Mesothelioma developing in carriers of inherited genetic mutations

Abstract

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.

Genomic profiling of multiple primary cancers including synchronous lung adenocarcinoma and bilateral malignant mesotheliomas: Identification of a novel BAP1 germline variant

“…The identified variant in this case has not been previously reported in families with BAP1‐TPDS. A recent review by Yoshikawa et al 10 . described three out of 101 Japanese patients with malignant mesothelioma who had BAP1 germline variants, none of which was identical to the variant in the present case.…”

“…The identified variant in this case has not been previously reported in families with BAP1-TPDS. A recent review by Yoshikawa et al 10 none of which was identical to the variant in the present case. Although the patient had no melanocytic lesion, which is one of the hallmarks of BAP1-TPDS, complete loss of BAP1 expression in all cancers strongly suggests the pathogenicity of this variant.…”

Dysregulation of the Ubiquitin Proteasome System in Human Malignancies: A Window for Therapeutic Intervention

“…The tumor suppressor functions of BAP1 have been linked to its dual activity in the nucleus, where it has roles in DNA repair [ 80 , 81 ] and transcription [ 82 , 103 , 104 , 105 ], and regulation of cell death [ 83 , 106 ] and mitochondrial metabolism [ 107 , 108 ] in the cytoplasm. Being a tumor suppressor, loss of BAP1 through germline and somatic mutations has been directly linked to the predisposition of BAP1-mutated individuals to various malignancies including mesothelioma [ 109 , 110 , 111 , 112 , 113 , 114 ], uveal melanoma [ 115 , 116 ], cutaneous melanoma [ 117 ], and clear cell renal cell carcinoma [ 118 , 119 , 120 ]. Importantly, inherited BAP1 mutations in the form of truncating mutations have been detected in families with members diagnosed with mesothelioma, uveal melanoma, or breast cancer, suggesting a BAP1 familial cancer syndrome due to germline BAP1 mutations [ 109 , 121 , 122 , 123 ].…”

How to Better Understand the Influence of Host Genetics on Developing an Effective Immune Response to Thoracic Cancers

“…Elevation of the tumor mutational burden, enhanced antigen presentation and cellular immunity, and increased PD-L1 expression, are all correlated with the presence of ARID1A and ARID1B mutations; suggesting that mutated ARID1A and ARID1B could serve as novel biomarkers to predict sensitivity and prognosis to ICB in advanced NSCLC patients ( 55 ). Additionally, rare missense variants in genes encoding SWI/SNF chromatin remodeling components and genes encoding the histone methyl transferases, SETD2 and SETDB1 , were identified in a cohort of Japanese mesothelioma patients ( 56 ).…”