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<p>Given their rarity and diversity, a fundamental understanding of the genomic underpinnings for many sarcoma subtypes is still lacking. To better define the molecular landscape of this group of diseases, we perform matched whole exome sequencing and RNA sequencing on a cohort of 1340 sarcoma tumor specimens. We identify recurrent somatic mutations and observe an increased mutational burden in metastatic vs. primary samples (<i>p</i> &lt; 0.001). We observe frequent copy number alterations including whole genome doubling, with this feature being more common in metastatic tumors (p = 0.026). Estimation of immune cell abundances followed by hierarchical clustering identifies five immune subtypes ranging from low to high and we observe inferior overall survival in immune deplete clusters compared to immune enriched (<i>p &lt;</i> 0.01). Interestingly, GIST predominantly form a distinct “immune intermediate” cluster that is marked by a specific enrichment for NK cells (FDR &lt; 0.01).</p>

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Genomic, transcriptomic, and immunogenomic landscape of over 1300 sarcomas of diverse histology subtypes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月6日

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  • Alex Soupir,
  • Oscar E. Ospina,
  • Oliver Hampton,
  • Michelle Churchman,
  • Michael Radmacher,
  • Dale Hedges,
  • David McKean,
  • Phaedra Agius,
  • Saman Zeeshan,
  • Nathan D. Seligson,
  • Raphael Pollock,
  • David Liebner,
  • James L. Chen,
  • Gabriel Tinoco,
  • Bodour Salhia,
  • Martin McCarter,
  • Breelyn A. Wilky,
  • Benjamin J. Miller,
  • Michael J. Cavnar,
  • John S. Groundland,
  • Bryan P. Schneider,
  • Gregory Riedlinger,
  • Stephen B. Edge,
  • Christopher A. Moskaluk,
  • Kenneth Cardona,
  • Abdul Rafeh Naqash,
  • Ricardo J. Gonzalez,
  • John E. Mullinax,
  • David M. Joyce,
  • Odion Binitie,
  • G. Douglas Letson,
  • Arash O. Naghavi,
  • Mihaela Druta,
  • Damon R. Reed,
  • Erin M. Siegel,
  • Jamie K. Teer,
  • Brooke L. Fridley,
  • Andrew S. Brohl

摘要

Given their rarity and diversity, a fundamental understanding of the genomic underpinnings for many sarcoma subtypes is still lacking. To better define the molecular landscape of this group of diseases, we perform matched whole exome sequencing and RNA sequencing on a cohort of 1340 sarcoma tumor specimens. We identify recurrent somatic mutations and observe an increased mutational burden in metastatic vs. primary samples (p < 0.001). We observe frequent copy number alterations including whole genome doubling, with this feature being more common in metastatic tumors (p = 0.026). Estimation of immune cell abundances followed by hierarchical clustering identifies five immune subtypes ranging from low to high and we observe inferior overall survival in immune deplete clusters compared to immune enriched (p < 0.01). Interestingly, GIST predominantly form a distinct “immune intermediate” cluster that is marked by a specific enrichment for NK cells (FDR < 0.01).