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

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

Publication date: Mar 12, 2019

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 de-activated 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.

Lund-Andersen, C., Nakken, S., Nygard, S., Fromm, B., Aasheim, L.B., Davidson, B., Julsrud, L., Abrahamsen, T.W., Kristensen, A.T., Dybdahl, B., Larsen, S.G., Hovig, E., and Flatmark, K. Integrative genomic analysis of peritoneal malignant mesothelioma: Understanding a case with extraordinary chemotherapy response. 04213. 2019 Cold Spring Harb Mol Case Stud.

Concepts Keywords
AKT Chemotherapy
Chemotherapy Recombination
Cold Spring PTEN
Copy Number Variants Peritoneal mesothelioma
Exome Pemetrexed
EZH2 Mesothelioma
Homologous Recombination Cancer research
Homozygous Oncology
Mesothelioma Signal transduction
MiRNA Proteins
MTOR Occupational diseases
Nucleotide Enzymes
PARP Cancer
Pemetrexed Branches of biology
Peritoneal Chemotherapy
Peritoneal Mesothelioma Surgery
PI3K Extensive peritoneal mesothelioma
Platinum Tumor
Precision Medicine Molecular understanding disease
Prognosis Peritoneal malignant mesothelioma
PTEN
RNA Seq
Sequencing

Semantics

Type Source Name
gene UNIPROT EZH2
gene UNIPROT COL11A2
gene UNIPROT PARP1
gene UNIPROT PTEN
disease DOID cancer
gene UNIPROT MTOR
gene UNIPROT AKT1
gene UNIPROT PIK3CG
gene UNIPROT PIK3CD
gene UNIPROT PIK3CB
gene UNIPROT PIK3CA
disease MESH defects
pathway BSID DNA Repair
pathway BSID Homologous Recombination
pathway BSID Homologous recombination
gene UNIPROT PBRM1
gene UNIPROT MAGI1
gene UNIPROT BAP1
gene UNIPROT RNF2
gene UNIPROT LATS1
pathway BSID Gene Expression
disease MESH Tumor
drug DRUGBANK Pemetrexed
drug DRUGBANK Platinum
disease DOID peritoneal mesothelioma
disease MESH rare disease
disease DOID malignant mesothelioma

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