Jianming Pei

Fox Chase Cancer Center, Filadelfia, Pennsylvania, United States

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Publications (34)182.67 Total impact

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    ABSTRACT: Malignant mesothelioma (MM) is an aggressive tumor arising from mesothelial linings of the serosal cavities. Pleural space is the most common site, accounting for about 80% of cases, while peritoneum makes up the majority of the remaining 20%. While histologically similar, tumors from these sites are epidemiologically and clinically distinct and their attribution to asbestos exposure differs. We compared DNA array-based findings from 48 epithelioid peritoneal MMs and 41 epithelioid pleural MMs to identify similarities and differences in copy number alterations (CNAs). Losses in 3p (BAP1 gene), 9p (CDKN2A) and 22q (NF2) were seen in tumors from both tumor sites, although CDKN2A and NF2 losses were seen at a higher rate in pleural disease (p<0.01). Overall, regions of copy number gain were more common in peritoneal MM, whereas losses were more common in pleural MM, with regions of loss containing known tumor suppressor genes and regions of gain encompassing genes encoding receptor tyrosine kinase pathway members. Cases with known asbestos causation (n=32) were compared with those linked to radiation exposure (n=9). Deletions in 6q, 14q, 17p and 22q, and gain of 17q were seen in asbestos-associated but not radiation-related cases. As reported in post-radiation sarcoma, gains outnumbered losses in radiation-associated MM. The patterns of genomic imbalances suggest overlapping and distinct molecular pathways in MM of the pleura and peritoneum, and that differences in causation (i.e., asbestos vs. radiation) may account for some of these site-dependent differences.
    No preview · Article · Feb 2016 · Cancer biology & therapy
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    ABSTRACT: We report a high-risk cancer family with multiple mesotheliomas, cutaneous melanomas, basal cell carcinomas, and meningiomas segregating with a germline nonsense mutation in BAP1 (c.1938T>A; p.Y646X). Notably, most (four of five) mesotheliomas were peritoneal rather than the usually more common pleural form of the disease, and all five mesothelioma patients also developed second or third primary cancers, including two with meningiomas. Another family member developed both cutaneous melanoma and breast cancer. Two family members had basal cell carcinomas, and six others had melanocytic tumors, including four cutaneous melanomas, one uveal melanoma, and multiple benign melanocytic tumors. The family resides in a subtropical area, and several members had suspected exposure to asbestos either occupationally or in the home. We hypothesize that the concurrence of a genetic predisposing factor and environmental exposure to asbestos and UV irradiation contributed to the high incidence of multiple cancers seen in this family, specifically mesothelioma and various skin tumors, respectively.
    Full-text · Article · Sep 2015 · Cancer letters
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    ABSTRACT: We report a family with domestic exposure to asbestos and diagnosis of multiple cancers, including eight pleural malignant mesotheliomas and several other lung or pleural tumors. DNA sequence analysis revealed no evidence for an inherited mutation of BAP1. Sequence analysis of other potentially relevant genes, including TP53, CDKN2A, and BARD1, also revealed no mutation. DNA microarray analysis of tissue from two mesotheliomas revealed multiple genomic imbalances, including consistent losses of overlapping segments in 2q, 6q, 9p, 14q, 15q, and 22q, but no losses of chromosome 3 harboring the BAP1 locus. However, the results of immunohistochemical analysis demonstrated loss of nuclear BAP1 staining in three of six mesotheliomas tested, suggesting that somatic alterations of BAP1 occurred in a subset of tumors from this family. Since mesothelioma could be confirmed in only a single generation, domestic exposure to asbestos may be the predominant cause of mesothelioma in this family. Given the existence of unspecified malignant pleural tumors and lung cancers in a prior generation, we discuss the possibility that some other tumor susceptibility or modifier gene(s) may contribute to the high incidence of mesothelioma in this family. Because the incidence of mesothelioma in this family is higher than that expected even in workers heavily exposed to asbestos, we conclude that both asbestos exposure and genetic factors have played a role in the high rate of mesothelioma and potentially other pleural or lung cancers seen in this family. .
    Full-text · Article · Sep 2015 · Cancer Genetics
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    ABSTRACT: Introduction: and Objective: Sarcomatoid differentiation in renal cell carcinoma (sRCC) is associated with a very poor prognosis. The identification of genetic alterations that drive this aggressive phenotype could aid in the development of more effective targeted therapies. In this study, we aimed to pinpoint unique copy number alterations (CNAs) in sRCC when compared to classical RCC subtypes. Methods: Genomic copy number analysis was performed using single nucleotide polymorphism (SNP)-based microarrays on tissue extracted from the tumors of 81 patients who underwent renal mass excision, including 17 with sRCC. Results: sRCC tumors exhibited significantly higher numbers of CNAs when compared to clear cell (ccRCC), papillary (pRCC) and chromophobe RCC (chRCC) (mean 18.0 vs. 5.8, 6.5, and 7.2, respectively; p <0.0001). Copy number losses of chromosome arms 9q, 15q, 18p/q, and 22q and gains of gains of 1q and 8q occurred in a significantly higher proportion of sRCC tumors compared to the other 3 histologies. Patients with sRCC tumors demonstrated significantly worse overall survival when compared to those without sRCC on Kaplan-Meier analysis (p=0.0001). Patients with 9 or more CNAs also demonstrated significantly worse overall survival compared to those with fewer than 9 CNAs (p=0.004). Conclusions: Sarcomatoid differentiation in RCC is associated with a high rate of chromosomal imbalances with losses of 9q, 15q, 18p/q and 22q, and gains of 1q and 8q occurring at significantly higher frequencies in comparison to non-sRCC tumors. Identification of candidate driver genes or tumor suppressor loci within these chromosomal regions may help identify targets for future therapies.
    Full-text · Article · Apr 2015 · The Journal of Urology
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    ABSTRACT: Constitutive activation of AKT is a frequent occurrence in the development of human T-cell acute lymphocytic leukemia/lymphomas (T-ALLs), due largely to inactivation of PTEN. Up regulation of MYC is also commonly observed in human T-ALLs. We previously demonstrated that expression of a constitutively active form of Lck-Akt2 alone is sufficient to initiate T-cell lymphoma in mice, and that tumor formation typically requires up regulation of Myc or Dlx5 caused by specific chromosomal rearrangements. Furthermore, Lck-Dlx5 mice develop T-ALLs that consistently acquire overexpression of Myc and activation of Akt, the latter due to loss of Pten expression. Proliferation of T-ALL cells from Lck-Dlx5 mice was found to be highly sensitive to the Akt pathway inhibitors BEZ235 and RAD001, as well as to JQ1, an inhibitor of bromodomain proteins, one of which (BRD4) regulates Myc transcription. Additionally, low concentrations of BEZ235 were found to cooperate with JQ1 to enhance cell cycle arrest. Higher concentrations of BEZ235 (≥0.5 µM) promoted cell death, although the addition of JQ1 did not result in a further increase in apoptosis. In contrast, the specific Myc inhibitor 10058-F4 caused apoptosis, and when combined with BEZ235 (≥0.5 µM), an enhanced effect on apoptosis was consistently observed. In addition, BEZ235 and RAD001 potentiated vincristine-induced apoptosis when the cells were treated with both drugs simultaneously, whereas pretreatment with BEZ235 antagonized the cell-killing effect of vincristine. Collectively, these experimental findings provide rationale for the design of novel combination therapies for T-ALL that includes targeting of AKT and MYC.
    No preview · Article · Mar 2015 · Cancer biology & therapy

  • No preview · Conference Paper · Oct 2014
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    ABSTRACT: Malignant mesotheliomas are highly aggressive tumors usually caused by exposure to asbestos. Germline inactivating mutations of BAP1 predispose to mesothelioma and certain other cancers. However, why mesothelioma is the predominate malignancy in some BAP1 families and not others, and whether exposure to asbestos is required for development of mesothelioma in BAP1 mutation carriers, are not known. To address these questions experimentally, we generated a Bap1+/- knockout mouse model to assess its susceptibility to mesothelioma upon chronic exposure to asbestos. Bap1+/- mice exhibited a significantly higher incidence of asbestos-induced mesothelioma than WT littermates (73% vs. 32%, respectively). Furthermore, mesotheliomas arose at an accelerated rate in Bap1+/- mice compared to WT animals (median survival, 43 weeks versus 55 weeks after initial exposure, respectively) and showed increased invasiveness and proliferation. No spontaneous mesotheliomas were seen in unexposed Bap1+/- mice followed for up to 87 weeks of age. Mesothelioma cells from Bap1+/- mice showed biallelic inactivation of Bap1, consistent with its proposed role as a recessive cancer susceptibility gene. Unlike in wild-type mice, mesotheliomas from Bap1+/- mice did not require homozygous loss of Cdkn2a. However, normal mesothelial cells and mesothelioma cells from Bap1+/- mice showed downregulation of Rb through a p16(Ink4a)-independent mechanism, suggesting that predisposition of Bap1+/- mice to mesothelioma may be facilitated, in part, by cooperation between Bap1 and Rb. Drawing parallels to human disease, these unbiased genetic findings indicate that BAP1 mutation carriers are predisposed to the tumorigenic effects of asbestos and suggest that high penetrance of mesothelioma requires such environmental exposure.
    Preview · Article · Jun 2014 · Cancer Research

  • No preview · Article · Apr 2014 · The Journal of Urology

  • No preview · Article · Apr 2014 · The Journal of Urology
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    ABSTRACT: Single nucleotide polymorphism (SNP)-based chromosome microarray analysis was used to uncover copy neutral loss of heterozygosity (LOH) in the long arm of chromosome 20 in blood or bone marrow specimens from three patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). All three patients presented with lymph node enlargement. While one of the patients has had a complicated clinical course, the other two have a more indolent disease. Sequence analysis of the tumor suppressor gene ASXL1, which is located in 20q and is commonly mutated in malignant myeloid diseases and occasionally in CLL/SLL specimens, revealed no mutations in our three patients with copy neutral LOH in 20q. The possible contribution of other imprinted microRNAs and antisense genes residing in 20q to the pathogenesis of a subset of CLL/SLL patients is discussed. These findings illustrate the value of SNP arrays for the detection of novel recurrent genomic alterations that may contribute to CLL/SLL onset or progression.
    No preview · Article · Mar 2014 · Cancer Genetics
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    ABSTRACT: Although Inflammatory Breast Cancer (IBC) is recognized as the most metastatic variant of locally advanced breast cancer, the molecular basis for the distinct clinical presentation and accelerated program of metastasis of IBC is unknown. Reverse phase protein arrays revealed activation of the receptor tyrosine kinase, anaplastic lymphoma kinase (ALK) and biochemically-linked downstream signaling molecules including JAK1/STAT3, AKT, mTor, PDK1, and AMPKβ in pre-clinical models of IBC. To evaluate the clinical relevance of ALK in IBC, analysis of 25 IBC patient tumors using the FDA approved diagnostic test for ALK genetic abnormalities was performed. These studies revealed that 20/25 (80%) had either increased ALK copy number, low level ALK gene amplification, or ALK gene expression, with a prevalence of ALK alterations in basal-like IBC. One of 25 patients was identified as having an EML4-ALK translocation. The generality of gains in ALK copy number in basal-like breast tumors with IBC characteristics was demonstrated by analysis of 479 breast tumors using the TGCA data-base and our newly developed 79 IBC-like gene signature. The small molecule dual tyrosine kinase cMET/ALK inhibitor, Crizotinib (PF-02341066/Xalkori®, Pfizer Inc), induced both cytotoxicity (IC50 = 0.89 μM) and apoptosis, with abrogation of pALK signaling in IBC tumor cells and in FC-IBC01 tumor xenograft model, a new IBC model derived from pleural effusion cells isolated from an ALK+ IBC patient. Based on these studies, IBC patients are currently being evaluated for the presence of ALK genetic abnormalities and when eligible, are being enrolled into clinical trials evaluating ALK targeted therapeutics. Electronic supplementary material The online version of this article (doi:10.1186/2193-1801-2-497) contains supplementary material, which is available to authorized users.
    Full-text · Article · Oct 2013 · SpringerPlus
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    ABSTRACT: Inflammatory breast cancer (IBC) is the most aggressive type of advanced breast cancer characterized by rapid proliferation, early metastatic development and poor prognosis. Since there are few preclinical models of IBC, there is a general lack of understanding of the complexity of the disease. Recently, we have developed a new model of IBC derived from the pleural effusion of a woman with metastatic secondary IBC. FC-IBC02 cells are triple negative and form clusters (mammospheres) in suspension that are strongly positive for E-cadherin, β-catenin and TSPAN24, all adhesion molecules that play an important role in cell migration and invasion. FC-IBC02 cells expressed stem cell markers and some, but not all of the characteristics of cells undergoing epithelial mesenchymal transition (EMT). Breast tumor FC-IBC02 xenografts developed quickly in SCID mice with the presence of tumor emboli and the development of lymph node and lung metastases. Remarkably, FC-IBC02 cells were able to produce brain metastasis in mice on intracardiac or intraperitoneal injections. Genomic studies of FC-IBC02 and other IBC cell lines showed that IBC cells had important amplification of 8q24 where MYC, ATAD2 and the focal adhesion kinase FAK1 are located. MYC and ATAD2 showed between 2.5 and 7 copies in IBC cells. FAK1, which plays important roles in anoikis resistance and tumor metastasis, showed 6–4 copies in IBC cells. Also, CD44 was amplified in triple-negative IBC cells (10–3 copies). Additionally, FC-IBC02 showed amplification of ALK and NOTCH3. These results indicate that MYC, ATAD2, CD44, NOTCH3, ALK and/or FAK1 may be used as potential targeted therapies against IBC. Electronic supplementary material The online version of this article (doi:10.1007/s10549-013-2600-4) contains supplementary material, which is available to authorized users.
    Full-text · Article · Jun 2013 · Breast Cancer Research and Treatment
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    ABSTRACT: Advanced renal cell carcinoma (RCC) is an invariably fatal cancer. Currently, small-molecule inhibitors that target cell-growth, angiogenesis, or nutrient-sensing pathways represent the primary pharmacological interventions for this disease, but these inhibitors only delay tumor progression and are not curative. The cytokine interferon (IFN)-γ showed the potential to provide lasting remission in several phase I/II trials for advanced RCC, but subsequent trials, including a multi-center phase III study using IFN-γ as a monotherapy for RCC, were less promising. Notably, these trials were designed to exploit the indirect immune-modulatory effects of IFN-γ, while its direct anti-tumor properties - including its ability to trigger programmed cell death in tumors - remain mostly untapped. Here, we show that the proteasome inhibitor bortezomib (PS-341, Velcade) sensitizes otherwise-resistant RCC cells to direct necrotic death by IFN-γ. Mechanistically, we demonstrate that bortezomib functions at least in part by inhibiting pro-survival NF-κB signaling. In the absence of this signal, IFN-γ triggers programmed necrosis (or 'necroptosis') dependent on the kinase RIP1. When taken together with the observation that NF-κB signaling is elevated in RCC, these results provide rationale for the combined use of IFN-γ and bortezomib in the treatment of metastatic RCC.
    No preview · Article · May 2013 · Molecular Cancer Therapeutics
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    Jianming Pei · Suresh C Jhanwar · Joseph R Testa
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    ABSTRACT: We describe genomic findings in a case of CLL with del(17p13.1) by FISH, in which SNP array analysis revealed chromothripsis, a phenomenon by which regions of the cancer genome are shattered and recombined to generate frequent oscillations between two DNA copy number states. The findings illustrate the value of SNP arrays for precise whole genome profiling in CLL and for the detection of alterations that would be overlooked with a standard FISH panel. This second report of chromothripsis in CLL indicates that this phenomenon is a recurrent change in this disease.
    Full-text · Article · Dec 2012 · Leukemia Research Reports
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    ABSTRACT: Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
    No preview · Article · Dec 2012 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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    ABSTRACT: 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.
    Full-text · Article · Aug 2011 · Nature Genetics

  • No preview · Article · Jul 2011 · Cancer Research
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    ABSTRACT: The CDKN2A/ARF locus encompasses overlapping tumor suppressor genes p16(INK4A) and p14(ARF), which are frequently co-deleted in human malignant mesothelioma (MM). The importance of p16(INK4A) loss in human cancer is well established, but the relative significance of p14(ARF) loss has been debated. The tumor predisposition of mice singly deficient for either Ink4a or Arf, due to targeting of exons 1α or 1β, respectively, supports the idea that both play significant and nonredundant roles in suppressing spontaneous tumors. To further test this notion, we exposed Ink4a(+/-) and Arf(+/-) mice to asbestos, the major cause of MM. Asbestos-treated Ink4a(+/-) and Arf(+/-) mice showed increased incidence and shorter latency of MM relative to wild-type littermates. MMs from Ink4a(+/-) mice exhibited biallelic inactivation of Ink4a, loss of Arf or p53 expression and frequent loss of p15(Ink4b). In contrast, MMs from Arf(+/-) mice exhibited loss of Arf expression, but did not require loss of Ink4a or Ink4b. Mice doubly deficient for Ink4a and Arf, due to deletion of Cdkn2a/Arf exon 2, showed accelerated asbestos-induced MM formation relative to mice deficient for Ink4a or Arf alone, and MMs exhibited biallelic loss of both tumor suppressor genes. The tumor suppressor function of Arf in MM was p53-independent, since MMs with loss of Arf retained functional p53. Collectively, these in vivo data indicate that both CDKN2A/ARF gene products suppress asbestos carcinogenicity. Furthermore, while inactivation of Arf appears to be crucial for MM pathogenesis, the inactivation of both p16(Ink4a) and p19(Arf) cooperate to accelerate asbestos-induced tumorigenesis.
    Preview · Article · Apr 2011 · PLoS ONE
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    Dataset: Figure S1
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    ABSTRACT: Immunohistochemical staining of a MM tumor with anti-mesothelin (MSN) or anti-MSN plus blocking peptide to show specificity of staining. (TIF)
    Preview · Dataset · Apr 2011
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    Dataset: File S1
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    ABSTRACT: MM Markers for primary cell cultures derived from asbestos-treated mice. (DOC)
    Preview · Dataset · Apr 2011