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

Our plain-English summary of Integrative genomic analysis of peritoneal malignant mesothelioma: understanding a case with extraordinary chemotherapy response, by C. Lund-Andersen, S. Nakken, S. Nygård, et al (Cold Spring Harbor Molecular Case Studies, 2019).

The study

• Authors: C. Lund-Andersen, S. Nakken, S. Nygård, B. Fromm, L.B. Aasheim, B. Davidson, L. Julsrud, T.W. Abrahamsen, A.T. Kristensen, B. Dybdahl, S.G. Larsen, E. Hovig, K. Flatmark
• Journal: Cold Spring Harbor Molecular Case Studies
• Published: 2019;5(2)
• Type of article: Case report
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2019 Lund-Andersen et al.; Published by Cold Spring Harbor Laboratory Press.

In plain English

This case report from Oslo University Hospital, Norway, described a 19-year-old woman with no known asbestos exposure. In 2013 she was diagnosed with widespread, inoperable malignant peritoneal mesothelioma, epithelioid subtype. Platinum/pemetrexed chemotherapy produced an excellent clinical and radiological response. Her peritoneal cancer index fell from 39 at diagnosis to 16 at surgery in 2015. By 2018 her disease was progressing. The authors analyzed the genes of tumor samples taken before and after chemotherapy. They found 121 somatic mutations before treatment and 429 after. Both samples had mutations in LATS1 and LATS2, loss of both copies of the BAP1 and PBRM1 genes, and a DNA-repair-related mutational signature (S3). After treatment, the PI3K/AKT/mTOR pathway showed increased activity, and immune-cell markers such as CD8 were more highly expressed. The authors concluded that LATS1/2 were the main mutational drivers together with loss of BAP1 and PBRM1, which may have contributed to the chemotherapy response. They also concluded that the tumor's profile suggested possible benefit from experimental drugs targeting PARP, EZH2 or the PI3K/AKT/mTOR pathway, and possibly from immune checkpoint inhibition.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: case report with genomic and transcriptional analysis (exome sequencing, RNA sequencing, small RNA sequencing) of tumor samples taken before and after chemotherapy
• Who was studied: one 19-year-old woman with disseminated malignant peritoneal mesothelioma, epithelioid subtype, diagnosed in 2013 and treated at Oslo University Hospital, Norway; tumor samples taken in 2013 (T1) and 2015 (T2)
• Exposure: No known asbestos exposure. The treatment studied was palliative chemotherapy: cisplatin-pemetrexed (10 cycles), carboplatin-pemetrexed (6 cycles) and carboplatin alone (2 cycles). This was followed by surgery with hyperthermic intraperitoneal chemotherapy (cisplatin and doxorubicin).
• Main results:
  • At first surgery the disease was unresectable, with a peritoneal cancer index of 39
  • After chemotherapy, laparotomy in 2015 showed a peritoneal cancer index of 16
  • Exome sequencing found 121 somatic variants in the pre-treatment sample (T1) and 429 in the post-treatment sample (T2)
  • No cancer-relevant inherited (germline) mutations were found
  • LATS1 and LATS2 were mutated in both tumor samples
  • Both samples showed total (homozygous) loss of BAP1 and PBRM1
  • A mutational signature associated with failure of homologous recombination DNA repair and with response to platinum therapy (S3) was found in both samples
  • Tumor mutational burden was low: 0.87 mutations per megabase in T1 and 3.82 in T2
  • RNA sequencing found 6228 genes expressed differently after treatment, of which 51% were down-regulated
  • After treatment the PI3K/AKT/mTOR pathway showed increased activity
  • CD8, a marker of cytotoxic T-cells, was threefold up-regulated in T2 (adjusted P = 0.03)
  • 139 microRNAs differed at least twofold in T2 compared with T1: 19 up-regulated and 120 down-regulated
• The authors' conclusion: The authors concluded that LATS1/2 were the main mutational drivers together with total loss of BAP1 and PBRM1, which may also have contributed to the extraordinary chemotherapy response. They also concluded that the molecular profile suggests potential benefit from experimental targeting of PARP, EZH2 and the PI3K/AKT/mTOR pathway, and possibly from immune checkpoint inhibition.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Chemotherapy, Prognosis, Peritoneal Mesothelioma, Palliative Care, Pemetrexed (Alimta), BAP1.

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