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Dr. Carbone proposed 7, 8 ,9 and later proved,10 ,11 that gene x environment interactions cause Malignant Mesothelioma and other cancers. His multi-national team discovered that BAP1 germline mutations predispose individuals to Malignant Mesothelioma and other environmentally related malignancies, such as uveal and cutaneous melanoma 10 ,11. BAP1 is the first, and so far only, gene shown to modulate environmental carcinogenesis. 10,11

Briefly, through a 14-year study of an epidemic of Malignant Mesothelioma in Cappadocia, Turkey, where over 50% of the population exposed to erionite fibers dies of Malignant Mesothelioma. 7,8 9 Dr. Carbone’s team discovered that susceptibility to Malignant Mesothelioma was transmitted in a Mendelian fashion. Dr. Carbone formulated the hypothesis that the cause of the epidemic was gene-environment interaction.7,9 

These initial studies were funded through grants Dr. Carbone received from the American Cancer Society.  In subsequent studies, funded by a P01 from the National Cancer Institute, Dr. Carbone’s team discovered that germline BAP1 truncating mutations caused a very high incidence of Malignant Mesothelioma in some families in the US and abroad in the absence of occupational exposure to asbestos.10,11 Moreover, using a BAP1+/- mouse model, they demonstrated that mice carrying germline BAP1 mutations develop Malignant Mesothelioma following exposure to very low doses of asbestos that rarely caused Malignant Mesothelioma in wild-type mice. 12

Dr. Carbone’s data, confirmed and expanded by other scientists worldwide, showed that germline BAP1 mutations are also associated with uveal melanoma, renal cell carcinoma11. At a young age, carriers of BAP1 germline mutations start developing benign melanocytic skin tumors called melanocytic BAP1-mutated atypical intradermal tumors (MBAITs). 14 MBAITs provide physicians with a visual clue to identify BAP1 mutation carriers that Dr. Carbone’s team are monitoring for early detection of eye and skin melanoma, Malignant Mesothelioma and other malignancies.

The incidence of cancer among carriers of germline BAP1 mutations is extremely high: so far, all carriers have developed one or more cancer by age 55. 15 However, Dr. Carbone discovered that Malignant Mesothelioma and other cancers that develop in a background of BAP1+/- germline mutations are associated with prolonged survival of 5-10 or more years, 15 which may be in part related to early detection since these families are closely monitored, and in part to a possibly less aggressive tumor phenotype.

Dr. Carbone’s research team are building a large—and presently only—BAP1+/- family cohort. They have studied over 50 families with multiple cases of Malignant Mesothelioma and other malignancies, and have tissues and clinical records of several members from each of these families. They have identified four families that share the same BAP1 point mutation. 16 In addition, they discovered that the four families are related, descending from a German couple that immigrated to the US in the early 1700s 16. From this extended family, the team has built a pedigree encompassing ~80,000 people, and are identifying additional branches of this family that carry the mutation. Dr. Carbone’s researchers are enrolling BAP1+/- carriers in a screening program for early detection of eye and skin melanoma, cancers that are cured when detected early, and for biomarkers studies. 17

Informational Video About This Research

In addition, by using a combination of Sanger sequencing, MLPA, RNA and DNA methylation analyses, Dr. Carbone’s team have detected BAP1 inactivation in ~60% of sporadic Malignant Mesothelioma, 18 making BAP1 the most commonly mutated gene in Malignant Mesothelioma, a finding confirmed by others (reviewed in reference 19). This finding underscores the pivotal role of BAP1 in Malignant Mesothelioma. BAP1 is a member of the ubiquitin C-terminal hydrolase (UCH) subfamily of de-ubiquitinating enzymes (DUBs) and is found associated with multi-protein complexes that regulate cell cycle, differentiation, apoptosis, gluconeogenesis, and the DNA damage response.11  

Future Research Plans

  • AIM 1.  Elucidate The Role Of BAP1 In Cancer Initiation
    Dr. Carbone’s goal is to identify the key mechanisms of BAP1 activity. They anticipate that the identification of these mechanisms should provide valuable targets for prevention and therapy, and elucidate the cellular activities that influence gene x environment interaction in carcinogenesis.
  • AIM 2. Identify and validate novel gene variants that predispose to Malignant Mesothelioma
    Dr. Carbone postulates that—as with other cancers—additional genetic variants influence Malignant Mesothelioma development and individual susceptibility to asbestos.

The proposed research program stems from Dr. Carbone’s discovery that genetics modulates environmental carcinogenesis and that germline BAP1 mutations cause a novel cancer syndrome characterized by a very high incidence of Malignant Mesothelioma, uveal melanoma, and other cancers. 10 ,11; 13 , 14 , 15 , 16 Over the past 10 years, his team has assembled a unique cohort of families carrying germline BAP1 mutations, biospecimens and derived cell lines.10 ,11;13 , 14 , 15 , 16 The identification of BAP1 and the anticipated identification of novel germline DNA variants, that similarly to BAP1 predispose to Malignant Mesothelioma, will allow the team to study the molecular pathways involved in sporadic and familial Malignant Mesothelioma, a necessary step towards designing novel therapies for Malignant Mesothelioma. The proposed studies are relevant to Malignant Mesothelioma and to the other malignancies associated with the BAP1 cancer syndrome11 and will elucidate the activity of BAP1 and its role in causing Malignant Mesothelioma; the mechanisms responsible for the increased susceptibility of BAP1+/- mutants to low doses of asbestos; the set of genetic alterations that occur in the early stages of Malignant Mesothelioma development in BAP1 mutation carriers exposed to low doses of asbestos; and the evaluation of HMGB1 isoforms as biomarkers for mineral fiber exposure and early detection of Malignant Mesothelioma, which should impact patients by improving survival. The goal of Dr. Carbone’s research is to develop effective preventive strategies for Malignant Mesothelioma and to increase early diagnosis and long-term survivors among Malignant Mesothelioma patients.

REFERENCES

  1. Carbone M, Ly BH, Dodson RF, Pagano I, Morris PT, Dogan UA, Gazdar AF, Pass HI, Yang H. Malignant mesothelioma: Facts, myths and hypotheses. Malignant mesothelioma: Facts, myths and hypotheses. Journal of  Cellular Physiology, 227: 44-58, 2012 Jan. PMCID: PMC3143206.
  2. Henley SJ, Larson TC, Wu M, et al. Mesothelioma incidence in 50 states and the District of Columbia, United States, 2003-2008. International Journal of Occupational and Environmental Health 2013;19:1-10.
  3. Flores RM, Pass HI, Seshan VE, Dycoco J, Zakowski M, Carbone M, Bains MS, Rusch VW. Extrapleural Pneumonectomy Versus Pleurectomy Decortication in the Surgical Management of Malignant Pleural Mesothelioma. Journal of Thoracic Cardiovascular Surgery, 2008.
  4. Carbone M, Baris YI, Bertino P, Brass B, Comertpay S, Dogan AU, Gaudino G, Jube S, Kanodia S, Partridge CR, Pass HI, Rivera ZS, Steele I, Tuncer M, Way S, Yang H, Miller A. Erionite exposure in North Dakota and Turkish villages with mesothelioma. Proceedings of the National Academy of Science USA, 108:13618-23, 2011.
  5. Baumann F, Buck BJ, Metcalf RV, McLaurin BT, Merkler D, and Carbone M. The presence of asbestos in the natural environment is likely related to mesothelioma in young individuals and women from Southern Nevada. Journal of Thoracic Oncology, 10:731-7, 2015.
  6. Yang H, Rivera Z, Jube S, Nasu M, Bertino P, Goparaju C, Franzoso G, Lotze MT, Krausz T, Pass HI, Bianchi ME, and Carbone M. Programmed necrosis induced by asbestos in human mesothelial cells causes high-mobility group box 1 protein release and resultant inflammation. Proceedings of the National Academy of Science USA, 107: 12611-12616, 2010. PMCID: PMC2906549.
  7. Carbone M, Emri S, Dogan U, Steele I, Tuncer M, Pass HI, Baris YI. A mesothelioma epidemic in Cappadocia: scientific developments and unexpected social outcomes. Nature Reviews Cancer, 7:147-154, 2007.
  8. Roushdy-Hammady I, Siegel J, Emri S, Testa JR and Carbone M. A genetic-susceptibility factor malignant mesothelioma in the Cappadocian region of Turkey. The Lancet, 357:444-445, 2001.
  9. Dogan UA, Baris YI, Dogan M, Emri S, Steele I, Elmishad AG, and Carbone M. Genetic Predisposition to Fiber Carcinogenesis Causes a mesothelioma Epidemic in Turkey. Cancer Research, 66:5063-5068, 2006.
  10. Testa JR, Cheung M, Pei J, Below JE, Tan Y, Sementino E, Cox N, Dogan AU, Pass, HI, Trusa S, Hesdorffer M, Nasu M, Powers A, Rivera Z, Comertpay S, Tanji M, Gaudino G, Yang H, and Carbone M. Germline BAP1 mutations predispose to malignant mesothelioma. Nature Genetics, 43: 1022-25, 2011.
  11. Carbone M, Yang H, Pass HI, Krausz T, Testa JR, Gaudino G. Bap1 and cancer. Nature Review Cancer, 13:153-159, 2013.
  12. Napolitano A, Pellegrini L, Dei A, Larson D, Tanji M, Flores EG, Kendrick B, Lapid D, Powers A, Kanodia S, Pastorino S, Pass HI, Dixit V, Yang H, and Carbone M. Minimal asbestos exposure in germline BAP1 heterozygous mice is associated with deregulated inflammatory response and increased risk of mesothelioma. Oncogene, Advance online publication, June 29, 2015.
  13. Pena-Llopis S, Vega-Rubin-de-Celis S, Liao A, et al. BAP1 loss defines a new class of renal cell carcinoma. Nature Genetics, 2012;44:751-759.
  14. Carbone M, Ferris LK, Baumann F, Napolitano A, Lum CA, Flores EG, Gaudino G, Powers A, Bryant-Greenwood  P, Krausz T, Hyjek E, Tate R, Friedberg J, Weigel T, Pass HI, Yang H.  BAP1 cancer syndrome: malignant mesothelioma, uveal and cutaneous melanoma, and MBAITs.  Journal of Translational Medicine, 10:179, 2012.
  15. Baumann F, Flores E, Napolitano A, Kanodia A, Taioli E, Pass H, Yang H, and Carbone M. Mesothelioma Patients with Germline BAP1 Mutations Have Seven-Fold Improved Long-term Survival. Carcinogenesis, 36:76-81, 2015.
  16. Carbone M, Flores EG, Emi M, Johnson TA, Tsunoda T, Behner D, Hoffman H, Hesdorffer M, Nasu M, Napolitano A, Power A, Minaai M, Baumann F, Bryant-Greenwood P, Lauk O, Kirschner MB, Weder W, Opitz I, Pass HI, Gaudino G, Pastorino S, Yang H. Combined genetic and genealogic studies uncover a large BAP1 cancer syndrome kindred, tracing back nine generations to a common ancestor from the 1700s. PLoS Genetics, Advance online publication, Dec 18, 2015
  17. Napolitano A, Antoine DJ , Pellegrini L, Baumann F, Pagano IS , Pastorino S, Goparaju CM, Prokrym K, Canino C, Pass HI, Carbone M.  and Yang H. HMGB1 and its hyper-acetylated isoform are sensitive and specific serum biomarkers to detect asbestos exposure and to identify mesothelioma patients. Clinical Cancer Research, Advance online publication, Jan 5, 2016.
  18. Nasu M, Emi M, Pastorino S, Tanji M, Powers A, Baumann F, Zhang YA, Gazdar A, Kanodia S, Tiirikainen M, Flores E, Gaudino G, Becich GJ, Pass HI, Yang H, and Carbone M. High incidence of somatic BAP1 alterations in sporadic malignant mesothelioma. Journal of Thoracic Oncology, 10:565-76, 2015.
  19. Carbone M., et al. Consensus Report of the 2015 Weinman International Conference on Mesothelioma. Journal of Thoracic Oncology, accepted
  20. Carbone M and Yang H. Molecular pathways: targeting mechanisms of asbestos and erionite carcinogenesis in mesothelioma. Clinical Cancer Research, 18:598-604, 2012.
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