Nat Commun: The clonal structure of malignant pleural mesothelioma can be used as a prognostic indicator and affect the tumor microenvironment

Malignant pleural mesothelioma (MPM) is a rare and incurable cancer.
Its incidence is still increasing globally.
The global annual incidence rate is 7 to 40 cases per million people, and there are approximately 38,400 deaths each year.

MPM is usually diagnosed 20-50 years after exposure to asbestos , and it is developing along an unknown evolutionary trajectory.
In the past two decades, there has been only very limited drug development for this commonly fatal cancer, and there is a lack of personalized treatment methods.

To clarify the intragenomic tumor heterogeneity (ITH) in MPM, the researchers performed multiregional exome sequencing on 90 tumor samples from 22 MPM patients obtained during surgery.

Genomic intratumoral heterogeneity of MPM

The researchers found that the heterogeneity within the exogenous tumor varies greatly across the entire cohort.
The phylogenetic tree model reflects the steep gradient of genome instability.
Through the migration learning model, the researchers detected repeated evolution and resolved 5 predictable clusters.

The clone structure shapes the immune microenvironment of MPM

BAP1/-3p21 and FBXW7/-chr4 events always occurred in early clones.
On the contrary, the NF2/-22q event that led to the inactivation of the Hippo pathway mainly occurred in the late cloning period, while the subcloning showed parallel evolution, indicating that evolution was restricted.
At 12 years after surgery, one patient had a very advanced somatic NF2/22q change.
The clone structure and evolution cluster determine the inflammatory response and immune escape of MPM.

All in all, the results of this study reveal the potential evolutionary bottleneck of drug-ready in MPM, as well as the influence of clonal structure on the shaping of immune pattern, and may determine the clinical response to immune checkpoint suppression.