Francine Baumann

Mesothelioma patients with germline BAP1 mutations have 7-fold improved long-term survival

BRCA1-associated protein-1 (BAP1) mutations cause a new cancer syndrome, with a high rate of malignant mesothelioma (MM). Here, we tested the hypothesis that MM associated with germline BAP1 mutations has a better prognosis compared with sporadic MM. We compared survival among germline BAP1 mutation MM patients with that of all MM (N = 10 556) recorded in the United States Surveillance, Epidemiology, and End Results (SEER) data from 1973 to 2010. We identified 23 MM patients--11 alive--with germline BAP1 mutations and available data on survival. Ten patients had peritoneal MM, ten pleural MM and three MM in both locations. Thirteen patients had one or more malignancies in addition to MM. Actuarial median survival for the MM patients with germline BAP1 mutations was 5 years, as compared with <1 year for the median survival in the United States SEER MM group. Five-year survival was 47%, 95% confidence interval (24-67%), as compared with 6.7% (6.2-7.3%) in the control SEER group. Analysis of the pooled cohort of germline BAP1 mutation MM showed that patients with peritoneal MM (median survival of 10 years, P = 0.0571), or with a second malignancy in addition to MM (median survival of 10 years, P = 0.0716), survived for a longer time compared with patients who only had pleural MM, or MM patients without a second malignancy, respectively. In conclusion, we found that MM patients with germline BAP1 mutations have an overall 7-fold increased long-term survival, independently of sex and age. Appropriate genetic counseling and clinical management should be considered for MM patients who are also BAP1 mutation carriers.

Pleural Mesothelioma in New Caledonia: Associations with Environmental Risk Factors

Background High incidences of malignant mesothelioma (MM) have been observed in New Caledonia. Previous work has shown an association between MM and soil containing serpentinite. Objectives We studied the spatial and temporal variation of MM and its association with environmental factors. Methods We investigated the 109 MM cases recorded in the Cancer Registry of New Caledonia between 1984 and 2008 and performed spatial, temporal, and space–time cluster analyses. We conducted an ecological analysis involving 100 tribes over a large area including those with the highest incidence rates. Associations with environmental factors were assessed using logistic and Poisson regression analyses. Results The highest incidence was observed in the Houaïlou area with a world age-standardized rate of 128.7 per 100,000 person-years [95% confidence interval (CI), 70.41–137.84]. A significant spatial cluster grouped 18 tribes (31 observed cases vs. 8 expected cases; p = 0.001), but no significant temporal clusters were identified. The ecological analyses identified serpentinite on roads as the greatest environmental risk factor (odds ratio = 495.0; 95% CI, 46.2–4679.7; multivariate incidence rate ratio = 13.0; 95% CI, 10.2–16.6). The risk increased with serpentinite surface, proximity to serpentinite quarries and distance to the peridotite massif. The association with serpentines was stronger than with amphiboles. Living on a slope and close to dense vegetation appeared protective. The use of whitewash, previously suggested to be a risk factor, was not associated with MM incidence. Conclusions Presence of serpentinite on roads is a major environmental risk factor for mesothelioma in New Caledonia.

The Presence of Asbestos in the Natural Environment is Likely Related to Mesothelioma in Young Individuals and Women from Southern Nevada

Background: Inhalation of asbestos and other mineral fibers is known causes of malignant mesothelioma (MM) and lung cancers. In a setting of occupational exposure to asbestos, MM occurs four to eight times more frequently in men than in women, at the median age of 74 years, whereas an environmental exposure to asbestos causes the same number of MMs in men and women, at younger ages. Methods: We studied the geology of Nevada to identify mineral fibers in the environment. We compared MM mortality in different Nevada counties, per sex and age group, for the 1999 to 2010 period. Results: We identified the presence of carcinogenic minerals in Nevada, including actinolite asbestos, erionite, winchite, magnesioriebeckite, and richterite. We discovered that, compared with the United States and other Nevada counties, Clark and Nye counties, in southern Nevada, had a significantly higher proportion of MM that occurred in young individuals (<55 years) and in women. Conclusions: The elevated percentage of women and individuals younger than 55 years old, combined with a sex ratio of 1:1 in this age group and the presence of naturally occurring asbestos, suggests that environmental exposure to mineral fibers in southern Nevada may be contributing to some of these mesotheliomas. Further research to assess environmental exposures should allow the development of strategies to minimize exposure, as the development of rural areas continues in Nevada, and to prevent MM and other asbestos-related diseases.

Consensus Report of the 2015 Weinman International Conference on Mesothelioma

ABSTRACT On November 9 and 10, 2015, the International Conference on Mesothelioma in Populations Exposed to Naturally Occurring Asbestiform Fibers was held at the University of Hawaii Cancer Center in Honolulu, Hawaii. The meeting was cosponsored by the International Association for the Study of Lung Cancer, and the agenda was designed with significant input from staff at the U.S. National Cancer Institute and National Institute of Environmental Health Sciences. A multidisciplinary group of participants presented updates reflecting a range of disciplinary perspectives, including mineralogy, geology, epidemiology, toxicology, biochemistry, molecular biology, genetics, public health, and clinical oncology. The group identified knowledge gaps that are barriers to preventing and treating malignant mesothelioma (MM) and the required next steps to address barriers. This manuscript reports the groups efforts and focus on strategies to limit risk to the population and reduce the incidence of MM. Four main topics were explored: genetic risk, environmental exposure, biomarkers, and clinical interventions. Genetics plays a critical role in MM when the disease occurs in carriers of germline BRCA1 associated protein 1 mutations. Moreover, it appears likely that, in addition to BRCA1 associated protein 1, other yet unknown genetic variants may also influence the individual risk for development of MM, especially after exposure to asbestos and related mineral fibers. MM is an almost entirely preventable malignancy as it is most often caused by exposure to commercial asbestos or mineral fibers with asbestos‐like health effects, such as erionite. In the past in North America and in Europe, the most prominent source of exposure was related to occupation. Present regulations have reduced occupational exposure in these countries; however, some people continue to be exposed to previously installed asbestos in older construction and other settings. Moreover, an increasing number of people are being exposed in rural areas that contain noncommercial asbestos, erionite, and other mineral fibers in soil or rock (termed naturally occurring asbestos [NOA]) and are being developed. Public health authorities, scientists, residents, and other affected groups must work together in the areas where exposure to asbestos, including NOA, has been documented in the environment to mitigate or reduce this exposure. Although a blood biomarker validated to be effective for use in screening and identifying MM at an early stage in asbestos/NOA‐exposed populations is not currently available, novel biomarkers presented at the meeting, such as high mobility group box 1 and fibulin‐3, are promising. There was general agreement that current treatment for MM, which is based on surgery and standard chemotherapy, has a modest effect on the overall survival (OS), which remains dismal. Additionally, although much needed novel therapeutic approaches for MM are being developed and explored in clinical trials, there is a critical need to invest in prevention research, in which there is a great opportunity to reduce the incidence and mortality from MM.

HMGB1 and Its Hyperacetylated Isoform are Sensitive and Specific Serum Biomarkers to Detect Asbestos Exposure and to Identify Mesothelioma Patients

Purpose: To determine whether serum levels of high mobility group box protein 1 (HMGB1) could differentiate malignant mesothelioma patients, asbestos-exposed individuals, and unexposed controls. Experimental Design: Hyperacetylated and nonacetylated HMGB1 (together referred to as total HMGB1) were blindly measured in blood collected from malignant mesothelioma patients (n = 22), individuals with verified chronic asbestos exposure (n = 20), patients with benign pleural effusions (n = 13) or malignant pleural effusions not due to malignant mesothelioma (n = 25), and healthy controls (n = 20). Blood levels of previously proposed malignant mesothelioma biomarkers fibulin-3, mesothelin, and osteopontin were also measured in nonhealthy individuals. Results: HMGB1 serum levels reliably distinguished malignant mesothelioma patients, asbestos-exposed individuals, and unexposed controls. Total HMGB1 was significantly higher in malignant mesothelioma patients and asbestos-exposed individuals compared with healthy controls. Hyperacetylated HMGB1 was significantly higher in malignant mesothelioma patients compared with asbestos-exposed individuals and healthy controls, and did not vary with tumor stage. At the cut-off value of 2.00 ng/mL, the sensitivity and specificity of serum hyperacetylated HMGB1 in differentiating malignant mesothelioma patients from asbestos-exposed individuals and healthy controls was 100%, outperforming other previously proposed biomarkers. Combining HMGB1 and fibulin-3 provided increased sensitivity and specificity in differentiating malignant mesothelioma patients from patients with cytologically benign or malignant non–mesothelioma pleural effusion. Conclusions: Our results are significant and clinically relevant as they provide the first biomarker of asbestos exposure and indicate that hyperacetylated HMGB1 is an accurate biomarker to differentiate malignant mesothelioma patients from individuals occupationally exposed to asbestos and unexposed controls. A trial to independently validate these findings will start soon. Clin Cancer Res; 22(12); 3087–96. ©2016 AACR.

Environmental risk of mesothelioma in the United States: An emerging concern—epidemiological issues

ABSTRACT Despite predictions of decline in mesothelioma following the ban of asbestos in most industrial countries, the incidence is still increasing globally, particularly in women. Because occupational exposure to asbestos is the main cause of mesothelioma, it occurs four- to eightfold more frequently in men than women, at a median age of 74 years. When mesothelioma is due to an environmental exposure, the M:F sex ratio is 1:1 and the median age at diagnosis is ~60 years. Studying environmental risk of mesothelioma is challenging because of the long latency period and small numbers, and because this type of exposure is involuntary and unknown. Individual-based methods cannot be used, and new approaches need to be found. To better understand the most recent trends of mesothelioma in the United States, all mesothelioma deaths reported to the Centers for Disease Control and Prevention (CDC) during 1999–2010 were analyzed. Among all mesothelioma deaths in the United States, the 1920s birth cohort significantly predominated, and the proportion of younger cohorts constantly decreased with time, suggesting a decline in occupational exposure in these cohorts. The M:F mesothelioma sex ratio fell with time, suggesting an increased proportion of environmental cases. Environmental exposures occur in specific geographic areas. At the large scale of a state, mesotheliomas related to environmental exposure are diluted among occupational cases. The spatial analysis at a smaller scale, such as county, enables detection of areas with higher proportions of female and young mesothelioma cases, thus indicating possible environmental exposure, where geological and environmental investigations need to be carried out.

Reply to “No Increased Risk for Mesothelioma in Relation to Natural-Occurring Asbestos in Southern Nevada”

We appreciate the interest and review of our paper1 by Pinheiro and Jin2, as they provide us an opportunity to re-open a dialogue with the Department of Health and Human Services, Nevada, with whom Dr. Pinheiro is associated. Environmental epidemiology is a relatively recent science and, because it deals with small numbers and exposures that cannot be assessed on individuals, it uses specific methods that are different from classical cancer epidemiology3. Pinheiro and Jin: “the proper indicator of risk in a population or a subpopulation is the incidence rate”. While this is often true, it would be incorrect for this situation because most mesotheliomas are due to occupational exposure to asbestos4, therefore, the incidence (or mortality) rates reflect the process and/or use of asbestos in the studied area. Incidence rates cannot distinguish between occupational and environmentally-caused mesotheliomas. Occupational exposure leads to a mesothelioma Male:Female (M:F) sex-ratio of 4–8:1, with a mean age of diagnosis of 74 years-old, because of the 30–50 years latency between initial exposure and mesothelioma development. In places where people were only environmentally exposed to carcinogenic fibers, the M:F sex-ratio is about 1:1 and the mean age of diagnosis is 50–605–7. In places where both types of exposure exist, the M:F sex ratio decreases and the proportion of young (<55 years old) cases increases, compared to places with occupational exposure only. Consequently, we used the significant decrease of mesothelioma M:F sex-ratio and the increase of young cases as indicators of possible environmental exposure to carcinogenic fibers. Pinheiro and Jin: “there is no scientific consensus on the use of the sex ratio and the proportion under 55 as indicators of environmental (non-occupational) exposure to asbestos or NOA”. The epidemiology of mesothelioma from mixed environmental and occupational exposures to carcinogenic fibers has never specifically been studied. However, the studies of populations exposed to carcinogenic fibers from their natural environment, without occupational exposure to asbestos, showed a mesothelioma M:F sex-ratio of about 1:1 and a higher proportion of young cases5–7. There are no published studies contradicting or questioning the methodology we used. The first International Conference On Mesothelioma In Populations Exposed To Naturally Occurring Asbestiform Fibers sponsored by the NCI, NIEHS and IASLC, will be held in Honolulu Nov 9–10; methodology will be one of the topics discussed. We would welcome Drs. Pinheiro and Jin. Pinheiro and Jin: “a male to female sex ratio can be elevated just by virtue of a low number of male cases rather than an actual increased absolute number among females”. Although this statement appears incorrect –M:F would be elevated by an increase in males and /or a decrease in females- , we think we understand what they mean. However, a lower mesothelioma incidence/mortality in male and in old age groups simply reflects a lower occupational exposure to asbestos. In the absence of environmental exposure, a low level of occupational exposure leads to a lower mesothelioma incidence in both males and females, and in both old and young age groups, with a M:F sex-ratio still around 4–8:1, and less than 10% of mesothelioma cases in young individuals. If there is environmental exposure in a region where a low level of occupational exposure exists, the environmental exposure causes additional mesothelioma cases in both males and females, leading to a decreased sex ratio and increased proportion of young mesothelioma cases –as observed in Southern Nevada, while the total incidence in male and in old age groups may still be low compared to regions with higher occupational exposure. Pinheiro and Jin question why the study periods are different in the incidence data that we used to compare mesothelioma incidence by state, and the mortality data that we analyzed by gender, age group and county. The answer is simple: the incidence data that we used are public, available by state only, and 2006–2010 was the longest available period of time, while the Center for Disease Control (CDC) mesothelioma mortality data that we obtained to carry out our analysis by county were available for 1999–2010. Additionally, we merely cited the US states which presented the lowest and highest mesothelioma incidence in the US, the lowest and highest sex ratio, and the lowest and highest proportion of young adults. We did not make any statistical comparison using these numbers, which were given as examples; we did not give any p-value comparing Nevada and any of the seven states cited in Table 21. We thank Pinheiro and Jin for highlighting the erroneous total number of mesotheliomas in Table 21. Curiously, they also made a mistake: 31,408 + 133 = 31,541 instead of 31,545 as they stated. Pinheiro and Jin: “For the immediately younger (0–49) and older age groups (0–59) the risk in Nevada is fundamentally the same as in the US”, suggesting that only the 0–54 years-old group would be different. But their own Table 1 shows higher risk in Nevada for the 0–59 years old group, and higher risk in the 0–49 years old group for Southern Nevada, compared with the US. In addition, because of the small numbers, their 95% confidence intervals are large and do not allow for any significant comparison. Consequently, incidence/mortality rates clearly cannot be used to measure environmental exposures. Pinheiro and Jin graciously comment “We praise Baumann for producing a body of literature on mesothelioma and exposure to natural-occurring asbestos (NOA). The recent discovery of NOA in Southern Nevada has raised our interest in the surveillance of mesothelioma in the region”. So it appears we all agree that our findings identifying environmental exposure to asbestos in Southern Nevada are important and require follow up because asbestos causes mesothelioma. Therefore, we are puzzled by the title of their letter, a title that cannot be supported by data, and that in fact contradicts published evidence that exposure to asbestos increases the risk of mesothelioma and that such exposure is occurring in Southern Nevada8–10. Risk is defined as the product of hazard and vulnerability (or exposure)11. Southern Nevadans are indeed being exposed to the hazard of asbestos fibers and therefore are at increased risk for mesothelioma and other asbestos-related diseases1,12. For example, ambient air measured for Phase I of the Boulder City Bypass showed the presence of airborne asbestos fibers10. Moreover, some individuals may be exposed to significantly higher concentrations through recreational activities, such as off-road vehicle recreation, horseback riding, mountain bicycle riding, hiking, and other activities that are popular in the desert areas where asbestos fibers occur1,8–10,14. Environmental epidemiology is about identifying areas in which environmental risk exists and work with local experts and authorities to eliminate or at least mitigate the risk. We hope that we will be allowed to further investigate the areas in Southern Nevada where exposure occurs and where there is an apparent increase of mesothelioma among young adults. We would welcome the opportunity to work together with Nevada epidemiologists and the Nevada health authorities to help identify measures to reduce environmental exposure to asbestos and to other carcinogenic fibers and the consequent risk of mesothelioma, as we have done in other parts of the US and of the world6,14,15.

Abstract 3112: HMGB1 and its isoform are sensitive and specific biomarkers to detect asbestos exposure and to identify mesothelioma patients

Millions of people have been potentially exposed to asbestos, the primary cause of malignant mesothelioma (MM). Presently, no reliable biomarkers are available to identify among potentially exposed people, those individuals who have actually been exposed and who are at high risk of MM. High Mobility Group Box Protein-1 (HMGB1) is a key mediator of asbestos-induced inflammation and MM pathogenesis. Recently, HMGB1 hyper-acetylation has been functionally associated to its active release by inflammatory cells. Here, we compared the serum levels of total and hyper-acetylated HMGB1 in individuals professionally exposed to asbestos, MM patients and healthy unexposed controls. HMGB1 serum levels reliably distinguished asbestos-exposed individuals and MM patients from unexposed controls. Moreover, the levels of total and hyper-acetylated HMGB1 were significantly higher in MM patients compared to asbestos-exposed individuals, and did not vary with tumor stage, suggesting that early lesions are also associated to increased HMGB1 levels. At a cutoff value of 2.00 ng/mL, the sensitivity and specificity of hyper-acetylated serum HMGB1 in differentiating MM patients from asbestos-exposed individuals was 100%, outperforming, in parallel experiments, other previously proposed biomarkers: osteopontin, fibulin-3, and mesothelin. When comparing MM patients to patients with other non-MM cytologically benign or malignant pleural effusion, the combination of two biomarkers, HMGB1 and fibulin-3, provided the highest sensitivity and specificity in differentiating these two groups. We propose total and hyper-acetylated HMGB1 as valuable biomarkers to differentiate MM patients from individuals professionally exposed to asbestos and from unexposed people. Citation Format: Andrea Napolitano, Daniel J. Antoine, Laura Pellegrini, Francine Baumann, Ian Pagano, Sandra Pastorino, Chandra M. Goparaju, Kirill Prokrym, Claudia Canino, Harvey I. Pass, Michele Carbone, Haining Yang. HMGB1 and its isoform are sensitive and specific biomarkers to detect asbestos exposure and to identify mesothelioma patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3112.

Abstract 4796: A founder mutation in the BAP1 gene among four caucasian families with high incidences of malignant peritoneal mesothelioma and uveal melanoma: a molecular and genealogical study in a 10-generation BAP1 cancer syndrome kindred

The BAP1 cancer syndrome is characterized by a high incidence of malignant mesothelioma (MM), uveal melanoma (UM), cutaneous melanoma (CM), clear cell renal cell carcinoma (ccRCC), and it is expected that the clinical phenotype will continue to broaden in scope. Molecular screening for BAP1 gene mutations among 29 patients selected for clinically apparent familial MM led to the identification of a heterozygous C base deletion mutation (c.1832delC, p.Leu573fs*3) shared by four of those patients. The frame shift deletion is predicted to truncate the BAP1 protein, and immunohistochemistry analysis of tumor specimens revealed predominant cytoplasmic staining. We genotyped 650K SNPs of the four MM samples and four controls and carried out principal component analysis and whole-genome identity-by-descent analysis using publicly available genotype data from the 1000 Genomes Project, UK10K Project, and NHIBL Exome Sequencing Project. These analyses showed that the four MM patients are of Central Europe ancestry and that some are related by a kinship coefficient of 0.0186. Haplotype analysis showed the presence of significantly shared segments around the BAP1 gene (LOD>37.1). The pairwise extent of shared segments between any of the four MM patients ranged in length from 9.1 to 34.2 Mbp and indicates the c.1832delC variant originated in a recent common ancestor within five to ten generations. Through a combined molecular genomic and genealogical approach, we ascertained, to our knowledge, the largest known genealogically connected BAP1 cancer syndrome kindred (K4), whose members can trace descent from a common ancestor in the 17th century. This pedigree provided a unique opportunity to examine effects of BAP1 alteration on tumor expression on various body sites and would facilitate study of gene-gene and gene-environment interaction involving the BAP1 gene. It also suggests that molecular screening of the BAP1 gene, coupled with genealogical research, would be an effective strategy for the early detection and early intervention for BAP1-associated malignancies. Citation Format: Erin Flores, Mitsuru Emi, Todd Johnson, Tatsuhiko Tsunoda, Dusty Behner, Harriet Hoffman, Mary Hesdorffer, Masaki Nasu, Andrea Napolitano, Francine Baumann, Haining Yang, Michele Carbone. A founder mutation in the BAP1 gene among four caucasian families with high incidences of malignant peritoneal mesothelioma and uveal melanoma: a molecular and genealogical study in a 10-generation BAP1 cancer syndrome kindred. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4796. doi:10.1158/1538-7445.AM2015-4796

Abstract 446: BAP1 mutation in mesothelioma and “BAP1 Cancer Syndrome”

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Malignant mesothelioma (MM) is a lethal cancer whose pathogenesis results from complex interactions between host genetics and environmental carcinogens, such as asbestos and erionite fibers. Recently, BAP1 (BRCA associated protein 1) has been identified as a novel MM tumor suppressor gene located at 3p21, a region frequently deleted in MM, which encodes for a deubiquitinase enzyme known to target histones and other proteins. We discovered that germline BAP1 mutations cause a novel cancer syndrome characterized by a significant excess of both pleural and peritoneal MM, uveal and cutaneous melanoma and possibly other tumors. In the same study, we reported that 22% sporadic MM tumors, among the Caucasian population, harbored somatic BAP1 mutations. Several other studies supported a relevant role of BAP1 in MM. However, a significant variation in the frequency of BAP1 mutation was found across different studies and populations. In fact, one research group found BAP1 gene altered in 61% of tumor samples from a Japanese cohort, pointing out to a possible influence of ethnicity on the prevalence of BAP-1 alterations among MM patients. However, the limitations in tumor sample sizes and methodological differences across studies do not allow for conclusive associations. We are now further analyzing BAP1 status and possible clinicopathological associations using different and more sensitive methods, such as MPLA, DNA and RNA sequencing, DNA copy number and methylation. Our preliminary results indicate that, regardless of ethnicity, BAP1 plays a crucial role in MM pathogenesis. More experiments are urgently needed to see whether BAP1 expression could be used in diagnostic, prognostic, or therapeutic settings. The impact of this work will extend to other cancers with BAP1 mutations. Citation Format: Masaki Nasu, Andrea Napolitano, Sandra Pastorino, Mika Tanji, Erin Flores, Francine Baumann, Amy Powers, Giovanni Gaudino, Harvey I. Pass, Haining Yang, Michele Carbone. BAP1 mutation in mesothelioma and “BAP1 Cancer Syndrome”. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 446. doi:10.1158/1538-7445.AM2014-446