Heterozygous germline <i>BLM</i> mutations increase susceptibility to asbestos and mesothelioma.
Abstact
Rare biallelic <i>BLM</i> gene mutations cause Bloom syndrome. Whether <i>BLM</i> heterozygous germline mutations (<i>BLM</i><sup>+/-</sup>) cause human cancer remains unclear. We sequenced the germline DNA of 155 mesothelioma patients (33 familial and 122 sporadic). We found 2 deleterious germline <i>BLM</i><sup>+/-</sup> 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 <i>BLM</i> were affected. Furthermore, among 122 patients with sporadic mesothelioma treated at the US National Cancer Institute, 5 carried pathogenic germline <i>BLM</i><sup>+/-</sup> mutations. Therefore, 7 of 155 apparently unrelated mesothelioma patients carried <i>BLM</i><sup>+/-</sup> mutations, significantly higher (<i>P</i> = 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 (<i>P</i> = 0.0017 given a 0.00039 allele frequency). Experiments in primary mesothelial cells from <i>Blm</i><sup>+/-</sup> mice and in primary human mesothelial cells in which we silenced <i>BLM</i> revealed that reduced BLM levels promote genomic instability while protecting from cell death and promoted TNF-α release. <i>Blm</i><sup>+/-</sup> 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. <i>Blm</i><sup>+/-</sup> mice exposed to asbestos had a significantly shorter survival and higher incidence of mesothelioma compared to controls. We propose that germline <i>BLM</i><sup>+/-</sup> mutations increase the susceptibility to asbestos carcinogenesis, enhancing the risk of developing mesothelioma.
Authors
- Ak G
- Akarsu M
- Bononi A
- Carbone M
- Carparelli L
- Emi M
- Ferro A
- Gaudino G
- Goto K
- Groden J
- Grzymski JJ
- Hassan R
- Kim JH
- Metintas M
- Minaai M
- Morrow B
- Nasu M
- Novelli F
- Pagano I
- Pass HI
- Pastorino S
- Suarez JS
- Takinishi Y
- Tanji M
- Xu R
- Yang H
- Yoshikawa Y