Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy

Raffit Hassan, Betsy Morrow, Anish Thomas, Tom Walsh, Ming K Lee, Suleyman Gulsuner, Meghana Gadiraju, Vasiliki Panou, Shaojian Gao, Idrees Mian, Javed Khan, Mark Raffeld, Snehal Patel, Liqiang Xi, Jun S Wei, Mary Hesdorffer, Jingli Zhang, Kathleen Calzone, Arpita Desai, Emerson PadiernosChristine Alewine, David S Schrump, Seth M Steinberg, Hedy L Kindler, Mary-Claire King, Jane E Churpek

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22 Citations (Scopus)

Abstract

Survival from malignant mesothelioma, particularly pleural mesothelioma, is very poor. For patients with breast, ovarian, or prostate cancers, overall survival is associated with increased sensitivity to platinum chemotherapy due to loss-of-function mutations in DNA repair genes. The goal of this project was to evaluate, in patients with malignant mesothelioma, the relationship between inherited loss-of-function mutations in DNA repair and other tumor suppressor genes and overall survival following platinum chemotherapy. Patients with histologically confirmed malignant mesothelioma were evaluated for inherited mutations in tumor suppressor genes. Survival was evaluated with respect to genotype and site of mesothelioma. Among 385 patients treated with platinum chemotherapy, median overall survival was significantly longer for patients with loss-of-function mutations in any of the targeted genes compared with patients with no such mutation (P = 0.0006). The effect of genotype was highly significant for patients with pleural mesothelioma (median survival 7.9 y versus 2.4 y, P = 0.0012), but not for patients with peritoneal mesothelioma (median survival 8.2 y versus 5.4 y, P = 0.47). Effect of patient genotype on overall survival, measured at 3 y, remained independently significant after adjusting for gender and age at diagnosis, two other known prognostic factors. Patients with pleural mesothelioma with inherited mutations in DNA repair and other tumor suppressor genes appear to particularly benefit from platinum chemotherapy compared with patients without inherited mutations. These patients may also benefit from other DNA repair targeted therapies such as poly-ADP ribose polymerase (PARP) inhibitors.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number18
Pages (from-to)9008-9013
Number of pages6
ISSN0027-8424
DOIs
Publication statusPublished - 30 Apr 2019

Keywords

  • BAP1
  • DNA repair genes
  • Mesothelioma
  • Nherited genetics
  • Survival |

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    Hassan, R., Morrow, B., Thomas, A., Walsh, T., Lee, M. K., Gulsuner, S., Gadiraju, M., Panou, V., Gao, S., Mian, I., Khan, J., Raffeld, M., Patel, S., Xi, L., Wei, J. S., Hesdorffer, M., Zhang, J., Calzone, K., Desai, A., ... Churpek, J. E. (2019). Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy. Proceedings of the National Academy of Sciences of the United States of America, 116(18), 9008-9013. https://doi.org/10.1073/pnas.1821510116