Lineage-defined leiomyosarcoma subtypes emerge years before diagnosis and determine patient survival.
Lineage-defined leiomyosarcoma subtypes emerge years before diagnosis and determine patient survival.
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DOI：
10.1038/s41467-021-24677-6
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发表时间：
2021-07-23
影响因子：
16.6
通讯作者：
Shlien A
中科院分区：
文献类型：
--
作者：
Anderson ND;Babichev Y;Fuligni F;Comitani F;Layeghifard M;Venier RE;Dentro SC;Maheshwari A;Guram S;Wunker C;Thompson JD;Yuki KE;Hou H;Zatzman M;Light N;Bernardini MQ;Wunder JS;Andrulis IL;Ferguson P;Razak ARA;Swallow CJ;Dowling JJ;Al-Awar RS;Marcellus R;Rouzbahman M;Gerstung M;Durocher D;Alexandrov LB;Dickson BC;Gladdy RA;Shlien A
平滑肌肉瘤(LMS)是一种遗传异质性肿瘤，沿平滑肌线分化。目前，LMS的治疗不受分子亚型的影响，并与高度可变的存活率相关。虽然疾病部位继续决定临床治疗，但遗传因素对LMS亚型、起源和时间的贡献尚不清楚。在这里，我们分析了70个基因组和130个转录本，包括多个肿瘤区域和成对的转移。分子图谱突出了LMS的非常早期的起源。我们发现了三种特殊的LMS亚型，它们可能来自不同的平滑肌细胞谱系。其中，具有高免疫浸润性的去分化LMS和主要起源于妇科的肿瘤含有基因组dystrophin缺失和/或dystrophin表达缺失，获得了最高的基因组突变负担，并与较差的生存相关。同源重组缺陷导致全基因组的突变特征，以及对PARP捕捉器和其他DNA损伤反应抑制剂的相应敏感性，提示LMS有希望的治疗策略。最后，通过系统发育重建，我们提出了在LMS诊断之前几十年出现播种致命性转移的克隆的证据。平滑肌肉瘤(LMS)的异质性使得该病的治疗具有挑战性。在这里，作者使用基因组学和转录组学分析了LMS的异质性和分子LMS亚型，发现起源于不同的谱系，并与生存有关，此外还有早期转移克隆的出现。
Leiomyosarcomas (LMS) are genetically heterogeneous tumors differentiating along smooth muscle lines. Currently, LMS treatment is not informed by molecular subtyping and is associated with highly variable survival. While disease site continues to dictate clinical management, the contribution of genetic factors to LMS subtype, origins, and timing are unknown. Here we analyze 70 genomes and 130 transcriptomes of LMS, including multiple tumor regions and paired metastases. Molecular profiling highlight the very early origins of LMS. We uncover three specific subtypes of LMS that likely develop from distinct lineages of smooth muscle cells. Of these, dedifferentiated LMS with high immune infiltration and tumors primarily of gynecological origin harbor genomic dystrophin deletions and/or loss of dystrophin expression, acquire the highest burden of genomic mutation, and are associated with worse survival. Homologous recombination defects lead to genome-wide mutational signatures, and a corresponding sensitivity to PARP trappers and other DNA damage response inhibitors, suggesting a promising therapeutic strategy for LMS. Finally, by phylogenetic reconstruction, we present evidence that clones seeding lethal metastases arise decades prior to LMS diagnosis. Heterogeneity in leiomyosarcomas (LMS) makes treatment of the disease challenging. Here the authors analyze LMS heterogeneity and molecular LMS subtypes using genomics and transcriptomics, finding origins in distinct lineages and associations with survival, in addition to the early emergence of metastatic clones.
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影响因子：
8
作者：
Beck, A. H.;Lee, C-H;Witten, D. M.;Gleason, B. C.;Edris, B.;Espinosa, I.;Zhu, S.;Li, R.;Montgomery, K. D.;Marinelli, R. J.;Tibshirani, R.;Hastie, T.;Jablons, D. M.;Rubin, B. P.;Fletcher, C. D.;West, R. B.;van de Rijn, M.
通讯作者：
van de Rijn, M.
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
46.9
作者：
Becht, Etienne;McInnes, Leland;Newell, Evan W.
通讯作者：
Newell, Evan W.
DOI：
10.1158/1078-0432.ccr-14-3141
发表时间：
2015-08-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Guo X;Jo VY;Mills AM;Zhu SX;Lee CH;Espinosa I;Nucci MR;Varma S;Forgó E;Hastie T;Anderson S;Ganjoo K;Beck AH;West RB;Fletcher CD;van de Rijn M
通讯作者：
van de Rijn M
影响因子：
5.4
作者：
Dentro, Stefan C.;Wedge, David C.;Van Loo, Peter
通讯作者：
Van Loo, Peter