Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer
Divergent trajectories to structural diversity impact patient survival in high grade serous ovarian cancer
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结构多样性的不同轨迹影响高级别浆液性卵巢癌患者的生存
DOI：
10.1101/2024.01.12.575376
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Ewing A
中科院分区：
文献类型：
--
作者：
Ewing A
破译肿瘤基因组的结构变异对于确定驱动肿瘤进展的事件以及更好地理解肿瘤的适应和进化至关重要。高级别浆液性卵巢癌（HGSOC）是一种典型的肿瘤类型，表现出极端的，但特征不明显的结构多样性。我们利用一个大型（N=324）、深度全基因组测序数据集，全面描述了驱动HGSOC的突变景观。我们揭示了两种不同的进化轨迹，影响患者的生存，并涉及不同的基因组环境。一种涉及同源重组修复缺陷（HRD），另一种以全基因组重复（WGD）为主，常伴有染色体断裂、断裂融合桥和染色体外DNA。这些轨迹有助于结构变异热点，包含具有显著改变表达的新候选驱动基因。虽然结构变异主要驱动肿瘤发生，但我们也发现高mtDNA突变负荷与较短的患者生存期相关，并与核基因组的改变结合作用，影响预后，并提出了患者分层的新策略。
Deciphering the structural variation across tumour genomes is crucial to determine the events driving tumour progression and better understand tumour adaptation and evolution. High grade serous ovarian cancer (HGSOC) is an exemplar tumour type showing extreme, but poorly characterised structural diversity. We comprehensively describe the mutational landscape driving HGSOC, exploiting a large (N=324), deeply whole genome sequenced dataset. We reveal two divergent evolutionary trajectories, affecting patient survival and involving differing genomic environments. One involves homologous recombination repair deficiency (HRD) while the other is dominated by whole genome duplication (WGD) with frequent chromothripsis, breakage-fusion-bridges and extra-chromosomal DNA. These trajectories contribute to structural variation hotspots, containing novel candidate driver genes with significantly altered expression. While structural variation predominantly drives tumorigenesis, we also find high mtDNA mutation loads associated with shorter patient survival, and acting in combination with alterations in the nuclear genome to impact prognosis and suggesting new strategies for patient stratification.
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癌症基因组地图集中的致癌信号通路。
影响因子：
64.5
作者：
Sanchez-Vega F;Mina M;Armenia J;Chatila WK;Luna A;La KC;Dimitriadoy S;Liu DL;Kantheti HS;Saghafinia S;Chakravarty D;Daian F;Gao Q;Bailey MH;Liang WW;Foltz SM;Shmulevich I;Ding L;Heins Z;Ochoa A;Gross B;Gao J;Zhang H;Kundra R;Kandoth C;Bahceci I;Dervishi L;Dogrusoz U;Zhou W;Shen H;Laird PW;Way GP;Greene CS;Liang H;Xiao Y;Wang C;Iavarone A;Berger AH;Bivona TG;Lazar AJ;Hammer GD;Giordano T;Kwong LN;McArthur G;Huang C;Tward AD;Frederick MJ;McCormick F;Meyerson M;Cancer Genome Atlas Research Network;Van Allen EM;Cherniack AD;Ciriello G;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
50.3
作者：
Berger AC;Korkut A;Kanchi RS;Hegde AM;Lenoir W;Liu W;Liu Y;Fan H;Shen H;Ravikumar V;Rao A;Schultz A;Li X;Sumazin P;Williams C;Mestdagh P;Gunaratne PH;Yau C;Bowlby R;Robertson AG;Tiezzi DG;Wang C;Cherniack AD;Godwin AK;Kuderer NM;Rader JS;Zuna RE;Sood AK;Lazar AJ;Ojesina AI;Adebamowo C;Adebamowo SN;Baggerly KA;Chen TW;Chiu HS;Lefever S;Liu L;MacKenzie K;Orsulic S;Roszik J;Shelley CS;Song Q;Vellano CP;Wentzensen N;Cancer Genome Atlas Research Network;Weinstein JN;Mills GB;Levine DA;Akbani R
通讯作者：
Akbani R
影响因子：
64.8
作者：
Patch, Ann-Marie;Christie, Elizabeth L.;Bowtell, David D. L.
通讯作者：
Bowtell, David D. L.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
20.8
作者：
Gorelick, Alexander N.;Kim, Minsoo;Chatila, Walid K.;La, Konnor;Hakimi, A. Ari;Berger, Michael F.;Taylor, Barry S.;Gammage, Payam A.;Reznik, Ed
通讯作者：
Reznik, Ed