Clinically and biologically relevant subgroups of Wilms tumour defined by genomic and epigenomic analyses.
Clinically and biologically relevant subgroups of Wilms tumour defined by genomic and epigenomic analyses.
复制标题
DOI：
10.1038/s41416-020-01102-1
复制
发表时间：
2021-01
影响因子：
8.8
通讯作者：
Weksberg R
中科院分区：
文献类型：
--
作者：
Brzezinski J;Choufani S;Romao R;Shuman C;Chen H;Cunanan J;Bagli D;Grant R;Lorenzo A;Weksberg R
尽管Wilms肿瘤（WT）的治愈率很高，但许多患者接受治疗时伴有长期并发症。我们的目标是使用全基因组分析对WT进行分层，以确定可能从减少治疗中受益的患者的候选分子特征。我们生成了来自本中心或儿童肿瘤组收集的wt -肾对（n = 57）和未配对肿瘤（n = 27）的DNA甲基化和外显子组测序数据。将样本分为发现集（n = 32）和验证集（n = 52）。DNA甲基化分析揭示了WT的两个亚群具有不同的特征。亚组A具有与成熟肾脏相似的DNA甲基化谱，而亚组B具有全基因组DNA甲基化失调。在B亚组肿瘤中，非同义错义突变和染色体片段畸变的发生率较高，这表明该组具有与其表观遗传状态相关的基因组不稳定性。A亚组双侧病变比例较高。具有高危组织学或复发患者的肿瘤仅在b亚组中发现。我们已经确定了亚组特异性分子事件，可以为未来支持更有针对性的治疗方法和患者分层的工作提供信息。基于这些发现，我们提出了一种新的发育肿瘤模型。
Although cure rates for Wilms tumours (WT) are high, many patients receive therapy with attendant long-term complications. Our goal was to stratify WT using genome-wide analyses to identify candidate molecular features for patients who would benefit from a reduction in therapy. We generated DNA methylation and exome sequencing data on WT–kidney pairs (n = 57) and unpaired tumours (n = 27) collected either at our centre or by the Children’s Oncology Group. Samples were divided into a discovery set (n = 32) and validation set (n = 52). Analysis of DNA methylation revealed two subgroups of WT with distinct features. Subgroup A has a similar DNA methylation profile to mature kidney, while Subgroup B has genome-wide dysregulation of DNA methylation. The rate of non-synonymous missense mutations and segmental chromosomal aberrations was higher in Subgroup B tumours, suggesting that this group has genome instability related to its epigenetic state. Subgroup A had a higher proportion of cases of bilateral disease. Tumours with high-risk histology or from patients who relapsed were only found in Subgroup B. We have identified subgroup-specific molecular events that could inform future work supporting more targeted therapeutic approaches and patient stratification. We propose a novel developmental tumour model based on these findings.
登录
查看更多内容
影响因子：
64.8
作者：
Capper D;Jones DTW;Sill M;Hovestadt V;Schrimpf D;Sturm D;Koelsche C;Sahm F;Chavez L;Reuss DE;Kratz A;Wefers AK;Huang K;Pajtler KW;Schweizer L;Stichel D;Olar A;Engel NW;Lindenberg K;Harter PN;Braczynski AK;Plate KH;Dohmen H;Garvalov BK;Coras R;Hölsken A;Hewer E;Bewerunge-Hudler M;Schick M;Fischer R;Beschorner R;Schittenhelm J;Staszewski O;Wani K;Varlet P;Pages M;Temming P;Lohmann D;Selt F;Witt H;Milde T;Witt O;Aronica E;Giangaspero F;Rushing E;Scheurlen W;Geisenberger C;Rodriguez FJ;Becker A;Preusser M;Haberler C;Bjerkvig R;Cryan J;Farrell M;Deckert M;Hench J;Frank S;Serrano J;Kannan K;Tsirigos A;Brück W;Hofer S;Brehmer S;Seiz-Rosenhagen M;Hänggi D;Hans V;Rozsnoki S;Hansford JR;Kohlhof P;Kristensen BW;Lechner M;Lopes B;Mawrin C;Ketter R;Kulozik A;Khatib Z;Heppner F;Koch A;Jouvet A;Keohane C;Mühleisen H;Mueller W;Pohl U;Prinz M;Benner A;Zapatka M;Gottardo NG;Driever PH;Kramm CM;Müller HL;Rutkowski S;von Hoff K;Frühwald MC;Gnekow A;Fleischhack G;Tippelt S;Calaminus G;Monoranu CM;Perry A;Jones C;Jacques TS;Radlwimmer B;Gessi M;Pietsch T;Schramm J;Schackert G;Westphal M;Reifenberger G;Wesseling P;Weller M;Collins VP;Blümcke I;Bendszus M;Debus J;Huang A;Jabado N;Northcott PA;Paulus W;Gajjar A;Robinson GW;Taylor MD;Jaunmuktane Z;Ryzhova M;Platten M;Unterberg A;Wick W;Karajannis MA;Mittelbronn M;Acker T;Hartmann C;Aldape K;Schüller U;Buslei R;Lichter P;Kool M;Herold-Mende C;Ellison DW;Hasselblatt M;Snuderl M;Brandner S;Korshunov A;von Deimling A;Pfister SM
通讯作者：
Pfister SM
影响因子：
14.8
作者：
Kumar, Prateek;Henikoff, Steven;Ng, Pauline C.
通讯作者：
Ng, Pauline C.
影响因子：
4.3
作者：
Caldas HC;Lojudice FH;Dias C;Fernandes-Charpiot IMM;Baptista MASF;Kawasaki-Oyama RS;Sogayar MC;Takiya CM;Abbud-Filho M
通讯作者：
Abbud-Filho M
影响因子：
9
作者：
Fernandez CV;Perlman EJ;Mullen EA;Chi YY;Hamilton TE;Gow KW;Ferrer FA;Barnhart DC;Ehrlich PF;Khanna G;Kalapurakal JA;Bocking T;Huff V;Tian J;Geller JI;Grundy PE;Anderson JR;Dome JS;Shamberger RC
通讯作者：
Shamberger RC
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay