Context.—

Although many mesotheliomas are related to asbestos exposure, not all are, and there is increasing information on other causes of mesothelioma.

Objective.—

To provide a review of non-asbestos causes for malignant mesothelioma.

Data Sources.—

Review of relevant published literature via PubMed and other search engines.

Conclusions.—

Currently, most pleural mesotheliomas (70% to 90%) in men in Europe and North America are attributable to asbestos exposure; for peritoneal mesothelioma the proportion is lower. In North America few mesotheliomas in women at any site are attributable to asbestos exposure, but in Europe the proportion is higher and varies considerably by locale. In certain geographic locations other types of mineral fibers (erionite, fluoro-edenite, and probably balangeroite) can induce mesothelioma. Therapeutic radiation for other malignancies is a well-established cause of mesothelioma, with relative risks as high as 30. Carbon nanotubes can also induce mesotheliomas in animals but there are no human epidemiologic data that shed light on this issue. Chronic pleural inflammation may be a cause of mesothelioma but the data are scanty. Although SV40 can induce mesotheliomas in animals, in humans the epidemiologic data are against a causative role. A small number of mesotheliomas (probably in the order of 1%) are caused by germline mutations/deletions of BRCA1-associated protein–1 (BAP1) in kindreds that also develop a variety of other cancers. All of these alternative etiologies account for a small proportion of tumors, and most mesotheliomas not clearly attributable to asbestos exposure are spontaneous (idiopathic).

There is a complex relationship between malignant mesothelioma and its etiologic agents. The proportion of cases attributable to asbestos varies according to sex, anatomic location, fiber type, occupation, and industry.14  Whilst most pleural mesotheliomas in males are causally related to prior occupational amphibole asbestos exposure, the relationship between asbestos and mesothelioma is subject to considerable sex- and site-specific variation. For workers heavily exposed to commercial forms of amphibole asbestos, between 2% and 18% have developed pleural mesothelioma. Following occupational chrysotile exposure the incidence of pleural mesothelioma ranges from 0% to 0.47% (the latter recorded in chrysotile miners/millers).5 

Historically, peritoneal mesotheliomas were associated with heavy commercial amphibole asbestos exposures.6  Such exposures are now uncommon and currently the epidemiologic evidence correlating time trends, incidence in both sexes, and asbestos exposure suggests that a much smaller fraction of tumors in men are related to asbestos, and very few tumors in women.7  Recently, one mineralogic study8  identified almost 50% (20 of 42) of peritoneal mesotheliomas arising in persons with fiber counts within background control values, indicating a likely alternative cause in these tumors.

Owing to the rarity of malignant pericardial and testicular mesotheliomas, analytic epidemiologic studies do not exist but an ecologic study of Surveillance, Epidemiology, and End Results (SEER) data did not support the role for asbestos in these sites.9,10  Anecdotal case studies of pericardial, gonadal, and localized mesotheliomas report an inconstant relationship with asbestos and alone do not allow for any definite causal association with asbestos to be made.1113 

It is clear that not all mesotheliomas are related to asbestos exposure. In this article we review the current literature on non-asbestos–induced mesothelioma.

MINERAL FIBERS OTHER THAN ASBESTOS

Erionite

Erionite is a fibrous form of zeolite that has physical characteristics resembling the amphiboles amosite or crocidolite.14  Erionite is a potassium aluminum silicate with variable amounts of calcium and sodium, found mostly in volcanic regions associated with rhyolitic tuffs. Deposits have been described in the Cappadocian region of Turkey, but some of the highest concentrations of this fiber can be found in the Intermountain West of the United States from Oregon into Mexico and the Sierra Madre Occidental region.1517  High amounts of airborne erionite were found in North Dakota after hundreds of miles of roads were surfaced with erionite-containing gravel.18  More recently, erionite has also been identified in North Eastern Italy.19 

Baris and colleagues20  and Artvinli and Baris21  first reported an outbreak of mesothelioma in 2 small villages in the Anatolian region of Turkey. Some of the villagers also had chronic fibrosing pleurisy. Ferruginous bodies with erionite cores were isolated from the lungs of some of these villagers.22  The cause of the outbreak was believed to be exposure to erionite fibers used in the whitewash on the exterior of houses in the villages, although some asbestos was also identified in the region.23  Subsequent studies demonstrated other malignancies among the villagers as well, including lung cancers.24  With greater than 50% of mesotheliomas in Turkish villagers being caused by erionite, a genetic predisposition to fiber-induced carcinogenesis was proposed by some researchers, although the same was challenged by others.25,26 

In consideration of the high concentration of erionite fibers in North America as noted above, perhaps it is not surprising that a high incidence of lung cancer and malignant mesothelioma has been identified in 1 rural area with erionite contamination.27  Kliment et al28  reported a case of a 47-year-old Mexican emigrant to the United States who was diagnosed with malignant pleural mesothelioma and pleural plaques. He had lived the first 20 to 25 years of his life in Central Mexico, and fiber burden analysis demonstrated considerable quantities of high-aspect ratio erionite fibers in the patient's lung tissue. Oczypok et al29  reported an additional case of a 53-year-old Mexican emigrant to the United States who was diagnosed with malignant pleural mesothelioma. He moved to the United States as a young adult, and analysis of his lung tissue samples revealed elevated quantities of high-aspect ratio erionite fibers. Similar fibers were identified in rhyolitic tuff material and soil on the family farm where the patient grew up.

Experimental animal studies have confirmed the high carcinogenic potential of erionite, including the production of malignant mesotheliomas.3032  Early changes including pleural fibrosis, mesothelial hyperplasia, and mesothelial dysplasia have also been reported.33,34  Although the exact mechanisms of carcinogenesis are unknown, it is of interest that like asbestos, erionite primes and activates the NLRP3 inflammasome, which in turn triggers an autocrine feedback loop in mesothelial cells. This feedback loop is modulated by the interleukin-1 receptor.35  Based on the foregoing, more cases of erionite-induced mesothelioma are likely to be identified in regions of the world where this fiber is prevalent and exposures to humans occur.

Fluoro-edenite

Fluoro-edenite is a non-asbestos mineral fiber with similar morphology and composition to the actinolite-tremolite series. It was originally characterized in 1997 from rock deposits taken near the city of Biancavilla (Catania, Eastern Sicily, Italy). The mineral ore was extracted from quarries in Monte Calvario, southeast of Biancavilla and subsequently commercially used as a building material for road paving, and residential and commercial plaster and mortar construction. A 10-fold increase in pleural neoplasms was reported in exposed subjects in a mortality study.36  Pleural plaques have also been identified in Biancavilla construction workers exposed to fluoro-edenite.37 

Animal experimental studies show mesothelioma induction following fluoro-edenite implantation in rat peritoneal cavities.38  In vitro studies show that fluoro-edenite is an inducer of DNA damage and reactive oxygen species production, with overall decreased cell viability.39  The International Agency for Research on Cancer has subsequently classified fibrous fluoro-edenite as carcinogenic to humans (group 1).40 

Balangeroite

This gageite-like mineral is a fibrous iron-rich magnesium silicate with a complex structure often intergrown with chrysotile deposits. It comprises around 0.2% to 0.5% contamination of the chrysotile from the San Vittore mine in Balangero, Italy. The fibrous mineral has similarities in morphology but lower biodurability than commercial amphiboles.4143  The role of this fibrous amphibolic mineral in the induction of mesothelioma in Balangero, Italy, is controversial with some authors attributing mesotheliomas to it and others questioning its precise role.4446  The controversy is complicated by the fact that the Balangero mine occasionally milled imported commercial amphibole from South Africa; this conclusion is supported by the fact that some Balangero chrysotile miners have identifiable commercial amphiboles (crocidolite, amosite) as well as noncommercial amphibole tremolite in lung tissue on mineral analysis.47,48 

Carbon Nanotubes

Carbon nanotubes have a number of wide applications in industry. They are formed from varying high-aspect ratio graphene cylinders, which can assume a fibrous habit. There has been concern that their close physical similarities to asbestos may pose a health risk.49  It is recognized that both in vitro and in vivo studies do not necessarily transfer any significance to human populations. Nonetheless, there exist in vitro studies that show carbon nanotube cytotoxicity, and in vivo studies have shown the development of mesothelioma in both genetically modified cancer-sensitized mice and Fischer 344 rats exposed to carbon nanotubes via peritoneal and intrascrotal inoculation, respectively.50,51  Pleural inflammation has been correlated with fiber length.52,53  Presently it is not practicable to evaluate at an epidemiologic level whether there exists any association between carbon nanotube exposure and human disease.

Other Minerals

A variety of man-made vitreous fibers have been studied to evaluate their potential to induce mesothelioma in humans. These include rock wool, slag wool, glass fiber, and glass filament. Systematic reviews of synthetic vitreous fibers have concluded that the combined evidence based on epidemiologic and toxicologic data provides little support of any increased risk of mesothelioma following exposure.54,55  Such man-made fibers have low biopersistence in tissue systems. In contrast, in vivo high-dose chronic inhalational experiments to more biopersistent refractory ceramic fibers have been associated with the induction of mesothelioma in Syrian golden hamsters.56 

Anecdotal case reports linking mesothelioma to metals beryllium and nickel,57,58  and crystalline silica in sugar cane,59  have never been supported by analytic epidemiologic studies. At present, the weight of evidence does not support that these minerals are causes of malignant mesothelioma in humans.

RADIATION

Radiation is a recognized pancarcinogen. The evidence linking radiation with malignant mesothelioma in humans has come from 3 sources: first, case reports, case series, and retrospective cohort studies of patients previously receiving therapeutic irradiation for tumors; second, from reported mesothelioma cases following radioactive thorium dioxide contrast medium “Thorotrast” and; third, from studies of atomic energy/nuclear industry workers exposed to prolonged lower levels of irradiation.

Pleural, peritoneal, and pericardial mesotheliomas have all been reported after radiotherapy to treat childhood and adolescent tumors, most notably with Hodgkin and non-Hodgkin lymphoma, germ cell neoplasms, Wilms tumor of the kidney, and breast cancer.6066  The latent period has been reported to be between 5 to more than 50 years with radiation-induced mesotheliomas showing an equal male to female ratio.67,68 

A variety of tumors including pleural and peritoneal mesothelioma, hepatocellular carcinoma, hemangioendothelioma, and cholangiocarcinoma have been reported after intravenous Thorotrast administration.6971  The radioactive 232ThO2 is insoluble and following injection, deposits in organs and is associated with slow decay and prolonged alpha-ray emission.

Mesotheliomas have also been reported in an occupational setting in radiation technologists exposed to external gamma-ray emission and internal radionuclides.72  The risk of mesothelioma was also elevated among British Atomic Energy workers employed between 1946 and 1990 and at the Idaho National Engineering and Environmental Laboratory where nuclear processing and demolition occurred, emphasizing the significance of external scatter radiation at lower doses.73,74 

Animal experiments with 239plutonium dioxide have shown epithelial tumors, sarcomas, and mesotheliomas in around 30% of rats after intraperitoneal injection.75  Inhalation and intrapleural injection studies showed much lower rates of mesothelioma formation (0.2% and 3.7%, respectively).76  Aerosolized 144cerium dioxide was found to induce mesothelioma in 0.7% of 566 rats.77 

A recent review of SEER data found that post external beam radiation mesothelioma risk increased with longer latency and showed a stronger association with peritoneal mesothelioma.78  A recent genetic profiling study of radiation-induced mesotheliomas showed some copy number gains outnumbering deletions, whereas deletions of 6q, 14q, 17p, and 22q were more frequently seen in those asbestos-associated mesotheliomas tested, signifying potential different molecular mechanisms of induction.79 

Overall there is consistency of evidence that shows radiation is a risk factor for malignant mesothelioma in directly irradiated tissues and to a lesser extent in tissue remote from the target area.

CHRONIC INFLAMMATION

Anecdotal reports of malignant mesothelioma of the pleura and peritoneum have been reported following chronic serosal inflammatory conditions.8085  In the pleura, malignant mesothelioma has occurred after therapeutic plombage post tuberculosis and in individuals with long-standing chronic empyema. Diffuse malignant mesothelioma of the peritoneum has similarly been reported in persons with recurrent peritonitis consequent to relapsing diverticulitis and in individuals with Crohn disease.86  In young patients, peritoneal mesothelioma has been observed following ventriculoperitoneal shunts for hydrocephaly. Peritoneal mesothelioma has also developed in several individuals with recurrent peritonitis resulting from familial Mediterranean fever.87 

The mechanisms by which chronic serosal inflammation contributes to the pathogenesis of mesothelioma are not known although it has been suggested that they may be mediated via chronic interleukin-6 production, a regulatory cytokine in acute phase reactions.88 

SIMIAN VIRUS 40

There has been considerable interest in the possible role of simian virus 40 (SV40) as an etiologic agent for human mesothelioma. SV40 is a DNA polyomavirus that commonly infects Asian macaque monkeys. In naturally immunocompetent hosts the virus generally produces inapparent infection. However, the SV40 virus has been shown to produce pathologic effects in either immunocompromised hosts and/or in nonhost species. SV40 is a transforming virus with tumorigenic effects observed in in vitro studies and following intrapleural or intracardiac injection studies in rodents.89  Human exposure to SV40 is believed to have largely occurred after administration of contaminated live and attenuated poliovirus vaccines, prepared from infected monkey kidney tissue culture cell lines.90  It is estimated that between 1954 and 1963, hundreds of millions of people worldwide were likely exposed to SV40 via this route.

The viral genome encodes several oncogenic proteins, most notably large T-antigen (Tag), which inactivate the tumor suppressor activity of p53 and p-retinoblastoma family proteins. Multiple researchers have demonstrated in archived samples the presence of either SV40 Tag DNA segments by polymerase chain reaction methodology or SV40 Tag protein by immunohistochemistry in a proportion of mesotheliomas.91,92  However, the detection rates of SV40 and human mesothelioma show considerable variability, with a number of laboratories not being able to confirm the presence of SV40 Tag protein or SV40 DNA in their mesothelioma cases.93,94  Additionally, there have been inconsistencies in the ability of different laboratories to detect SV40 sequences in the same specimens.95 

Irrespective of discussions regarding the consistency of the viral detection data, the presence of SV40 DNA and protein in mesothelioma does not allow for any causal relationship between the virus and the tumor to be drawn. In humans SV40 may be a passenger virus in the mesothelial cells without causing pathology or tumorigenesis.

Numerous epidemiologic studies have not demonstrated any association between mesothelioma incidence and polio vaccine administration.9698 

Overall the role of SV40 as an etiologic agent in human mesotheliomas is unconvincing.

BAP-1 CANCER-PREDISPOSITION SYNDROME

There has been much recent interest in the role of BAP-1 (BRCA1-associated protein–1) in mesothelioma. BAP-1 is a nuclear localizing deubiquitinating hydrolase enzyme.99  The BAP-1 gene is located on chromosome band 3p21. BAP-1 protein regulates genes concerned with cell cycle progression, DNA damage repair, and cellular differentiation. BAP-1 expression may be lost in tumors by deletion of the gene or by a variety of mutations that prevent deubiquitinating activity and nuclear localization. These findings have led to the suggestion that BAP-1 is a tumor suppressor gene and this idea is supported by the finding of an increase in spontaneous development of ovarian, lung, and breast carcinomas, and a few mesotheliomas ex asbestos in about half of mice with genetically engineered BAP-1 mutations that match those found in BAP-1 cancer syndrome families.100 

Germline BAP-1 mutations have been implicated in the induction of mesothelioma. Germline BAP-1 mutations are inherited in an autosomal dominant manner and confer a high risk of mesothelioma in individuals and in affected families. Recently, a BAP-1 hereditary cancer predisposition syndrome has been described,101  which includes in affected patients/families uveal and cutaneous melanomas, renal clear cell carcinomas, atypical spitzoid nevi (so-called melanocytic BAP-1–mutated atypical intradermal tumors), and probably other neoplasms including basal cell carcinoma and intrahepatic cholangiocarcinoma.102 

The incidence of BAP-1 germline mutations is not well defined. Testa et al101  reported that 7.7% (2 of 26) of spontaneous mesotheliomas carried BAP-1 germline mutations; however, 3 subsequent series totalling approximately 300 apparently sporadic cases examined with targeted deep sequencing revealed only 1 patient with a germline mutation,103105  suggesting that germline BAP-1 cancer syndrome cases account for at most a very small percentage of all mesotheliomas. Carbone et al106  reported a BAP-1 cancer syndrome kindred of around 80 000 individuals, with the kindred traceable back 9 generations to a couple that immigrated to the United States in the 1700s. This observation raises the possibility that germline BAP-1 mutations actually only occur in a few kindreds.

Because individuals carrying BAP-1 germline mutations are believed to start with only 1 abnormal allele, it has been proposed that germline BAP-1–associated mesotheliomas may reflect relatively low-level asbestos-induced mutations of the second allele in genetically susceptible hosts.107  There is some support for this idea from animal models. Xu et al108  generated BAP-1+/− mice and reported that these mice developed mesothelioma at twice the rate of wild-type mice after intraperitoneal injection of crocidolite asbestos; the tumors also occurred earlier in the BAP-1+/− mice. No mesotheliomas were found in BAP-1+/− mice not exposed to asbestos. Napolitano et al109  observed that BAP-1+/− mice had a significantly higher incidence of mesothelioma after intraperitoneal injection of crocidolite at a dose that rarely induced mesothelioma in wild-type mice. However, other animal studies have yielded conflicting results, with Kadariya et al100  observing mesothelioma formation without asbestos exposure in BAP-1 knockout mice.

The only study that, to our knowledge, has attempted to look at mesothelioma incidence in germline mutation and control groups is that of Ohar et al,107  who reported germline BAP-1 mutations in 9 of 150 patients with mesothelioma and a family history of cancer (6%) as compared to none in series of asbestos-exposed control case individuals without a family history of cancer. The authors concluded that these findings support a role for low-level asbestos exposure in the genesis of mesotheliomas. Unfortunately, the study design is flawed, since no details of the asbestos exposures were provided. Because of the vastly different potencies of chrysotile versus commercial amphibole exposure in producing mesothelioma and the importance of dose, latency, and tumor site, one would need groups properly matched for these features in order to determine whether BAP-1 germline mutations actually do increase the mesothelioma risk from asbestos exposure.

The interpretation of the human data is muddied by a lack of detail about putative asbestos exposures. Baumann et al110  reported that none of their 23 patients with germline mutations had occupational asbestos exposure and commented that these tumors either were caused by low-level environmental exposure to asbestos or were not caused by fiber carcinogenesis at all. However, the female preponderance and the fact that half of the tumors were peritoneal argue against low-level asbestos carcinogenesis, since most asbestos-induced mesotheliomas are pleural, and one would expect that asbestos carcinogenesis augmented by a genetic predisposition should maintain this ratio; indeed, if the presumption is that these patients had low-level inhalational exposures, it is hard to explain how they could develop more peritoneal than pleural mesotheliomas, since that kind of ratio has only been observed in a few worker cohorts with very high exposure to commercial amphibole (amosite or crocidolite) exposure.

Germline BAP-1 mutations may have implications in relation to prognosis. Baumann et al110  reported survival data on 23 patients with germline BAP-1 mutations and concluded that germline BAP-1–mutated mesotheliomas are associated with longer survival than the usual sporadic mesotheliomas. The male to female ratio was 9:14, and half of the patients were younger than 55 years. Of note, 10 of the tumors were peritoneal, 10 pleural, and 3 recorded as originating from both sites. The median survival for the pleural tumors was 2 years and for the peritoneal tumors, 10 years. The authors concluded that germline BAP-1–mutated mesotheliomas are associated with a longer survival than the usual sporadic mesothelioma. This idea must be viewed in light of the fact that 13 of the 23 subjects (56%) had a second malignancy, so the apparent longer survivals may reflect a lead time bias for subjects undergoing frequent medical surveillance. However, studies on mesotheliomas with somatic BAP-1 mutations (eg, Leblay et al111 ) have also found that such tumors are associated with longer survival, so loss of BAP-1 may in fact confer a better prognosis.

SPONTANEOUS (IDIOPATHIC) MESOTHELIOMAS

All of the etiologies discussed above account for a small proportion of mesotheliomas. After excluding tumors caused by asbestos exposure, the next largest fraction is spontaneous (idiopathic) mesothelioma.

The scientific evidence for a background rate of spontaneous mesotheliomas arising in unrelated fashion to asbestos comes from the following sources: first, no temporal relation between malignant mesothelioma in women and historic use of commercial forms of asbestos—the age-adjusted mesothelioma incidence in US women from 1973 to 2008 has been stable3,112 ; second, the occurrence of malignant mesotheliomas in children aged below the lowest recorded latent period for occupational asbestos-associated mesotheliomas113 ; third, cases of malignant mesothelioma in persons with no history of asbestos exposure despite extensive investigation and/or with detectable fibers on mineral analysis114 ; fourth, the spontaneous occurrence of various tumors including malignant mesothelioma in laboratory animals.115 

One approach to determining the proportion of mesotheliomas that are spontaneous is to examine the fraction reported as being caused by asbestos exposure. Various reports on this topic exist in the literature (see the Table).13,116120  However, the exact proportion of such spontaneous mesotheliomas as a fraction of all mesotheliomas is difficult to ascertain in a coherent fashion across studies because of varying study designs, different patient selection schemes, different views of what occupations entail significant asbestos exposure, as well as differences in the historic use of amphibole versus chrysotile asbestos between countries.

Mesotheliomas Attributable to Asbestos

Mesotheliomas Attributable to Asbestos
Mesotheliomas Attributable to Asbestos

From the Table it is clear that there is a definite and sometimes quite substantial fraction of mesotheliomas that have no identifiable external cause, and that, not surprisingly, this fraction is greater in women than men (for the simple reason that more men than women had occupational levels of asbestos exposure) and the fraction is greater in the peritoneum than pleura. The fraction with no identifiable external cause also is reported as higher in the United States as compared with European data sources.

Henley et al112  recently combined data from the National Program for Cancer Registries and SEER for mesotheliomas diagnosed between 2003 and 2008 and showed that overall female mesothelioma rates were flat, whereas male rates continue to decline. The results noted that the anatomic site of mesothelioma differed between men and women at different ages. Below 45 years of age, irrespective of anatomic site, mesothelioma was more common in women than men and peritoneal disease predominates, observed in 51% of cases. This observed age-, sex-, and site-specific demographic, as discussed earlier, argues against a fiber-induced carcinogenesis in which male sex and pleural disease predominate.

Historically, peritoneal mesotheliomas have been typically observed following heavy cumulative commercial amphibole asbestos exposures and nowadays such cases are increasingly uncommon. Recent updated trend analysis shows that the incidence of peritoneal mesotheliomas among both men and women shows little or no association with commercial asbestos use trends in the United States.7  Trends in some European countries also show that a large fraction of peritoneal mesothelioma is unrelated to asbestos with flat age-adjusted incidence rates in men and women.121,122  However, there is observed geographic variations in the attributable fraction to asbestos. Marinaccio et al,123  analyzing the Italian National Mesothelioma Register, concluded in their analysis that 76% (of 188) of male and 34% (of 50) of female peritoneal mesotheliomas had occupational asbestos exposure.

Recent studies have shown that many mesotheliomas harbor somatic mutations of BAP-1, NF2, and to a lesser extent, SETD2, TP53, DDX3X, ULK2, RYR2, CPAF45, SETDB1, and DDX51.124  Deletions of the 9p21 region containing p16INK4A, p15, p14, and MTAP are common in mesotheliomas. There also appear to be molecular differences between pleural and peritoneal mesothelioma cells in genomic copy number losses and gains, indicating that different genetic pathways may be implicated at the different site.79,125  However, there are no data thus far that would suggest specific etiologies associated with 1 or any combination of these mutations/deletions.

For pericardial and tunica vaginalis testis mesothelioma no analytic case-control epidemiologic studies exist to evaluate the relation between these tumors and asbestos. Ecologic studies using SEER data show trends in the incidence of pericardial and tunica vaginalis testis mesotheliomas that do not match those of pleural mesothelioma,9,10  and meta-analytic studies of large occupational cohorts with heavy asbestos exposures report no cases of pericardial or tunica vaginalis testis mesothelioma.4  For pericardial and tunica vaginalis testis mesothelioma the available evidence suggests most cases are spontaneous (idiopathic) mesotheliomas.

CONCLUSIONS

Mesothelioma has an evolving relationship with its varied causes. This is because first, the total number of cases attributable to asbestos is continuously diminishing in line with diminishing historic exposures. The scientific literature indicates that there is a definite and sometimes substantial fraction of mesotheliomas that have no history of asbestos exposure. This fraction is greater in the United States than in European countries, more in women than men, and greater in peritoneal than pleural mesotheliomas. In approximate terms, some 60% to 90% of mesotheliomas in US women (pleural and peritoneal sites, respectively), and a substantial proportion of peritoneal mesotheliomas in men are likely unrelated to asbestos.1,3,7,8,121,122  This is particularly so in younger patients (younger than 45 years). Second, there is an increasing awareness of alternative biopersistent mineral fibers that can induce mesothelioma in certain geographic locations. For a minority of patients with mesothelioma (for whom there is no history of asbestos exposure) there will be some discernible and specific carcinogenic agent (either a biopersistent mineral fiber or radiation exposure) that has induced the tumor. Third, and most significantly, there has been considerable expansion in the understanding of molecular genetics in mesothelioma.

As a cancer, mesothelioma is a genetic disease. In substantially less than 1% of patients with mesothelioma (when there is no external agent exposure), the mesothelioma will be induced by a specific inherited genetic mutation; scientific evidence presently favors the role of BAP-1. These genetically inherited mesotheliomas arise at a younger age, show no sex or clear anatomic site predilection with some involving multiple serosal sites. The presence of other concomitant cancers, in particular ocular, or cutaneous melanomas, and renal cell carcinomas, should prompt clear consideration of an inherited cancer predisposition syndrome and BAP-1 mutational status should be evaluated. The role of mutated BAP-1 in mesothelioma and its interaction with carcinogens is an evolving area. The available scientific literature is conflicting in animal studies. At present, the limited human data would favor the proposition that germline BAP-1 mutation can induce mesothelioma ex asbestos.

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Author notes

Drs Attanoos, Churg, Gibbs, and Roggli serve as expert witnesses for plaintiff/claimant and defendants in asbestos litigation. Dr Galateau-Salle has no relevant financial interest in the products or companies described in this article.