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Germline BAP1 mutations predispose to malignant mesothelioma
Testa, Joseph R; Cheung, Mitchell; Pei, Jianming; Below, Jennifer E; Tan, Yinfei; Sementino, Eleonora; Cox, Nancy J; Dogan, A Umran; Pass, Harvey I; Trusa, Sandra; Hesdorffer, Mary; Nasu, Masaki; Powers, Amy; Rivera, Zeyana; Comertpay, Sabahattin; Tanji, Mika; Gaudino, Giovanni; Yang, Haining; Carbone, Michele
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
PMCID:3184199
PMID: 21874000
ISSN: 1546-1718
CID: 149988
Erionite exposure in North Dakota and Turkish villages with mesothelioma
Carbone, Michele; Baris, Y Izzettin; Bertino, Pietro; Brass, Brian; Comertpay, Sabahattin; Dogan, A Umran; Gaudino, Giovanni; Jube, Sandro; Kanodia, Shreya; Partridge, Charles R; Pass, Harvey I; Rivera, Zeyana S; Steele, Ian; Tuncer, Murat; Way, Steven; Yang, Haining; Miller, Aubrey
Exposure to erionite, an asbestos-like mineral, causes unprecedented rates of malignant mesothelioma (MM) mortality in some Turkish villages. Erionite deposits are present in at least 12 US states. We investigated whether increased urban development has led to erionite exposure in the United States and after preliminary exploration, focused our studies on Dunn County, North Dakota (ND). In Dunn County, ND, we discovered that over the past three decades, more than 300 miles of roads were surfaced with erionite-containing gravel. To determine potential health implications, we compared erionite from the Turkish villages to that from ND. Our study evaluated airborne point exposure concentrations, examined the physical and chemical properties of erionite, and examined the hallmarks of mesothelial cell transformation in vitro and in vivo. Airborne erionite concentrations measured in ND along roadsides, indoors, and inside vehicles, including school buses, equaled or exceeded concentrations in Boyali, where 6.25% of all deaths are caused by MM. With the exception of outdoor samples along roadsides, ND concentrations were lower than those measured in Turkish villages with MM mortality ranging from 20 to 50%. The physical and chemical properties of erionite from Turkey and ND are very similar and they showed identical biological activities. Considering the known 30- to 60-y latency for MM development, there is reason for concern for increased risk in ND in the future. Our findings indicate that implementation of novel preventive and early detection programs in ND and other erionite-rich areas of the United States, similar to efforts currently being undertaken in Turkey, is warranted
PMCID:3158231
PMID: 21788493
ISSN: 1091-6490
CID: 138001
Epigenetic silencing of microRNA-34b/c plays an important role in the pathogenesis of malignant pleural mesothelioma
Kubo, Takafumi; Toyooka, Shinichi; Tsukuda, Kazunori; Sakaguchi, Masakiyo; Fukazawa, Takuya; Soh, Junichi; Asano, Hiroaki; Ueno, Tsuyoshi; Muraoka, Takayuki; Yamamoto, Hiromasa; Nasu, Yasutomo; Kishimoto, Takumi; Pass, Harvey I; Matsui, Hideki; Huh, Nam-Ho; Miyoshi, Shinichiro
PURPOSE: Malignant pleural mesothelioma (MPM) is an aggressive tumor with a dismal prognosis. Unlike other malignancies, TP53 mutations are rare in MPM. Recent studies have showed that altered expression of microRNA (miRNA) is observed in human malignant tumors. In this study, we investigated the alterations of miR-34s, a direct transcriptional target of TP53, and the role of miR-34s on the pathogenesis of MPM. EXPERIMENTAL DESIGN: Aberrant methylation and expression of miR-34s were examined in MPM cell lines and tumors. miR-34b/c was transfected to MPM cells to estimate the protein expression, cell proliferation, invasion, and cell cycle. RESULTS: Aberrant methylation was present in 2 (33.3%) of 6 MPM cell lines and 13 (27.7%) of 47 tumors in miR-34a and in all 6 MPM cell lines (100%) and 40 (85.1%) of 47 tumors in miR-34b/c. Expression of miR-34a and 34b/c in all methylated cell lines was reduced and restored with 5-aza-2'-deoxycytidine treatment. Because epigenetic silencing was the major event in miR-34b/c, we investigated the functional role of miR-34b/c in MPM. miR-34b/c-transfected MPM cells with physiologic miR-34b/c expression exhibited antiproliferation with G(1) cell cycle arrest and suppression of migration, invasion, and motility. The forced overexpression of miR-34b/c, but not p53, showed a significant antitumor effect with the induction of apoptosis in MPM cells. CONCLUSIONS: We show that the epigenetic silencing of miR-34b/c by methylation is a crucial alteration and plays an important role in the tumorigenesis of MPM, suggesting potential therapeutic options for MPM.
PMID: 21673066
ISSN: 1078-0432
CID: 156309
Recommendations for uniform definitions of surgical techniques for malignant pleural mesothelioma: a consensus report of the international association for the study of lung cancer international staging committee and the international mesothelioma interest group
Rice, David; Rusch, Valerie; Pass, Harvey; Asamura, Hisao; Nakano, Takashi; Edwards, John; Giroux, Dorothy J; Hasegawa, Seiki; Kernstine, Kemp H; Waller, David; Rami-Porta, Ramon
INTRODUCTION: Extrapleural pneumonectomy has been well defined; however, surgeons vary regarding the surgical extent and goals of 'pleurectomy/decortication' (P/D). We explored mesothelioma surgeons' concepts of P/D with the aim of unifying surgical nomenclature. METHODS: A web-based survey was administered to surgeons who operated on malignant pleural mesothelioma (MPM) for diagnosis, staging, palliation, or cytoreduction. One hundred thirty surgeons from 59 medical centers were included. Surgeons who did not perform surgery for MPM within the last year were excluded. RESULTS: There were 62 (48%) respondents from 39 medical centers in 14 countries. The mean number of patients with MPM seen annually at each medical center was 46, and the mean annual number of cytoreductive procedures performed per surgeon was 8. Most (88%) agreed that the goal of cytoreductive surgery should be macroscopic complete resection of tumor. P/D was defined as resection of parietal and visceral pleura with the aim of achieving macroscopic complete resection by 72% of respondents. If the diaphragm or pericardium required resection, 64% preferred the term 'radical P/D,' whereas 'P/D' (40%) or 'total pleurectomy' (39%) was preferred if these structures were not removed. Most surgeons believed that extrapleural pneumonectomy (90%) or 'radical P/D' (68%) could provide adequate cytoreduction, whereas only 23% thought that P/D could. CONCLUSIONS: There was significant variation regarding surgical nomenclature for procedures for MPM. The International Staging Committee of the International Association for the Study of Lung Cancer and the International Mesothelioma Interest Group recommend that P/D should aim to remove all macroscopic tumor involving the parietal and visceral pleura and should be termed 'extended' P/D when the diaphragm or pericardium is resected
PMID: 21847060
ISSN: 1556-1380
CID: 149989
Detection of integrin-linked kinase in the serum of patients with malignant pleural mesothelioma
Watzka, Stefan B; Posch, Florian; Pass, Harvey I; Huflejt, Margaret; Bernhard, David; Hannigan, Gregory E; Muller, Michael R
OBJECTIVE: Integrin-linked kinase, which is relevant to neoplastic transformation, is highly expressed in malignant pleural mesothelioma. Recently, detection of integrin-linked kinase in serum of patients with ovarian cancer has been reported. This study asks whether integrin-linked kinase can also be detected in serum of patients with malignant pleural mesothelioma and whether serum level has diagnostic or prognostic relevance for that disease. METHODS: A sandwich enzyme-linked immunosorbent assay was designed to detect integrin-linked kinase and applied to serum samples from 46 patients with malignant pleural mesothelioma, 98 patients with other malignant chest disease, and 23 patients with benign chest disease. Integrin-linked kinase serum concentration and clinical data were correlated statistically. RESULTS: Median serum integrin-linked kinase concentration was significantly higher in malignant pleural mesothelioma (8.89 ng/mL) than in other malignant chest disease (0.66 ng/mL) or benign chest disease (0.78 ng/mL, P < .001). There was no relevant correlation of serum integrin-linked kinase with cell lysis parameters (R(2) < 0.1). Serum integrin-linked kinase concentration greater than 2.48 ng/mL had diagnostic sensitivity of 80%, specificity of 95%, positive predictive value of 85.7%, negative predictive value of 92.7%, and overall accuracy of 91% for distinction between malignant pleural mesothelioma and other diseases. Serum integrin-linked kinase concentration in malignant pleural mesothelioma was independent of histologic subtype or asbestos exposure. There was no statistically significant impact of serum integrin-linked kinase concentration on prognosis. CONCLUSIONS: Integrin-linked kinase can be detected in serum of patients with malignant pleural mesothelioma and may be a diagnostic marker for the disease
PMID: 21620418
ISSN: 1097-685x
CID: 135519
Increased efficacy of doxorubicin delivered in multifunctional microparticles for mesothelioma therapy
Hillegass, Jedd M; Blumen, Steven R; Cheng, Kai; Macpherson, Maximilian B; Alexeeva, Vlada; Lathrop, Sherrill A; Beuschel, Stacie L; Steinbacher, Jeremy L; Butnor, Kelly J; Ramos-Nino, Maria E; Shukla, Arti; James, Ted A; Weiss, Daniel J; Taatjes, Douglas J; Pass, Harvey I; Carbone, Michele; Landry, Christopher C; Mossman, Brooke T
New and effective treatment strategies are desperately needed for malignant mesothelioma (MM), an aggressive cancer with a poor prognosis. We have shown previously that acid-prepared mesoporous microspheres (APMS) are nontoxic after intrapleural or intraperitoneal (IP) administration to rodents. The purpose here was to evaluate the utility of APMS in delivering chemotherapeutic drugs to human MM cells in vitro and in two mouse xenograft models of MM. Uptake and release of doxorubicin (DOX) alone or loaded in APMS (APMS-DOX) were evaluated in MM cells. MM cell death and gene expression linked to DNA damage/repair were also measured in vitro. In two severe combined immunodeficient mouse xenograft models, mice received saline, APMS, DOX or APMS-DOX injected directly into subcutaneous (SC) MM tumors or injected IP after development of human MMs peritoneally. Other mice received DOX intravenously (IV) via tail vein injections. In comparison to DOX alone, APMS-DOX enhanced intracellular uptake of DOX, MM death and expression of GADD34 and TP73. In the SC MM model, 3x weekly SC injections of APMS-DOX or DOX alone significantly inhibited tumor volumes, and systemic DOX administration was lethal. In mice developing IP MMs, significant (p < 0.05) inhibition of mesenteric tumor numbers, weight and volume was achieved using IP administration of APMS-DOX at one-third the DOX concentration required after IP injections of DOX alone. These results suggest APMS are efficacious for the localized delivery of lower effective DOX concentrations in MM and represent a novel means of treating intracavitary tumors
PMCID:3017728
PMID: 20830711
ISSN: 1097-0215
CID: 134262
Onconase mediated NFKbeta downregulation in malignant pleural mesothelioma
Goparaju, C M; Blasberg, J D; Volinia, S; Palatini, J; Ivanov, S; Donington, J S; Croce, C; Carbone, M; Yang, H; Pass, H I
Treatment of malignant pleural mesothelioma (MPM) with Ranpirnase (Onconase) results in disruption of protein translation and cell apoptosis. We hypothesize that Onconase exerts an effect via downregulation of nuclear factor kappa B (NFKbeta) by specific microRNAs (miRNAs) and that interference of this pathway could have implications for MPM resistance to chemotherapy. Three immortalized MPM cell lines (H2959, H2373 and H2591) were exposed to Onconase at 0-20 mug/ml. Cell counts were measured at 48 and 72 h. Gene expression in miRNA-enriched RNA was validated by reverse transcription-PCR (RT-PCR). The functional implications of miRNA expression were evaluated by transfecting miRNA mimics or inhibitors into MPM cell lines, and performing Matrigel invasion, cell proliferation, soft agar colony formation and scratch closure assays. Effects on NFKbeta expression and downstream targets including ABC transporters, BCL-xl and IAP were assessed by RT-PCR and western blotting. Treatment with 20 mug/ml of Onconase significantly decreased cell count and invasion. Hsa-miR-17* was significantly upregulated and hsa-miR-30c was significantly downregulated by Onconase treatment in all cell lines. Forced expression of hsa-miR-17* mimic and hsa-miR-30c inhibitor each significantly decreased functional activity of Onconase in all assays. NFKB1 (p50) expression and downstream targets were also decreased with Onconase treatment, as well as with forced expression of miRNA mimic and inhibitors. Onconase treatment caused a significant decrease in cell proliferation, invasion and in expression of certain miRNAs. Recapitulation of the resultant miRNA expression pattern with hsa-miR-17* mimic and hsa-miR-30c inhibitor resulted in downregulation of NFKB1 and reduced malignant behavior in functional assays. Thus, Onconase likely exerts its antitumor effect through these miRNAs
PMCID:3118086
PMID: 21317924
ISSN: 1476-5594
CID: 134435
INITIAL ANALYSIS OF IASLC MESOTHELIOMA DATABASE [Meeting Abstract]
Rusch, Valerie; Giroux, Dori; Kennedy, Catherine; Rice, David; Ruffini, Enrico; Pass, Harvey I.; Waller, David; Edwards, John; Cangir, Ayten K.; Asamura, Hisao
ISI:000208855802121
ISSN: 1556-0864
CID: 2964172
LUNG SPARING MAXIMAL CYTOREDUCTION FOR PLEURAL MESOTHELIOMA COMPARES FAVORABLY WITH EXTRAPLEURAL PNEUMONECTOMY [Meeting Abstract]
Pass, Harvey I.; Gadgeel, S.; Wozniak, Antoinette; Chachoua, Abraham
ISI:000208855802221
ISSN: 1556-0864
CID: 2964162
DETECTION OF MESOTHELIOMA IN ASBESTOS EXPOSED INDIVIDUALS WITH SOMAMER PROTEOMIC TECHNOLOGY [Meeting Abstract]
Ostroff, Rachel; Mehan, Michael R.; Stewart, Alex; Williams, Stephen; Levin, Stephen; Black, Brad; Harbut, Michael; Pass, Harvey I.
ISI:000208855802123
ISSN: 1556-0864
CID: 2964152