Mary Hesdorffer

Germline BAP1 mutations predispose to malignant mesothelioma

Because only a small fraction of asbestos-exposed individuals develop malignant mesothelioma, and because mesothelioma clustering is observed in some families, we searched for genetic predisposing factors. We discovered germline mutations in the gene encoding BRCA1 associated protein-1 (BAP1) in two families with a high incidence of mesothelioma, and we observed somatic alterations affecting BAP1 in familial mesotheliomas, indicating biallelic inactivation. In addition to mesothelioma, some BAP1 mutation carriers developed uveal melanoma. We also found germline BAP1 mutations in 2 of 26 sporadic mesotheliomas; both individuals with mutant BAP1 were previously diagnosed with uveal melanoma. We also observed somatic truncating BAP1 mutations and aberrant BAP1 expression in sporadic mesotheliomas without germline mutations. These results identify a BAP1-related cancer syndrome that is characterized by mesothelioma and uveal melanoma. We hypothesize that other cancers may also be involved and that mesothelioma predominates upon asbestos exposure. These findings will help to identify individuals at high risk of mesothelioma who could be targeted for early intervention.

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.

Combined Genetic and Genealogic Studies Uncover a Large BAP1 Cancer Syndrome Kindred Tracing Back Nine Generations to a Common Ancestor from the 1700s

We recently discovered an inherited cancer syndrome caused by BRCA1-Associated Protein 1 (BAP1) germline mutations, with high incidence of mesothelioma, uveal melanoma and other cancers and very high penetrance by age 55. To identify families with the BAP1 cancer syndrome, we screened patients with family histories of multiple mesotheliomas and melanomas and/or multiple cancers. We identified four families that shared an identical BAP1 mutation: they lived across the US and did not appear to be related. By combining family histories, molecular genetics, and genealogical approaches, we uncovered a BAP1 cancer syndrome kindred of ~80,000 descendants with a core of 106 individuals, whose members descend from a couple born in Germany in the early 1700s who immigrated to North America. Their descendants spread throughout the country with mutation carriers affected by multiple malignancies. Our data show that, once a proband is identified, extended analyses of these kindreds, using genomic and genealogical studies to identify the most recent common ancestor, allow investigators to uncover additional branches of the family that may carry BAP1 mutations. Using this knowledge, we have identified new branches of this family carrying BAP1 mutations. We have also implemented early-detection strategies that help identify cancers at early-stage, when they can be cured (melanomas) or are more susceptible to therapy (MM and other malignancies).

Germline BAP1 Mutational Landscape of Asbestos-Exposed Malignant Mesothelioma Patients with Family History of Cancer

Heritable mutations in the BAP1 tumor suppressor gene predispose individuals to mesothelioma and other cancers. However, a large-scale assessment of germline BAP1 mutation incidence and associated clinical features in mesothelioma patients with a family history of cancer has not been reported. Therefore, we examined the germline BAP1 mutation status of 150 mesothelioma patients with a family history of cancer, 50 asbestos-exposed control individuals with a family history of cancers other than mesothelioma, and 153 asbestos-exposed individuals without familial cancer. No BAP1 alterations were found in control cohorts, but were identified in nine of 150 mesothelioma cases (6%) with a family history of cancer. Alterations among these cases were characterized by both missense and frameshift mutations, and enzymatic activity of BAP1 missense mutants was decreased compared with wild-type BAP1. Furthermore, BAP1 mutation carriers developed mesothelioma at an earlier age that was more often peritoneal than pleural (five of nine) and exhibited improved long-term survival compared to mesothelioma patients without BAP1 mutations. Moreover, many tumors harboring BAP1 germline mutations were associated with BAP1 syndrome, including mesothelioma and ocular/cutaneous melanomas, as well as renal, breast, lung, gastric, and basal cell carcinomas. Collectively, these findings suggest that mesothelioma patients presenting with a family history of cancer should be considered for BAP1 genetic testing to identify those individuals who might benefit from further screening and routine monitoring for the purpose of early detection and intervention.

Changing Pattern in Malignant Mesothelioma Survival

Survival for mesothelioma has been shown to be poor, with marginal improvement over time. Recent advances in the understanding of pathophysiology and treatment of mesothelioma may impact therapy to improve survival that may not be evident from available clinical trials that are often small and not randomized. Therapies may affect survival differently based on mesothelioma location (pleural vs peritoneal). Data are conflicting regarding the effect of asbestos exposure on mesothelioma location. OBJECTIVES: We examined survival in a large cohort of mesothelioma subjects analyzed by tumor location and presence and mode of asbestos exposure. METHODS: Data were analyzed from cases (n = 380) diagnosed with mesothelioma from 1992 to 2012. Cases were either drawn from treatment referrals, independent medical evaluation for medical legal purposes, or volunteers who were diagnosed with mesothelioma. Subjects completed an occupational medical questionnaire, personal interview with the examining physician, and physician review of the medical record. RESULTS: This study reports better survival for mesothelioma than historical reports. Survival for peritoneal mesothelioma was longer than that for pleural mesothelioma (hazard ratio = 0.36, 95% confidence interval = 0.24-0.54, P < .001) after adjusting for gender and age at diagnosis. Non-occupational cases were more likely to be 1) diagnosed with peritoneal mesothelioma, 2) female, 3) exposed, and 4) diagnosed at a younger age and to have a 5) shorter latency compared to occupational cases (P < .001). CONCLUSION: Peritoneal mesothelioma was more likely associated with non-occupational exposure, thus emphasizing the importance of exposure history in enhancing early diagnosis and treatment impact.

Treatment of Malignant Pleural Mesothelioma: American Society of Clinical Oncology Clinical Practice Guideline

Purpose To provide evidence-based recommendations to practicing physicians and others on the management of malignant pleural mesothelioma. Methods ASCO convened an Expert Panel of medical oncology, thoracic surgery, radiation oncology, pulmonary, pathology, imaging, and advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and prospective and retrospective comparative observational studies published from 1990 through 2017. Outcomes of interest included survival, disease-free or recurrence-free survival, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. Results The literature search identified 222 relevant studies to inform the evidence base for this guideline. Recommendations Evidence-based recommendations were developed for diagnosis, staging, chemotherapy, surgical cytoreduction, radiation therapy, and multimodality therapy in patients with malignant pleural mesothelioma. Additional information is available at www.asco.org/thoracic-cancer-guidelines and www.asco.org/guidelineswiki .

Challenges Facing Mesothelioma Patients and Their Families: Medical/Legal Intersections

To enhance foresight for patients and their physicians, and to encourage mutual understanding of likely medical/legal events, this chapter addresses medical/legal aspects of lawsuits to obtain compensation for a mesothelioma possibly caused—in whole or in part—by intake of asbestos fibers. The chapter includes overview information on (1) the approximately 2000 US mesothelioma lawsuits filed in each of 2014 and 2015, (2) factors to consider when thinking about a mesothelioma lawsuit and considering lawyers for such a lawsuit, (3) the economics of mesothelioma claims, and (4) “asbestos trusts” and mesothelioma compensation. Also addressed are trial and pretrial “discovery” processes, including emotional and stress factors that may arise from actual or potential conflicting thoughts and priorities generated by simultaneously going through litigation and therapy. Medical data and medical record disclosure issues will arise when lawsuits and claims to trusts are asserted, including demands by lawyers and/or trusts for experts to have access to portions of biopsy samples or other biologic materials used to diagnose mesothelioma. Genetic testing for the person and/or family also may be requested, as was done during pretrial processes for an early 2016 mesothelioma trial which included expert testimony regarding the possible significance of germ line (inherited) genetic characteristics of the person afflicted by mesothelioma. Other pretrial discovery processes arise from the issues that will be resolved in trial. In mesothelioma cases, the overall issue typically is the “cause” of the tumor, as that term is defined and utilized in legal systems. Because of scientific issues about when and how asbestos intake can lead to mesothelioma, persons with mesothelioma and family members should expect to become involved in legal system processes aimed at collecting testimony and documents about the possible amounts and sources of asbestos intake for a particular person. Treating doctors and scientists may be called upon to provide expert testimony regarding which “exposures” to which asbestos products might or might not be deemed “enough” to be a legal cause of the mesothelioma. In addition, some lawyers and other professionals (e.g., actuaries) are starting to pay attention to “molecular science,” including developments at the intersections between science and law regarding biomarkers, possible signatures in somatic mutation patterns, and individual variability, including the impact of individual variability for workplace regulations and “toxic tort” lawsuits. Most lawsuits settle without a trial, but each year, perhaps 40–100 mesothelioma cases will at least start a trial against some of the entities named as defendants, and these cases will generate the most pretrial discovery activity. In addition, trial dates are catalysts for settlements, so there also are extensive pretrial discovery processes for hundreds of cases set for trial each year.

Mesothelioma survivorship: challenges in delivering quality care

ABSTRACT Introduction: Mesothelioma is one of the only malignancies that has a direct correlation to asbestos exposure. Utilizing electron microscopy, asbestos fibers can be ascertained in the lungs of indviduals who have been exposed; through these means, approximately 80% of mesothelioma cases can be linked to asbestos exposure. Areas covered: The quality of care for mesothelioma survivors has yet to result in national guidelines, and there is a dearth of literature on the lived experience of the mesothelioma patient. This article will explore the challenges unique to mesothelioma, transitioning to long-term care, and the benefits of support network engagement. Expert commentary: Individuals diagnosed with mesothelioma are often challenged with having to navigate their post-active treatment care on their own. Complicated by the lack of support networks and clear guidelines, this results in poor emotional health. As treatments for mesothelioma and other cancers continue to be based on druggable targets rather than disease specific treatment, survivorship will need to redefined as those who are surviving a particular treatment rather than those surviving a mesothelioma diagnosis.

Abstract 1179: Combined genetic and genealogic studies uncover a large BAP1 cancer syndrome kindred, tracing back nine generations to a common ancestor from the 1700s

Germline BAP1 mutations cause a cancer syndrome characterized by high incidence of mesothelioma (MM), uveal melanoma and other cancers, and by very high penetrance, as all individuals carrying BAP1 mutations developed at least one, and usually several, malignancies throughout their lives. Through screening MM patients with histories of multiple cancers, we found four supposedly unrelated patients that shared an identical germline BAP1 mutation. We investigated whether this BAP1 mutation occurred in a ‘hot-spot’ for “de novo” mutations or whether these four MM patients shared a common ancestor. Using molecular genomics analyses we found that they are related. By genealogic studies we traced their ancestor to a couple that emigrated from Germany to North America in the early 1700’s; we traced the subsequent migration of their descendants, who are now living in at least three different US States. Our findings demonstrate that BAP1 mutations are transmitted among subsequent generations over the course of centuries. This knowledge and methodology is being used to identify additional branches of the family carrying BAP1 mutations. Our study shows that the application of modern genomic analyses, coupled with “classical” family histories collected by the treating physician, and with genealogical searches, offer a powerful strategy to identify high-risk germline BAP1 mutation carriers that will benefit from genetic counseling and early detection cancer screening. Citation Format: Michele Carbone, Erin G. Flores, Mitsuru Emi, Giovanni Gaudino, Sandra Pastorino, Haining Yang, Todd Johnson, Tatsuhiko Tsunoda, Mary Hesdorffer, Harvey I. Pass. Combined genetic and genealogic studies uncover a large BAP1 cancer syndrome kindred, tracing back nine generations to a common ancestor from the 1700s. [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 1179.

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