Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma

Angela Bononi; Keisuke Goto; Guntulu Ak; Yoshie Yoshikawa; Mitsuru Emi; Sandra Pastorino; Lorenzo Carparelli; Angelica Ferro; Masaki Nasu; Jin-Hee Kim; Joelle S. Suarez; Ronghui Xu; Mika Tanji; Yasutaka Takinishi; Michael Minaai; Flavia Novelli; Ian Pagano; Giovanni Gaudino; Harvey I. Pass; Joanna Groden; Joseph J. Grzymski; Muzaffer Metintas; Muhittin Akarsu; Betsy Morrow; Raffit Hassan; Haining Yang; Michele Carbone

doi:10.1073/pnas.2019652117

Edited by Webster K. Cavenee, Ludwig Institute for Cancer Research, La Jolla, CA, and approved November 11, 2020 (received for review September 17, 2020)

Significance

We found that the probability of carrying heterozygous germline BLM mutations is significantly higher among mesothelioma patients than in the general population. In vitro and in vivo experiments suggest that heterozygous BLM mutations increase susceptibility to mesothelioma. BLM-mutation carriers are at higher risk of developing mesothelioma, and their risk increases upon asbestos exposure. Therefore, BLM mutation carriers should benefit from prevention and screening for early detection. We suggest that genetic testing to identify carriers of BLM heterozygous mutations and genetic counseling would help identify individuals at higher risk of mesothelioma and provide mutation carriers the option to implement simple preventive measures to reduce exposure to asbestos and other carcinogenic fibers to decrease their risk of developing 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.

Footnotes

↵¹A.B., K.G., G.A., Y.Y. contributed equally to this work.
↵²To whom correspondence may be addressed. Email: haining{at}hawaii.edu or mcarbone{at}cc.hawaii.edu.

Author contributions: A.B., H.Y., and M.C. designed research; A.B., K.G., G.A., Y.Y., L.C., A.F., M.N., J.-H.K., J.S.S., R.X., M.T., F.N., J.J.G., and M.A. performed research; G.A., Y.Y., H.I.P., J.G., J.J.G., M.M., B.M., and R.H. contributed new reagents/analytic tools; A.B., Y.Y., M.E., S.P., M.N., J.-H.K., J.S.S., Y.T., M.M., I.P., G.G., J.J.G., M.M., B.M., R.H., H.Y., and M.C. analyzed data; and A.B., H.Y., and M.C. wrote the paper.
Competing interest statement: M.C. and H.Y. have grants from the NIH, National Cancer Institute, the US Department of Defense, and the UH Foundation through donations to support research on “Pathogenesis of Malignant Mesothelioma” from Honeywell International Inc, Riviera United‐4‐a Cure, and the Maurice and Joanna Sullivan Family Foundation. M.C. has a patent issued for BAP1. M.C and H.Y. have a patent issued for “Using Anti‐HMGB1 Monoclonal Antibody or other HMGB1 Antibodies as a Novel Mesothelioma Therapeutic Strategy” and a patent issued for “HMGB1 As a Biomarker for Asbestos Exposure and Mesothelioma Early Detection.” M.C. is a board‐certified pathologist who provides consultation for mesothelioma expertise and diagnosis. H.I.P. has funding from the National Cancer Institute, the Department of Defense, the Center for Disease Control, Genentech, and Belluck and Fox. R.H. has received funding for conduct of clinical trials via a cooperative research and development agreement between the National Cancer Institute and Bayer AG, Aduro BioTech, TCR2 Therapeutics, and Morphotek Inc. His work is supported NIH Intramural Award BC010816. Eskisehir Osmangazi University funded the study for the whole-genome sequencing analyses of Turkish people. G.A., M.A., A.B, B.M., K.G., S.P., L.C., A.F., M.N., J.S.S., R. X., M.T., Y.T., M.M., M.M., F.N., G.G., M.E., Y.Y., have nothing to disclose.
This article is a PNAS Direct Submission.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2019652117/-/DCSupplemental.