Phylogenetic Analysis of Cancer Evolution in Malignant Pleural Mesothelioma to Identify Driver Genes

Malignant Pleural Mesothelioma (MPM) is a rare type of cancer which occurs in the mesothelium of the lungs, and is characterised by a long latency period followed by a highly aggressive phase once fully developed. The initial tumour is the result of exposure to asbestos, and the prognosis is very poor once diagnosis has taken place. Currently, several genes have been associated with MPM, but no drivers have been identified via phylogenetic analysis. In order to identify potential driver genes which cause the cancer to mutate into its aggressive state, three distinct phylogenetic pipelines were established to process whole-exome sequencing data taken from 25 MPM patients from the MEDUSA cohort. The first pipeline used copy number calls generated from the patient cohort and incorporated them into a phylogenetic inference software in order to generate trees displaying the evolution of the cancer across 4-5 samples per patient. The second pipeline used single-nucleotide variations generated from the patient cohort and incoporated them into a second phylogenetic inference software to generate a different set of trees. The third pipeline used the output from the first in order to generate a third set of trees and establish an order of mutation for events found in the truncal regions of the first tree set. Each pipeline provided strong evidence for the Neurofibromin 2/Merlin (NF2) gene as a potential driver in the progression of the cancer from its latent state. This phylogenetic inference is among the first times such a method has been used for MPM, with the findings possibly revealing candidates for potential drug-targeting in the cancer.