Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy

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.

Keywords: BAP1; DNA repair genes; inherited genetics; mesothelioma; survival.

Fig. 1.

Inherited mutations in mesothelioma. (A) Genes with inherited damaging mutations in patients with malignant mesothelioma from the NCI series. (B) Somatic mutations in tumors from mesothelioma patients with inherited mutations in BAP1. LOH is loss of heterozygosity at BAP1. Dark red boxes represent truncating mutations; pink boxes represent missense mutations, in-frame deletions, or LOH. (C) BAP1 protein, indicating functional domains and sites of mutations in mesothelioma patients and their tumors. (D) History of cancer other than mesothelioma in patients with inherited BAP1 mutations versus patients with no inherited mutation. (E) History of cancer in parents, siblings, or children of patients with inherited BAP1 mutations versus patients with no inherited mutation.

Fig. 2.

Survival of patients with mesothelioma treated with platinum chemotherapy, by patient’s genotype and primary site of tumor. Survival of patients with an inherited damaging mutation in any targeted gene is indicated in blue; survival of patients with no inherited mutation is indicated in red. (A) All mesothelioma patients with versus without inherited mutations. Median survival: 8.0 vs. 2.9 y, P = 0.0006. (B) Pleural mesothelioma patients with versus without inherited mutations. Median survival: 7.9 vs. 2.4 y, P = 0.0012. (C) Peritoneal mesothelioma patients with versus without inherited mutation. Median survival: 8.2 vs. 5.4 y, P = 0.47.