Journal Article

DKFZ-2022-01599

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Lineage-defined leiomyosarcoma subtypes emerge years before diagnosis and determine patient survival.

Anderson, N. D. ; Babichev, Y. ; Fuligni, F. ; Comitani, F. ; Layeghifard, M. ; Venier, R. E. ; Dentro, S.Extern* ; Maheshwari, A. ; Guram, S. ; Wunker, C. ; Thompson, J. D. ; Yuki, K. E. ; Hou, H. ; Zatzman, M. ; Light, N. ; Bernardini, M. Q. ; Wunder, J. S. ; Andrulis, I. L. ; Ferguson, P. ; Razak, A. R. A. ; Swallow, C. J. ; Dowling, J. J. ; Al-Awar, R. S. ; Marcellus, R. ; Rouzbahman, M. ; Gerstung, M.Extern* ; Durocher, D. ; Alexandrov, L. B. ; Dickson, B. C. ; Gladdy, R. A. ; Shlien, A.

2021
Nature Publishing Group UK [London]

Abstract: 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.

Keyword(s): Adult (MeSH) ; Aged (MeSH) ; Aged, 80 and over (MeSH) ; Clonal Evolution (MeSH) ; Cohort Studies (MeSH) ; Female (MeSH) ; Gene Expression Profiling: methods (MeSH) ; Gene Expression Regulation, Neoplastic (MeSH) ; Genetic Predisposition to Disease: genetics (MeSH) ; Genomics: methods (MeSH) ; Humans (MeSH) ; Leiomyosarcoma: classification (MeSH) ; Leiomyosarcoma: diagnosis (MeSH) ; Leiomyosarcoma: genetics (MeSH) ; Male (MeSH) ; Middle Aged (MeSH) ; Muscle, Smooth: metabolism (MeSH) ; Muscle, Smooth: pathology (MeSH) ; Mutation (MeSH) ; RNA-Seq: methods (MeSH) ; Survival Analysis (MeSH)

---

---

Database coverage:
; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 10 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

---