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.In the United States, the incidence rate of mesothelioma varies between fewer than one case per 100,000 persons in states with no asbestos industry to two to three cases per 100,000 persons in states with an asbestos industry (
1,
2). Asbestos causes DNA damage and apoptosis (
3) and promotes a chronic inflammatory reaction that supports the emergence of malignant cells (
4). Fortunately, only a small fraction of exposed individuals develop mesothelioma; for example, 4.6% of deaths in miners who worked in asbestos mines for over 10 y were caused by mesothelioma (
1). Therefore, multiple cases of mesothelioma in the same family are rare and suggest genetic predisposition (
5). In 2001, we discovered that susceptibility to mesothelioma was transmitted in a Mendelian fashion across multiple generations in some Turkish families exposed to the carcinogenic fiber erionite, pointing to gene × environment interaction (G×E) as the cause (
6). In 2011, we discovered that carriers of heterozygous germline
BRCA1-associated protein–1 (
BAP1) mutations (
BAP1+/−) developed mesothelioma and uveal melanoma (
5), findings expanded and confirmed by us and by multiple research teams (reviewed in refs.
1,
7,
8). Moreover, heterozygous germline
Bap1 mutations (
Bap1+/−) significantly increased susceptibility to asbestos-induced mesothelioma in mice (
9,
10), evidence of G×E. Reduced BAP1 levels impair DNA repair (
11) as well as different forms of cell death (
3,
12) and induce metabolic alterations (
13–
15) that together favor cancer development and growth.Recent studies revealed that mesothelioma may also develop among carriers of germline mutations of additional tumor-suppressor genes that cause well-defined cancer syndromes, including
MLH1 and
MLH3 (Lynch syndrome),
TP53 (Li–Fraumeni syndrome), and
BRCA1-2 (Breast and Ovarian Cancer syndrome) (
16,
17). When all germline mutations are combined, it has been estimated that about 12% of mesotheliomas occur in carriers of heterozygous germline mutations of
BAP1, the most frequent mutation among patients with mesothelioma, or of other tumor suppressors. Some of these mutations may sensitize the host to asbestos carcinogenesis, according to a G×E scenario (
17). Thus, presently, mesothelioma is considered an ideal model to study G×E in cancer (
17). As part of the Healthy Nevada Project (HNP), we are studying G×E in northern Nevada, a region with an unusually high risk of exposure to carcinogenic minerals and arsenic, which may be related to the high cancer rates in this region (
18). We are investigating genetic variants that may increase cancer risk upon exposure to carcinogens to implement preventive strategies.Biallelic mutations of the Bloom syndrome gene (
BLM) cause Bloom syndrome, an autosomal-recessive tumor predisposition syndrome characterized by pre- and postnatal growth deficiency, photosensitivity, type 2 diabetes, and greatly increased risk of developing various types of cancers.
BLM is a RecQ helicase enzyme that modulates DNA replication and repair of DNA damage by homologous recombination (
19). In patients affected by Bloom syndrome, the absence of the BLM protein causes chromosomal instability, increased number of sister chromatid exchanges, and increased numbers of micronuclei (
20–
22). In addition, BLM is required for p53-mediated apoptosis (
23), a process critical to eliminate cells that have accumulated DNA damage. Impaired DNA repair together with altered apoptosis resulted in increased cancer incidence (
17,
24). Of course, inactivating germline
BLM heterozygous (
BLM+/−) mutations are much more common than biallelic
BLM (
BLM−/−) mutations, with an estimated frequency in the general population of 1 in 900 based on data from the Exome Aggregation Consortium (
25).
BLM+/− mutation carriers do not show an obvious phenotype; however, some studies have suggested that carriers of these mutations may have an increased cancer risk (
17,
24). Mice carrying
Blm+/− mutations are prone to develop a higher rate of malignancies in the presence of contributing factors, such as concurrent heterozygous mutations of the adenomatous polyposis coli (
Apc) gene, or upon infection with murine leukemia virus (
26). However, in studies in which
Blm+/− mice were crossed with tuberous sclerosis 1-deficient (
Tsc1+/−) mice that are predisposed to renal cystadenomas and carcinomas, Wilson et al. found that
Tsc1+/− Blm+/− mice did not show significantly more renal cell carcinomas compared with
Tsc1+/− BlmWT mice (
27). In humans, a large study involving 1,244 patients with colon cancer and 1,839 controls of Ashkenazi Jewish ancestry, in which
BLM+/− frequency is as high as 1 in 100 individuals (
28), suggested that carriers of germline
BLM+/− mutations might have a twofold increase in colorectal cancer (CRC) (
29). A smaller study did not confirm these results, but reported a trend of increasing incidence of adenomas—premalignant lesions—among
BLM+/− mutation carriers (
30). In addition,
BLM+/− mutations were found overrepresented among early-onset (<45 y old) CRC patients (
25). Other studies associated
BLM+/− mutations to an increased risk of breast (
31,
32) and prostate cancer (
33), but the low power of these studies hampered definite conclusions. In summary, it appears possible that
BLM+/− mutations may increase cancer risk in the presence of contributing factors.
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