Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma

Abstract

Rare biallelic BLM gene mutations cause Bloom syndrome. Whether BLM heterozygous germline mutations (BLM+/−) cause human cancer remains unclear. We sequenced the germline DNA of 155 mesothelioma patients (33 familial and 122 sporadic). We found 2 deleterious germline BLM+/− mutations within 2 of 33 families with multiple cases of mesothelioma, one from Turkey (c.569_570del; p.R191Kfs*4) and one from the United States (c.968A>G; p.K323R). Some of the relatives who inherited these mutations developed mesothelioma, while none with nonmutated BLM were affected. Furthermore, among 122 patients with sporadic mesothelioma treated at the US National Cancer Institute, 5 carried pathogenic germline BLM+/− mutations. Therefore, 7 of 155 apparently unrelated mesothelioma patients carried BLM+/− mutations, significantly higher (P = 6.7E-10) than the expected frequency in a general, unrelated population from the gnomAD database, and 2 of 7 carried the same missense pathogenic mutation c.968A>G (P = 0.0017 given a 0.00039 allele frequency). Experiments in primary mesothelial cells from Blm+/− mice and in primary human mesothelial cells in which we silenced BLM revealed that reduced BLM levels promote genomic instability while protecting from cell death and promoted TNF-α release. Blm+/− mice injected intraperitoneally with asbestos had higher levels of proinflammatory M1 macrophages and of TNF-α, IL-1β, IL-3, IL-10, and IL-12 in the peritoneal lavage, findings linked to asbestos carcinogenesis. Blm+/− mice exposed to asbestos had a significantly shorter survival and higher incidence of mesothelioma compared to controls. We propose that germline BLM+/− mutations increase the susceptibility to asbestos carcinogenesis, enhancing the risk of developing mesothelioma.

Durvalumab with platinum-pemetrexed for unresectable pleural mesothelioma: survival, genomic and immunologic analyses from the phase 2 PrE0505 trial

“…BAP1, a nuclear ubiquitin carboxyterminal hydrolase, has been reported to be frequently mutated in the germline and tumor cells of patients with MPM 17,18,20 . Heterozygous germline BAP1 alterations predispose to mesothelioma, especially in the context of asbestos exposure 21 , and, similarly, germline BLM mutations might increase susceptibility to asbestos carcinogenesis and emergence of mesothelioma 22 . Inactivation of tumor suppressor genes, such as BAP1, NF2, CDKN2A, TP53 and SETD2, by sequence or structural alterations, is thought to be the predominant oncogenic mechanism for MPM 17 .…”

Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma

“…Interestingly, a recent study has revealed that BAP1 is not the only cancer-susceptibility-gene predisposing to mesothelioma. Bononi et al have shown that heterozygous mutations in the Bloom syndrome gene (BLM), a gene involved in the DNA repair, promote the development of mesothelioma and the risk is further increased by exposure to asbestos (122).…”

“…Bononi et al. have shown that heterozygous mutations in the Bloom syndrome gene ( BLM ), a gene involved in the DNA repair, promote the development of mesothelioma and the risk is further increased by exposure to asbestos ( 122 ).…”

Incidence, mortality and survival in malignant pleural mesothelioma before and after asbestos in Denmark, Finland, Norway and Sweden

“…The estimated proportion of MPM caused by asbestos is at 80% or more [ 3 – 5 ]. Other possible causes or contributing factors include family history and related germline gene mutations (such BAP1 and BML), and exposure to erionite fibers in Turkey [ 6 – 10 ]. MPM is a fatal disease for which survival ranges between 4 and 12 months and for which unimodal or multimodal treatment is usually of little benefit [ 9 ].…”