Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma.
Heterozygous germline BLM mutations increase susceptibility to asbestos and mesothelioma.
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DOI：
10.1073/pnas.2019652117
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发表时间：
2020-12-29
影响因子：
11.1
通讯作者：
Carbone M
中科院分区：
文献类型：
--
作者：
Bononi A;Goto K;Ak G;Yoshikawa Y;Emi M;Pastorino S;Carparelli L;Ferro A;Nasu M;Kim JH;Suarez JS;Xu R;Tanji M;Takinishi Y;Minaai M;Novelli F;Pagano I;Gaudino G;Pass HI;Groden J;Grzymski JJ;Metintas M;Akarsu M;Morrow B;Hassan R;Yang H;Carbone M
我们发现间皮瘤患者携带杂合子种系BLM突变的概率明显高于一般人群。体外和体内实验表明，杂合BLM突变增加间皮瘤的易感性。blm突变携带者患间皮瘤的风险较高，接触石棉后风险增加。因此，BLM突变携带者应该从预防和早期发现筛查中获益。我们建议，通过基因检测来识别BLM杂合突变携带者和遗传咨询，将有助于识别间皮瘤高风险个体，并为突变携带者提供选择，采取简单的预防措施，减少接触石棉和其他致癌纤维，以降低他们患间皮瘤的风险。罕见的双等位基因BLM突变导致布鲁姆综合征。BLM杂合种系突变（BLM+/−）是否会导致人类癌症尚不清楚。我们对155例间皮瘤患者（33例家族性和122例散发性）的种系DNA进行了测序。我们在33例间皮瘤多发病例的2个家族中发现了2个有害的种系BLM+/−突变，一个来自土耳其（c.569_570del; p.R191Kfs*4），一个来自美国（c.968A>G; p.K323R）。一些遗传了这些突变的亲属患上了间皮瘤，而没有突变的BLM的亲属则没有受到影响。此外，在美国国家癌症研究所治疗的122例散发性间皮瘤患者中，5例携带致病性种系BLM+/−突变。因此，155例明显不相关的间皮瘤患者中有7例携带BLM+/ -突变，显著高于gnomAD数据库中一般不相关人群的预期频率（P = 6.7E-10）， 7例中有2例携带相同的错义致病突变c.968A>G （P = 0.0017，假设等位基因频率为0.00039）。在Blm+/−小鼠的原代间皮细胞和人的原代间皮细胞中进行的实验表明，Blm水平的降低可促进基因组不稳定性，同时保护细胞免于死亡，并促进TNF-α的释放。腹腔注射石棉的Blm+/−小鼠的促炎M1巨噬细胞和腹腔灌洗液中TNF-α、IL-1β、IL-3、IL-10和IL-12水平较高，这些发现与石棉致癌有关。与对照组相比，暴露于石棉的Blm+/−小鼠的生存期明显缩短，间皮瘤的发病率更高。我们认为种系BLM+/−突变增加了对石棉致癌的易感性，增加了发生间皮瘤的风险。
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. 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.
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影响因子：
11.2
作者：
Kadariya Y;Cheung M;Xu J;Pei J;Sementino E;Menges CW;Cai KQ;Rauscher FJ;Klein-Szanto AJ;Testa JR
通讯作者：
Testa JR
影响因子：
11.2
作者：
Mao FJ;Sidorova JM;Lauper JM;Emond MJ;Monnat RJ
通讯作者：
Monnat RJ
影响因子：
8.8
作者：
Baughman JM;Rose CM;Kolumam G;Webster JD;Wilkerson EM;Merrill AE;Rhoads TW;Noubade R;Katavolos P;Lesch J;Stapleton DS;Rabaglia ME;Schueler KL;Asuncion R;Domeyer M;Zavala-Solorio J;Reich M;DeVoss J;Keller MP;Attie AD;Hebert AS;Westphall MS;Coon JJ;Kirkpatrick DS;Dey A
通讯作者：
Dey A
影响因子：
28.2
作者：
Carbone M;Harbour JW;Brugarolas J;Bononi A;Pagano I;Dey A;Krausz T;Pass HI;Yang H;Gaudino G
通讯作者：
Gaudino G
影响因子：
11.4
作者：
Chan, Kok-Lung;North, Phillip S.;Hickson, Ian D.
通讯作者：
Hickson, Ian D.