Genomic Entropy confers an aggressive Phenotype in Mesothelioma

Higher genomic entropy in mesothelioma is linked to more aggressive tumor behavior and shorter survival, but the clinical relevance of these findings requires further investigation.

Summary and findings

This study investigated the genomic characteristics of 277 mesotheliomas, focusing on somatic copy number alterations and their association with tumor heterogeneity and patient outcomes. The findings suggest that genomic entropy, quantified by Weighted Shannon Entropy (WSE), correlates with tumor aggressiveness and shorter survival. No therapeutic claims are made.

Abstract

<title>Abstract</title> <p>Exposure to asbestos is the primary cause of mesothelioma, however the processes underpinning its initiation and evolutionary trajectory remain elusive. To address this knowledge gap, we conducted whole exome sequencing and phylogenetic analysis of 277 mesotheliomas. Using multidimensional Dirichlet process clustering we inferred phylogenies, uncovering mutation order dominated by early 13q,1p, 8p, 6q and 22q somatic copy number alterations. Mesotheliomas exhibit a spectrum of genomic intra-tumor heterogeneity spanning linear (L) to highly branched (B) tree topologies, quantifiable by the Weighted Shannon Entropy (WSE). Somatic copy number alterations emerge earlier than single nucleotide variants (SNVs), and at a much faster relative rate in L-mesotheliomas. BAP1 is the only positively selected driver in L-mesotheliomas, whereas, B-mesotheliomas harbor multiple positively selected drivers and an aggressive phenotype, including a bias of loss of RPL5, and MTAP deletion linked to breakpoint enriched with long interspersed nuclear elements. L-trees had lower WSE, but greater T-cell inflammation and tertiary lymphoid structures, despite having a lower neoantigen burden. WSE is higher in larger volume, immunologically cold mesotheliomas, and is associated with shorter survival. In summary, progressive genomic heterogeneity is a defining feature of more aggressive mesothelioma yet illuminates opportunities for precision therapeutic intervention.</p>

Key findings

• Not reported in abstract.

Limitations

• Not reported in abstract.

Elsewhere in the PE 22-28 corpus