Mesothelioma: Scientific clues for prevention, diagnosis, and therapy

Abstract

Mesothelioma affects mostly older individuals who have been occupationally exposed to asbestos. The global mesothelioma incidence and mortality rates are unknown, because data are not available from developing countries that continue to use large amounts of asbestos. The incidence rate of mesothelioma has decreased in Australia, the United States, and Western Europe, where the use of asbestos was banned or strictly regulated in the 1970s and 1980s, demonstrating the value of these preventive measures. However, in these same countries, the overall number of deaths from mesothelioma has not decreased as the size of the population and the percentage of old people have increased. Moreover, hotspots of mesothelioma may occur when carcinogenic fibers that are present in the environment are disturbed as rural areas are being developed. Novel immunohistochemical and molecular markers have improved the accuracy of diagnosis; however, about 14% (high-resource countries) to 50% (developing countries) of mesothelioma diagnoses are incorrect, resulting in inadequate treatment and complicating epidemiological studies. The discovery that germline BRCA1-asssociated protein 1 (BAP1) mutations cause mesothelioma and other cancers (BAP1 cancer syndrome) elucidated some of the key pathogenic mechanisms, and treatments targeting these molecular mechanisms and/or modulating the immune response are being tested. The role of surgery in pleural mesothelioma is controversial as it is difficult to predict who will benefit from aggressive management, even when local therapies are added to existing or novel systemic treatments. Treatment outcomes are improving, however, for peritoneal mesothelioma. Multidisciplinary international collaboration will be necessary to improve prevention, early detection, and treatment.

Keywords: BRCA1-associated protein 1 (BAP1); asbestos; cancer syndromes; chromothripsis; gene-environment interaction; immunotherapy; mesothelioma.

FIGURE 1.

Several Asbestos Fibers Seen Inside Lung Alveoli. The biopsy is from a patient with mesothelioma who worked for “Eternit,” an Italian cement factory that was the major producer of cement-containing asbestos in Europe (both crocidolite and chrysotile were used to make cement) (original magnification ×200; Inset: ×1000).

FIGURE 2.

Histology and Immunohistochemistry of Mesotheliomas in Different Species. (Left Column) Hematoxylin and eosin (H & E) staining and (Right Column) immunohistochemistry for cytokeratin Cam5.2 and cytokeratin AE1/AE3 are shown. B indicates bird; C, cat; D, dog; H, horse; L, lion. Original magnification as indicated. These histologies are indistinguishable from those seen in human mesothelioma.

FIGURE 3.

BAP1 Controls Distinct Cellular Activities by Modulating DNA Repair and Ca²⁺ Intracellular Levels. In the nucleus, BRCA1-associated protein 1 (BAP1) regulates DNA repair. Increased DNA damage is observed in BAP1-mutant cells after exposure to asbestos, ultraviolet light, radiation, and chemotherapy. Similar results are observed in cells in which BAP1 levels are reduced using small-interfering RNA technology. In the cytoplasm, BAP1 deubiquitylates and thus stabilizes the IP3R3 receptor channel that regulates Ca²⁺ transfer from the endoplasmic reticulum (ER), in which Ca²⁺ is normally stored in the cell, to the cytoplasm. Ca²⁺ is released in areas of the ER that are in close contact with the mitochondrial outer membrane: these areas are called MAMs (mitochondrial-associated membranes). Here, Ca²⁺ flows through the voltage-dependent anion channel (VDAC) channel on the outer mitochondrial membrane and then is actively transported inside the mitochondria by the mitochondrial uniporter channel (MCU) located on the inner mitochondrial membrane. Inside the mitochondria, Ca²⁺ is required for the normal activity of the Krebs cycle. Reduced Ca²⁺ concentrations—as in cells carrying BAP1 mutations—impair mitochondrial respiration (Krebs cycle), and the cells switch to aerobic glycolysis (Warburg effect). Normally, when cells sense that DNA damage has occurred and that the damage cannot be repaired, they release higher than normal amounts Ca²⁺ from the ER through the IP3R3, leading to high mitochondrial Ca²⁺ concentrations, which, in turn, cause the release of cytochrome c from the mitochondria into the cytosol, in which cytochrome c starts the apoptotic process. Cells with mutated BAP1 cannot release sufficient amounts of Ca²⁺ to start the apoptotic process. Thus, cells with DNA mutation do not die; instead, they divide and, over time, may become malignant. Ub indicates ubiquitin.

FIGURE 4.

Mesothelioma Contains Numerous Mutations; However, Only a Few Genes Are Mutated in a Significant Number of Cases. This schematic compares significantly altered pathways identified using Mutational Significance in Cancer (MuSiC) pathway analysis and reported in Nature Genetics by Bueno et al (Bueno R, Stawiski EW, Goldstein LD, et al. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nat Genet. 2016;48:407–416) with the results of a very recent study from The Cancer Genome Atlas (TCGA) (Hmeljak J, Sanchez-Vega F, Hoadley KA, et al. Integrative molecular characterization of malignant pleural mesothelioma. Cancer Discov. 2018;8:1548–1565). Black-bordered genes indicate significantly mutated genes (false discovery rate [FDR] <0.05 in red text and 0.05 <FDR <0.2 in blue text) identified in the Bueno et al (cream), TCGA (light green), or both (dark brown) cohorts. Bar graphs above each significantly mutated gene display the number of tumors with the respective significantly mutated gene for epithelioid (dark gray), biphasic (orange), and sarcomatoid (red) histologies. BAP1 indicates BRCA1-associated protein 1.

FIGURE 5.

Chromothripsis and Predictive Neoantigen Formation in Mesothelioma. (A) This is a representative drawing of chromothripsis. “Normal” chromosomes occasionally can remain outside the nucleus after mitosis and are found in the cytoplasm surrounded by a nuclear membrane (micronuclei). During the subsequent mitosis, upon dissolution of the nuclear membrane, the extranuclear chromosome is exposed to the cytoplasm and becomes fragmented (breakage). The fragments can be re-incorporated into the nucleus, in which the DNA ligases bind them together randomly, resulting in major chromosomal rearrangement. Some fragments are lost. This process may be favored by DNA mutations, which may increase the chance that a chromosome lags behind during mitoses, resulting in a minichromosome (see Carbone M, Yang H, Gaudino G. Does chromothripsis make mesothelioma an immunogenic cancer? J Thorac Oncol. 2019;14:157–159). (B) In this genome plot of specimen ME018, the chromosomes are plotted in order by size as numbered near the margins. Curved pink lines represent intrachromosomal rearrangements, whereas light green lines represent interchromosomal rearrangements. Deletions are represented in red, and amplifications are represented in blue. Accordingly, the multiple pink lines on chromosomes 7 and 10 each represent chromothripsis. CNVs indicates copy number variations. (C) This drawing illustrates how mutant proteins may be processed by the proteasome and transported into the endoplasmic reticulum by transporter-associated with antigen processing (TAP). Peptides typically of 8 to 12 residues are loaded onto class I HLA molecules, migrate to the cell surface, and are presented. The expression of chromosomal rearrangements described in panel A potentially may provide a source of neoantigens that can be presented by tumor cells for recognition by the immune system.