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.

We detected low levels of acetylation for histone H3 tail lysines in malignant mesothelioma (MM) cell lines resistant to histone deacetylase inhibitors. To identify the possible genetic causes related to the low histone acetylation levels, whole‐exome sequencing was conducted with MM cell lines established from eight patients. A mono‐allelic variant of BRD1 was common to two MM cell lines with very low acetylation levels. We identified 318 homozygous protein‐damaging variants/mutations (18–78 variants/mutations per patient); annotation analysis showed enrichment of the molecules associated with mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complexes and co‐activators that facilitate initiation of transcription. In seven of the patients, we detected a combination of variants in histone modifiers or transcription factors/co‐factors, in addition to variants in mSWI/SNF. Direct sequencing showed that homozygous mutations in SMARCA4, PBRM1 and ARID2 were somatic. In one patient, homozygous germline variants were observed for SMARCC1 and SETD2 in chr3p22.1–3p14.2. These exhibited extended germline homozygosity and were in regions containing somatic mutations, leading to a loss of BAP1 and PBRM1 expression in MM cell line. Most protein‐damaging variants were heterozygous in normal tissues. Heterozygous germline variants were often converted into hemizygous variants by mono‐allelic deletion, and were rarely homozygous because of acquired uniparental disomy. Our findings imply that MM might develop through the somatic inactivation of mSWI/SNF complex subunits and/or histone modifiers, including BAP1, in subjects that have rare germline variants of these transcription regulators and/or transcription factors/co‐factors, and in regions prone to mono‐allelic deletion during oncogenesis.

SUMMARY: There exists an urgent need to develop iterative risk assessment strategies of zoonotic diseases. The aim of this study is to develop a method of prioritizing 98 zoonoses derived from animal pathogens in Japan and to involve four major groups of stakeholders: researchers, physicians, public health officials, and citizens. We used a combination of risk profiling and analytic hierarchy process (AHP). Profiling risk was accomplished with semi-quantitative analysis of existing public health data. AHP data collection was performed by administering questionnaires to the four stakeholder groups. Results showed that researchers and public health officials focused on case fatality as the chief important factor, while physicians and citizens placed more weight on diagnosis and prevention, respectively. Most of the six top-ranked diseases were similar among all stakeholders. Transmissible spongiform encephalopathy, severe acute respiratory syndrome, and Ebola fever were ranked first, second, and third, respectively.

Malignant mesothelioma is associated with the exposure to asbestos fibers. Recent discovery of the BAP1 cancer syndrome, a Mendelian disorder with high-penetrance autosomal dominant inheritance fostered the genotyping for nucleotide-level or larger structural alteration of germline DNA. Inherited heterozygous mutations of the BAP1 gene increase the susceptibility to carcinogenic fibers, leading to a concept of gene x environment interaction (GxE) as a pathogenetic mechanism of mesothelioma. Several studies on cohorts of unselected patients with mesothelioma or on familial/early-onset cohorts of mesothelioma cases converged on BAP1 as the more frequent germline mutated gene, followed by other genes involved in DNA repair and homologous recombination. Evidence has been emerging that patients with mesothelioma carrying germline mutations of BAP1 and of other genes, such as those involved in DNA repair and tumor suppressor genes, have better prognosis and higher chemosensitivity when compared with patients with germline wildtype Bap1. We report here a germline genomic analysis targeted 22 genes in a cohort of 101 Japanese patients irrespective of asbestos exposure, age at diagnosis, or personal or family history of cancer. By comparing the results with the Human Genetic Variation Database (HGVD) and the Genome Aggregation Database (gnomAD) we selected rare germline variants with a Combined Annotation Dependent Depletion (CADD) >20. We show here that 31 of 101 subjects were carrying 25 rare variants in 14 genes, neither reported in the HGVD nor in the gnomAD database for 14/25 variants. Besides pathogenic variants of BAP1, rare missense variants were found in genes encoding lysine-specific histone methyltransferase SETD2 and SETDB1 and genes encoding subunits of the mSWI/SNF chromatin remodeling complex. The complete scenario of the genetic background consisting of pathogenic germline variants required for the predisposition and GxE for pathogenesis of mesothelioma appears complex, and further large-scale studies are warranted.

We report that ~1.8% of all mesothelioma patients and 4.9% of those younger than 55, carry rare germline variants of the BRCA1 associated RING domain 1 ( BARD1) gene that were predicted to be damaging by computational analyses. We conducted functional assays, essential for accurate interpretation of missense variants, in primary fibroblasts that we established in tissue culture from a patient carrying the heterozygous BARD1 ^V523A mutation. We found that these cells had genomic instability, reduced DNA repair, and impaired apoptosis. Investigating the underlying signaling pathways, we found that BARD1 forms a trimeric protein complex with p53 and SERCA2 that regulates calcium signaling and apoptosis. We validated these findings in BARD1 -silenced primary human mesothelial cells exposed to asbestos. Our study elucidated mechanisms of BARD1 activity and revealed that heterozygous germline BARD1 mutations favor the development of mesothelioma and increase the susceptibility to asbestos carcinogenesis. These mesotheliomas are significantly less aggressive compared to mesotheliomas in asbestos workers.