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Targeted Next-Generation Sequencing Reveals a High Number of Genomic Mutations in Advanced Malignant Plural Mesothelioma

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Key Points

  • Mutations were clustered in two main pathways: p53/DNA repair and PI3K-AKT.
  • Mutations within the PIK3CA, STK11, or TP53 genes were associated with a decreased time to disease progression.
  • A genomic mutation in the BAP1 gene correlated with nuclear localization of the BAP1 protein.

Next-generation sequencing in malignant pleural mesothelioma tumors shows a complex mutational setting with a high number of genetic alterations in genes involved in DNA repair, cell survival, and cell proliferation pathways, according to a study by Lo Iacono et al in the Journal of Thoracic Oncology. Increased accumulation of mutations correlated with early progression of the tumor and decreased survival.

Malignant pleural mesothelioma is a fatal cancer associated with asbestos exposure that develops on the outer linings of the lungs. The 3-year survival rate is only 8%, and most patients are diagnosed with late-stage disease with limited therapeutic options. The use of next-generation sequencing has the potential to accurately describe the type, location, and number of genetic mutations in malignant pleural mesothelioma and allow for associations with patient characteristics, including survival data.

Study Details

Researchers from University of Torino, Orbassano, Italy, and Saint Antonio and Biagio General Hospital, Alessandria, Italy, used targeted next-generation sequencing to retrospectively sequence 52 genes in 123 patients with advanced (stage III and IV) malignant pleural mesothelioma and complete clinical information. Sequencing was conducted on genomic DNA isolated from archival formalin-fixed paraffin-embedded tumor tissue. Sanger sequencing was used to validate the next-generation sequencing results, and immunohistochemistry was used to examine the protein expression for two of the genes.

The findings demonstrated that the mutations clustered in two main pathways: p53/DNA repair and PI3K-AKT. Certain mutations within the PIK3CA, STK11, or TP53 genes were associated with a decreased time to disease progression. Additionally, there was a decrease in the time to disease progression and overall survival when there was an accumulation of multiple mutations. Finally, genomic mutation in the BAP1 gene, which resulted in amino acids changes within the BAP1 protein, correlated with nuclear localization of the BAP1 protein.

Concluding Thoughts

“Our results show that next-generation sequencing is clearly feasible despite the very well-known challenges of fragmented and low-yield genomic DNA isolated from formalin-fixed paraffin-embedded tumor tissue,” said the authors. “Our data did not identify any specific mutation as a single driver gene, as found in adenocarcinoma of the lung, however our data suggests that in malignant pleural mesothelioma there is an accumulation of several nondriver mutations, which may explain the extremely long latency phase of this asbestos-related disease.”

For the future, the authors suggested that “some of the mutations will further be assessed for functional changes and could be carefully considered as stratification factors for future clinical trials investigating the role of targeted-therapies in malignant pleural mesothelioma.”

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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