Single-cell genomic variation induced by mutational processes in cancer.
Single-cell genomic variation induced by mutational processes in cancer.
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DOI：
10.1038/s41586-022-05249-0
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发表时间：
2022-12
期刊：
影响因子：
64.8
通讯作者：
Aparicio, Samuel
中科院分区：
文献类型：
--
作者：
Funnell, Tyler;O'Flanagan, Ciara H.;Williams, Marc J.;McPherson, Andrew;McKinney, Steven;Kabeer, Farhia;Lee, Hakwoo;Salehi, Sohrab;Vazquez-Garcia, Ignacio;Shi, Hongyu;Leventhal, Emily;Masud, Tehmina;Eirew, Peter;Yap, Damian;Zhang, Allen W.;Lim, Jamie L. P.;Wang, Beixi;Brimhall, Jazmine;Biele, Justina;Ting, Jerome;Au, Vinci;Van Vliet, Michael;Liu, Yi Fei;Beatty, Sean;Lai, Daniel;Pham, Jenifer;Grewal, Diljot;Abrams, Douglas;Havasov, Eliyahu;Leung, Samantha;Bojilova, Viktoria;Moore, Richard A.;Rusk, Nicole;Uhlitz, Florian;Ceglia, Nicholas;Weiner, Adam C.;Zaikova, Elena;Douglas, J. Maxwell;Zamarin, Dmitriy;Weigelt, Britta;Kim, Sarah H.;Paula, Arnaud Da Cruz;Reis-Filho, Jorge S.;Martin, Spencer D.;Li, Yangguang;Xu, Hong;de Algara, Teresa Ruiz;Lee, So Ra;Llanos, Viviana Cerda;Huntsman, David G.;McAlpine, Jessica N.;Shah, Sohrab P.;Aparicio, Samuel
支持人类癌症基因组不稳定性的细胞间拷贝数改变如何驱动基因组和表型变异，从而导致癌症的进化，仍未得到充分研究。在这里，通过对野生型、TP53缺陷型和TP53缺陷型、BRCA1缺陷型或TP53缺陷型、BRCA2缺陷型乳腺上皮细胞(13,818个基因组)以及原发三阴性乳腺癌(TNBC)和高级别浆液性卵巢癌(HGSC)细胞(22,057个基因组)进行大规模单细胞全基因组测序，我们识别出三种不同的由细胞间结构变化定义的“前景”突变模式。细胞和克隆特异的高水平扩增、平行的单倍型特异拷贝数改变和拷贝数片段长度变异(锯齿状结构变异)具有可测量的表型和进化后果。在TNBC和HGSC中，已知癌基因的克隆特异性高水平扩增在具有折叠反转的肿瘤中非常普遍，相对于具有同源重组缺陷的肿瘤，并且与克隆到克隆表型变异的增加有关。平行的单倍型特异性改变也很常见，导致系统发育进化多样性和克隆特异性单等位基因表达。锯齿状变异在折返反转的肿瘤中增加，并与细胞群体基因组多样性的增加高度相关。总之，我们的发现表明，细胞之间的结构差异有助于TNBC和HGSC的表型和进化多样性的起源，并为深入了解单个肿瘤细胞的基因组和突变状态提供了洞察。单细胞全基因组测序显示，在三阴性乳腺癌和高级别浆液性卵巢癌中，细胞到细胞的结构变异和拷贝数的变化与基因组多样性和进化有关。
How cell-to-cell copy number alterations that underpin genomic instability in human cancers drive genomic and phenotypic variation, and consequently the evolution of cancer, remains understudied. Here, by applying scaled single-cell whole-genome sequencing to wild-type, TP53-deficient and TP53-deficient;BRCA1-deficient or TP53-deficient;BRCA2-deficient mammary epithelial cells (13,818 genomes), and to primary triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSC) cells (22,057 genomes), we identify three distinct ‘foreground’ mutational patterns that are defined by cell-to-cell structural variation. Cell- and clone-specific high-level amplifications, parallel haplotype-specific copy number alterations and copy number segment length variation (serrate structural variations) had measurable phenotypic and evolutionary consequences. In TNBC and HGSC, clone-specific high-level amplifications in known oncogenes were highly prevalent in tumours bearing fold-back inversions, relative to tumours with homologous recombination deficiency, and were associated with increased clone-to-clone phenotypic variation. Parallel haplotype-specific alterations were also commonly observed, leading to phylogenetic evolutionary diversity and clone-specific mono-allelic expression. Serrate variants were increased in tumours with fold-back inversions and were highly correlated with increased genomic diversity of cellular populations. Together, our findings show that cell-to-cell structural variation contributes to the origins of phenotypic and evolutionary diversity in TNBC and HGSC, and provide insight into the genomic and mutational states of individual cancer cells. Single-cell whole-genome sequencing shows that 'foreground' cell-to-cell structural variation and alterations in copy number are associated with genomic diversity and evolution in triple-negative breast and high-grade serous ovarian cancers.
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DOI：
10.1073/pnas.090013497
发表时间：
2000-05-09
影响因子：
11.1
作者：
Gisselsson, D;Pettersson, L;Mandahl, N
通讯作者：
Mandahl, N
DOI：
10.1093/bioinformatics/btx346
发表时间：
2017-10-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Gel B;Serra E
通讯作者：
Serra E
影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
DOI：
10.1073/pnas.0807297105
发表时间：
2008-09-30
影响因子：
11.1
作者：
Anderson, Ericka L.;Baltus, Andrew E.;Page, David C.
通讯作者：
Page, David C.
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel