气候变化领域集成服务门户(CCPortal): Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma

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DOI	10.1073/PNAS.2019652117
	Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma
	Bononi A.; Goto K.; Ak G.; Yoshikawa Y.; Emi M.; Pastorino S.; Carparelli L.; Ferro A.; Nasu M.; Kim J.-H.; Suarez J.S.; Xu R.; Tanji M.; Takinishi Y.; Minaai M.; Novelli F.; Pagano I.; Gaudino G.; Pass H.I.; Groden J.; Grzymski J.J.; Metintas M.; Akarsu M.; Morrow B.; Hassan R.; Yang H.; Carbone M.
发表日期	2021
ISSN	00278424
起始页码	33466
结束页码	33473
卷号	117 期号:52
英文摘要	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. © 2020 National Academy of Sciences. All rights reserved.
英文关键词	Asbestos; BLM; Genetics; Gene–environment; Mesothelioma
语种	英语
scopus关键词	Bloom syndrome helicase; crocidolite; RecQ helicase; adult; aged; animal; asbestosis; family; female; genetic predisposition; genetics; genomic instability; germline mutation; heterozygote; human; incidence; inflammation; male; mesothelioma; middle aged; mouse; pathology; Adult; Aged; Animals; Asbestos, Crocidolite; Asbestosis; Family; Female; Genetic Predisposition to Disease; Genomic Instability; Germ-Line Mutation; Heterozygote; Humans; Incidence; Inflammation; Male; Mesothelioma; Mice; Middle Aged; RecQ Helicases
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179667
作者单位	Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI 96813, United States; Department of Urology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, 739-8511, Japan; Lung and Pleural Cancers Research and Clinical Center, Eskisehir Osmangazi University, Eskisehir, 26040, Turkey; Department of Genetics, Hyogo College of Medicine, Hyogo, 663-8501, Japan; Department of Cardiovascular Surgery, New York University, New York, NY 10016, United States; VC Research, University of Illinois, Chicago, IL 60607, United States; Center for Genomic Medicine, Desert Research Institute and Renown Health, Reno, NV 89512, United States; Department of Chest Disease, Eskisehir City Hospital, Eskisehir, 26080, Turkey; Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, United States
推荐引用方式 GB/T 7714	Bononi A.,Goto K.,Ak G.,et al. Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma[J],2021,117(52).
APA	Bononi A..,Goto K..,Ak G..,Yoshikawa Y..,Emi M..,...&Carbone M..(2021).Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma.Proceedings of the National Academy of Sciences of the United States of America,117(52).
MLA	Bononi A.,et al."Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma".Proceedings of the National Academy of Sciences of the United States of America 117.52(2021).