATURE, 2020, 577 (7792) : 660-+
作者:  Rizal, Yan;  Westaway, Kira E.;  Zaim, Yahdi;  van den Bergh, Gerrit D.;  Bettis, E. Arthur, III;  Morwood, Michael J.;  Huffman, O. Frank;  Grun, Rainer;  Joannes-Boyau, Renaud;  Bailey, Richard M.;  Sidarto;  Westaway, Michael C.;  Kurniawan, Iwan;  Moore, Mark W.;  Storey, Michael;  Aziz, Fachroel;  Suminto;  Zhao, Jian-xin;  Aswan;  Sipola, Maija E.;  Larick, Roy;  Zonneveld, John-Paul;  Scott, Robert;  Putt, Shelby;  Ciochon, Russell L.
收藏  |  浏览/下载:21/0  |  提交时间:2020/05/13

Sea-level histories during the two most recent deglacial-interglacial intervals show substantial differences(1-3) despite both periods undergoing similar changes in global mean temperature(4,5) and forcing from greenhouse gases(6). Although the last interglaciation (LIG) experienced stronger boreal summer insolation forcing than the present interglaciation(7), understanding why LIG global mean sea level may have been six to nine metres higher than today has proven particularly challenging(2). Extensive areas of polar ice sheets were grounded below sea level during both glacial and interglacial periods, with grounding lines and fringing ice shelves extending onto continental shelves(8). This suggests that oceanic forcing by subsurface warming may also have contributed to ice-sheet loss(9-12) analogous to ongoing changes in the Antarctic(13,14) and Greenland(15) ice sheets. Such forcing would have been especially effective during glacial periods, when the Atlantic Meridional Overturning Circulation (AMOC) experienced large variations on millennial timescales(16), with a reduction of the AMOC causing subsurface warming throughout much of the Atlantic basin(9,12,17). Here we show that greater subsurface warming induced by the longer period of reduced AMOC during the penultimate deglaciation can explain the more-rapid sea-level rise compared with the last deglaciation. This greater forcing also contributed to excess loss from the Greenland and Antarctic ice sheets during the LIG, causing global mean sea level to rise at least four metres above modern levels. When accounting for the combined influences of penultimate and LIG deglaciation on glacial isostatic adjustment, this excess loss of polar ice during the LIG can explain much of the relative sea level recorded by fossil coral reefs and speleothems at intermediate- and far-field sites.