Integrative genomic analysis of peritoneal malignant mesothelioma: understanding a case with extraordinary chemotherapy response

Abstract

Peritoneal malignant mesothelioma is a rare disease with a generally poor prognosis and poor response to chemotherapy. To improve survival there is a need for increased molecular understanding of the disease, including chemotherapy sensitivity and resistance. We here present an unusual case concerning a young woman with extensive peritoneal mesothelioma who had a remarkable response to palliative chemotherapy (platinum/pemetrexed). Tumor samples collected at surgery before and after treatment were analyzed on the genomic and transcriptional levels (exome sequencing, RNA-seq, and smallRNA-seq). Integrative analysis of single nucleotide and copy-number variants, mutational signatures, and gene expression was performed to provide a comprehensive picture of the disease. LATS1/2 were identified as the main mutational drivers together with homozygous loss of BAP1 and PBRM1, which also may have contributed to the extraordinary chemotherapy response. The presence of the S3 mutational signature is consistent with homologous recombination DNA repair defects due to BAP1 loss. Up-regulation of the PI3K/AKT/mTOR pathway after treatment, supported by deactivated PTEN through miRNA regulation, is associated with cancer progression and could explain chemotherapy resistance. The molecular profile suggests potential benefit from experimental targeting of PARP, EZH2, the PI3K/AKT/mTOR pathway and possibly also from immune checkpoint inhibition. In addition to providing the molecular background for this unusual case of peritoneal mesothelioma, the results show the potential value of integrative genomic analysis in precision medicine.