Pervasive chromothripsis drives pleural mesothelioma to impact gene function and patient survival

Pleural mesothelioma (PM) is a complex tumor type, and researchers have now mapped out its genetic landscape using a large cohort of 443 patients. The study reveals that most genetic alterations in PM are caused by copy number alterations (CNAs), and a significant number of tumors exhibit complex rearrangements. The most common of these are chromothripsis (74% of cases) and chromoplexy (59%).

Chromothripsis, a catastrophic event in which a chromosome undergoes multiple breaks and rearrangements in a single event, plays a critical role in driving genetic changes in PM. This process leads to the deletion of known tumor suppressor genes, including CDKN2A, NF2, and BAP1. These genes are believed to be among the earliest events in the development of PM. Furthermore, the presence of chromothripsis in PM tumors is associated with significantly poorer patient survival rates.

The study also uncovers a complex interplay between the mitochondrial and nuclear genomes during the evolution of PM. This involves alterations to both genomes, as well as changes in mitochondrial expression levels. These findings shed light on the multifaceted nature of PM, highlighting the importance of considering both the nuclear and mitochondrial genomes in understanding this devastating disease.