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Dr. Michele Carbone's Scientific Publications

A Novel Mechanism of Late Gene Silencing Drives SV40 Transformation of Human Mesothelial Cells

A Novel Mechanism of Late Gene Silencing Drives SV40 Transformation of Human Mesothelial Cells

Cancer Research, November 2008: Volume 68, Issue 22

Suppression of the late gene expression, usually by integration of the viral DNA into the host genome, is a critical step in DNA tumor virus carcinogenesis. SV40 induces high rates of transformation in infected primary human mesothelial cells in tissue culture, leading to the formation of immortal cell lines (SV40-transformed human mesothelial cell lines, S-HML).

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Malignant Mesothelioma: Time to Translate?

Malignant Mesothelioma: Time to Translate?

Opinion: Lessons from the Clinic

Malignant Mesothelioma is a rare and poorly understood cancer with limited therapeutic approaches.

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Consensus Report of the 2015 Weinman International Conference on Mesothelioma

Consensus Report of the 2015 Weinman International Conference on Mesothelioma

Special Article in the Journal of Thoracic Oncology, August 2016

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 group’s efforts and focus on strategies to limit risk to the population and reduce the incidence of MM. Four main topics were explored:

  1. Genetic risk
  2. Environmental exposure
  3. Biomarkers
  4. Clinical interventions

Authors: Michele Carbone, MD, PhD, Shreya Kanodia, PhD, Ann Chao, PhD, Aubrey Miller, MD, Anil Wali, PhD, David Weissman, MD, Alex Adjei, MD, PhD, Francine Baumann, PhD, Paolo Boffetta, MD, PhD, Brenda Buck, PhD, Marc de Perrot, MD, A. Umran Dogan, PhD, Steve Gavett, PhD, Alessandro Gualtieri, PhD, Raffit Hassan, MD, Mary Hesdorffer, NP, Fred R. Hirsch, MD, PhD, David Larson, PhD, Weimin Mao, PhD, Scott Masten, PhD, Harvey I. Pass, PhD, Julian Peto, DSc, Enrico Pira, Phd, Ian Steele, MD, Anne Tsao, MD, Gavitt Alida Woodard, MD, Haining Yang, PhD, Shakun Malik, MD

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Positive nuclear BAP1 immunostaining helps differentiate non-small cell lung carcinomas from malignant mesothelioma

Positive nuclear BAP1 immunostaining helps differentiate non-small cell lung carcinomas from malignant mesothelioma

Differentiating between pleural malignant mesothelioma (MM) and lung cancer is often challenging. Immunohistochemical (IHC) stains used to distinguish these malignancies include markers  that are most often positive in malignant mesothelioma and less frequently positive in carcinomas, and vice versa. However, in 10 to 20% of the cases, the immunohistochemical staining results can be confusing and inconclusive,  and novel markers are sought to increase the diagnostic accuracy.

We stained 45 non-small cell lung cancers (32 adenocarcinomas and 13 squamous cell carcinomas) with a monoclonal antibody for BRCA1-associated protein 1 (BAP1) and also with an IHC panel we routinely use to help differentiate MM from carcinomas, which include calretinin, Wilms Tumor 1, cytokeratin 5, podoplantin D2-40, pankeratin CAM5.2, thyroid transcription factor 1, Napsin-A,  and p63.  Nuclear BAP1 expression was also analyzed in 35 MM biopsies. All 45 non-small cell lung cancer biopsies stained positive for nuclear BAP1, whereas 22/35 (63%)  MM biopsies lacked nuclear BAP1 staining, consistent with previous data. Lack of BAP1 nuclear staining was associated with MM. Focal BAP1 staining was observed in a subset of samples, suggesting polyclonality. Diagnostic accuracy of other classical IHC markers was in agreement with previous studies. Our study indicated that absence of nuclear BAP1 staining helps differentiate MM from lung carcinomas. We suggest that BAP1 staining should be added to the IHC panel that is currently used to distinguish these malignancies.  

 Authors: Michele Carbone, David Shimizu, Andrea Napolitano, Mika Tanji,  Harvey I. Pass, Haining Yang, Sandra Pastorino

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High Incidence of Somatic BAP1 Alterations in Sporadic Malignant Mesothelioma

High Incidence of Somatic BAP1 Alterations in Sporadic Malignant Mesothelioma

The BAP1 gene should be targeted to develop specific therapies for mesothelioma

Genetic mutations can be inherited at birth, and some of them cause disease and cancer, such as the BAP1 cancer syndrome. Alternatively, the same genes or others can become mutated in cancer cells.  Most mutations found in cancer cells are acquired during tumor growth and do not play a critical role in tumor initiation or growth. Some mutations, instead, are called driver mutations because they drive tumor growth.  Driver mutations are usually frequent in a given tumor type.

 

We found that BAP1 is the most commonly acquired mutation in sporadic mesothelioma, which means mesothelioma that does not occur because of inherited germline mutation (for example, mesothelioma caused by asbestos exposure).  We found that over 60% of sporadic mesotheliomas have mutated BAP1. This finding underscores the critical role of BAP1 in mesothelioma and points to BAP1 as the critical gene that should be targeted to develop specific therapies for mesothelioma. Our findings have been validated by several other independent studies, including those of Drs. Harvey Pass, Rafael Bueno, Giorgio Scagliotti, and others, which are reviewed in The Journal of Thoracic Oncology publication
Recent insights emerging from malignant mesothelioma genome sequencing.

 

Authors:  Masaki Nasu, Mitsuri Emi, Sandra Pastorino, Mika Tanji, Amy Powers, Hugh Lik, Francine Baumann, Yu-An, Mitsuru Emi, Sandra Pastorino, Mika Tanil, Amy Powers, Hugh Luk, Francine Baumann, Yu-an Zhang, Adi Gazdar, Shreya Kanodia, Maarit Tirikainen, Erin Flores, Giovanni Gaudino, Michael J. Becich, Harvey I. Pass, Haining Yang, Michele Carbone, MD, PhD.  

 

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