Frequent Somatic Mutation in Adult Intestinal Stem Cells Drives Neoplasia and Genetic Mosaicism during Aging.
Frequent Somatic Mutation in Adult Intestinal Stem Cells Drives Neoplasia and Genetic Mosaicism during Aging.
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DOI：
10.1016/j.stem.2015.09.016
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发表时间：
2015-12-03
期刊：
影响因子：
23.9
通讯作者：
Bardin, Allison J.
中科院分区：
文献类型：
--
作者：
Siudeja, Katarzyna;Nassari, Sonya;Gervais, Louis;Skorski, Patricia;Lameiras, Sonia;Stolfa, Donato;Zande, Maria;Bernard, Virginie;Frio, Thomas Rio;Bardin, Allison J.
成体干细胞可能获得改变细胞行为的突变，导致稳态功能下降或提供竞争优势，导致癌前病变。然而，频率，表型的影响，和机制的自发突变在老化过程中还不清楚。在这里，我们报告了两种机制的基因组不稳定性在成年果蝇肠道干细胞（ISCs），导致表型改变，在老化的肠道。首先，我们发现，在有丝分裂同源重组的结果在遗传嵌合体中的ISCs，经常引起的杂合性丢失。第二，DNA序列的体细胞缺失和大的结构重排，类似于癌症和先天性疾病中描述的那些，经常导致基因失活。这种修饰诱导ISCs中X连锁肿瘤抑制因子Notch的体细胞失活，导致野生型雄性自发性肿瘤形成。总之，我们的研究结果揭示了成体干细胞中频繁的基因组修饰，并表明体细胞遗传嵌合体对衰老组织具有重要的功能影响。衰老的果蝇肠道是遗传镶嵌体细胞重组、基因组缺失和重排发生在衰老的ISCs中肿瘤抑制因子Notch的体细胞失活导致雄性特异性瘤形成Bardin及其同事表明，衰老的果蝇肠道干细胞（ISCs）获得频繁的自发突变，包括由同源有丝分裂重组引起的频繁的杂合性丢失，导致克隆镶嵌。他们还显示了老化ISCs中的自发基因缺失和染色体重排，这可以通过使Notch失活来促进肿瘤形成。
Adult stem cells may acquire mutations that modify cellular behavior, leading to functional declines in homeostasis or providing a competitive advantage resulting in premalignancy. However, the frequency, phenotypic impact, and mechanisms underlying spontaneous mutagenesis during aging are unclear. Here, we report two mechanisms of genome instability in adult Drosophila intestinal stem cells (ISCs) that cause phenotypic alterations in the aging intestine. First, we found frequent loss of heterozygosity arising from mitotic homologous recombination in ISCs that results in genetic mosaicism. Second, somatic deletion of DNA sequences and large structural rearrangements, resembling those described in cancers and congenital diseases, frequently result in gene inactivation. Such modifications induced somatic inactivation of the X-linked tumor suppressor Notch in ISCs, leading to spontaneous neoplasias in wild-type males. Together, our findings reveal frequent genomic modification in adult stem cells and show that somatic genetic mosaicism has important functional consequences on aging tissues. The aging Drosophila intestine is genetically mosaic Somatic recombination, genomic deletions, and rearrangements occur in aging ISCs Somatic inactivation of the tumor-suppressor Notch causes male-specific neoplasia Bardin and colleagues show that aging Drosophila intestinal stem cells (ISCs) acquire frequent spontaneous mutations, including frequent loss of heterozygosity arising from homologous mitotic recombination that results in clonal mosaicism. They also show spontaneous gene deletions and chromosomal rearrangements in aging ISCs, which can promote neoplasia formation through inactivating Notch.
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影响因子：
30.8
作者：
Busque L;Patel JP;Figueroa ME;Vasanthakumar A;Provost S;Hamilou Z;Mollica L;Li J;Viale A;Heguy A;Hassimi M;Socci N;Bhatt PK;Gonen M;Mason CE;Melnick A;Godley LA;Brennan CW;Abdel-Wahab O;Levine RL
通讯作者：
Levine RL
影响因子：
4.5
作者：
Biteau B;Karpac J;Supoyo S;Degennaro M;Lehmann R;Jasper H
通讯作者：
Jasper H
DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
正常细胞的基因组测序揭示了发育谱系和突变过程。
影响因子：
64.8
作者：
Behjati, Sam;Huch, Meritxell;van Boxtel, Ruben;Karthaus, Wouter;Wedge, David C.;Tamuri, Asif U.;Martincorena, Inigo;Petljak, Mia;Alexandrov, Ludmil B.;Gundem, Gunes;Tarpey, Patrick S.;Roerink, Sophie;Blokker, Joyce;Maddison, Mark;Mudie, Laura;Robinson, Ben;Nik-Zainal, Serena;Campbell, Peter;Goldman, Nick;van de Wetering, Marc;Cuppen, Edwin;Clevers, Hans;Stratton, Michael R.
通讯作者：
Stratton, Michael R.
DOI：
10.1093/bioinformatics/btr670
发表时间：
2012-02-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Boeva V;Popova T;Bleakley K;Chiche P;Cappo J;Schleiermacher G;Janoueix-Lerosey I;Delattre O;Barillot E
通讯作者：
Barillot E