George F Murphy

Brigham and Women's Hospital, Boston, Massachusetts, United States

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Publications (220)1291.15 Total impact

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    ABSTRACT: Recent developments in genomic sequencing have advanced our understanding of the mutations underlying human malignancy. Melanoma is a prototype of an aggressive, genetically heterogeneous cancer notorious for its biologic plasticity and predilection towards developing resistance to targeted therapies. Evidence is rapidly accumulating that dysregulated epigenetic mechanisms (DNA methylation/demethylation, histone modification, non-coding RNAs) may play a central role in the pathogenesis of melanoma. Therefore, we sought to characterize the frequency and nature of mutations in epigenetic regulators in clinical, treatment-naïve, patient melanoma specimens obtained from one academic institution. Targeted next-generation sequencing for 275 known and investigative cancer genes (of which 41 genes, or 14.9 %, encoded an epigenetic regulator) of 38 treatment-naïve patient melanoma samples revealed that 22.3 % (165 of 740) of all non-silent mutations affected an epigenetic regulator. The most frequently mutated genes were BRAF, MECOM, NRAS, TP53, MLL2, and CDKN2A. Of the 40 most commonly mutated genes, 12 (30.0 %) encoded epigenetic regulators, including genes encoding enzymes involved in histone modification (MECOM, MLL2, SETD2), chromatin remodeling (ARID1B, ARID2), and DNA methylation and demethylation (TET2, IDH1). Among the 38 patient melanoma samples, 35 (92.1 %) harbored at least one mutation in an epigenetic regulator. The genes with the highest number of total UVB-signature mutations encoded epigenetic regulators, including MLL2 (100 %, 16 of 16) and MECOM (82.6 %, 19 of 23). Moreover, on average, epigenetic genes harbored a significantly greater number of UVB-signature mutations per gene than non-epigenetic genes (3.7 versus 2.4, respectively; p = 0.01). Bioinformatics analysis of The Cancer Genome Atlas (TCGA) melanoma mutation dataset also revealed a frequency of mutations in the 41 epigenetic genes comparable to that found within our cohort of patient melanoma samples. Our study identified a high prevalence of somatic mutations in genes encoding epigenetic regulators, including those involved in DNA demethylation, histone modification, chromatin remodeling, and microRNA processing. Moreover, UVB-signature mutations were found more commonly among epigenetic genes than in non-epigenetic genes. Taken together, these findings further implicate epigenetic mechanisms, particularly those involving the chromatin-remodeling enzyme MECOM/EVI1 and histone-modifying enzyme MLL2, in the pathobiology of melanoma.
    12/2015; 7(1). DOI:10.1186/s13148-015-0091-3
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    ABSTRACT: Melanomas in the vertical growth phase (VGP) not infrequently demonstrate cellular heterogeneity. One commonly encountered subpopulation displays small cell/nevoid morphology. Although its significance remains unknown, such subpopulations may pose diagnostic issues when faced with differentiating such changes from associated nevus or mistaking such regions for nevic maturation (pseudomaturation). That 'loss' of the epigenetic biomarker, 5-hydroxymethylcytosine (5-hmC), is a hallmark for melanoma and correlates with virulence prompted us to explore the diagnostic utility and biological implications of 5-hmC immunohistochemistry (IHC) in melanomas with small cell/nevoid subpopulations. Fifty-two cases were included in this study, including melanomas with small cell/nevoid subpopulations (MSCN) or melanomas with pre-existing nevus (MPEN). Semiquantitative and computer-validated immunohistochemical analyses revealed invariable, uniform loss of 5-hmC in the conventional melanoma component. By contrast, the nevic components in MPEN cases demonstrated strong nuclear immunopositivity. In MSCN cases, there was partial to complete loss of 5-hmC restricted to these nevoid areas. Based on recent data supporting tight correlation between 5-hmC loss and malignancy, our findings indicate a potential 'intermediate' biological nature for small cell/nevoid subpopulations. Because 5-hmC assisted in differentiating such regions from associated nevus, the use of 5-hmC as an adjunct to microstaging in difficult cases showing VGP heterogeneity should be further explored.
    Oncotarget 10/2015; · 6.36 Impact Factor
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    ABSTRACT: Therapeutic antibodies targeting programmed cell death 1 (PD-1) activate tumor-specific immunity and have shown remarkable efficacy in the treatment of melanoma. Yet, little is known about tumor cell-intrinsic PD-1 pathway effects. Here, we show that murine and human melanomas contain PD-1-expressing cancer subpopulations and demonstrate that melanoma cell-intrinsic PD-1 promotes tumorigenesis, even in mice lacking adaptive immunity. PD-1 inhibition on melanoma cells by RNAi, blocking antibodies, or mutagenesis of melanoma-PD-1 signaling motifs suppresses tumor growth in immunocompetent, immunocompromised, and PD-1-deficient tumor graft recipient mice. Conversely, melanoma-specific PD-1 overexpression enhances tumorigenicity, as does engagement of melanoma-PD-1 by its ligand, PD-L1, whereas melanoma-PD-L1 inhibition or knockout of host-PD-L1 attenuate growth of PD-1-positive melanomas. Mechanistically, the melanoma-PD-1 receptor modulates downstream effectors of mTOR signaling. Our results identify melanoma cell-intrinsic functions of the PD-1:PD-L1 axis in tumor growth and suggest that blocking melanoma-PD-1 might contribute to the striking clinical efficacy of anti-PD-1 therapy.
    Cell 09/2015; 162(6):1242-1256. DOI:10.1016/j.cell.2015.08.052 · 32.24 Impact Factor
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    ABSTRACT: Cell-based strategies represent a new frontier in the treatment of immune-mediated disorders. However, the paucity of markers for isolation of molecularly defined immunomodulatory cell populations poses a barrier to this field. Here, we show that ATP-binding cassette member B5 (ABCB5) identifies dermal immunoregulatory cells (DIRCs) capable of exerting therapeutic immunoregulatory functions through engagement of programmed cell death 1 (PD-1). Purified Abcb5(+) DIRCs suppressed T cell proliferation, evaded immune rejection, homed to recipient immune tissues, and induced Tregs in vivo. In fully major-histocompatibility-complex-mismatched cardiac allotransplantation models, allogeneic DIRCs significantly prolonged allograft survival. Blockade of DIRC-expressed PD-1 reversed the inhibitory effects of DIRCs on T cell activation, inhibited DIRC-dependent Treg induction, and attenuated DIRC-induced prolongation of cardiac allograft survival, indicating that DIRC immunoregulatory function is mediated, at least in part, through PD-1. Our results identify ABCB5(+) DIRCs as a distinct immunoregulatory cell population and suggest promising roles of this expandable cell subset in cellular immunotherapy. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 08/2015; 12(10). DOI:10.1016/j.celrep.2015.08.010 · 8.36 Impact Factor
  • Jason F Solus · George F Murphy · Stefan Kraft ·
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    ABSTRACT: Cutaneous squamous cell carcinomas mainly affect older, predominantly male patients. Most are due to chronic ultraviolet exposure, and associated with actinic keratoses. On the lower extremities, they occur more commonly in women. However, data on these tumors as a distinct group are scarce. We evaluated 61 squamous cell carcinomas of the lower extremities. Overall, 69% of patients were female. Mean age was 75 years. More than 90% of tumors were well differentiated, 3% showed perineural invasion, and none lymphovascular invasion. In all, 63.9% showed evidence of severe chronic sun damage. Associated actinic keratoses were identified in only 13% of cases. By contrast, 80% were associated with distinctive basal epidermal proliferations with a retiform growth pattern. These proliferations were evaluated immunohistochemically for keratinocyte stem cell markers, p53 and Notch1 in 15 cases. All cases were positive for cytokeratin 14, p53, and Notch1 (with variable intensity in the latter 2), and predominantly negative for cytokeratin 19. Interestingly, basal retiform proliferations were positive for cytokeratin 15 in 66% of cases. Fifteen head and neck squamous cell carcinomas were evaluated in comparison. Those lacked associated basal retiform proliferations except in 1 case. In contrast, 87% were associated with actinic keratoses and 100% with severe chronic sun damage. Actinic keratoses associated with head and neck tumors showed cytokeratin 15 staining only in 7% of cases (P = .003 compared with cytokeratin 15 in basal retiform proliferations associated with leg carcinomas). These findings support the hypothesis that lower extremity squamous cell carcinomas are distinct and may exhibit a pathogenesis less reliant on actinic damage. © The Author(s) 2015.
    International Journal of Surgical Pathology 08/2015; DOI:10.1177/1066896915599058 · 0.95 Impact Factor
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    ABSTRACT: In 2009 the revised 7(th) staging system for melanoma recommended the use of mitotic count to separate stage T1a from T1b. However, careful scrutiny of cases may lead to an inadvertent selection effect, with consequent increased reporting of mitotic counts. We investigated whether there is a significant increase in mitotic counts reported since 2009 for melanomas with a Breslow thickness of 1.0 mm or less. We conducted a retrospective, case-controlled study examining invasive melanoma cases at a large academic center. Mitotic counts were compared between pathology reports before 2009 (n = 61) and after 2009 (n = 125), with a subset of slides re-examined in a blinded fashion. Before the 2009 staging guidelines, 51% of cases had one or more mitosis reported compared to 38% after 2009 (p = 0.113). Blinded re-counting did not yield a significant difference when compared with the original pathology reports in either group. There was not a significant difference in the number of mitoses reported after the implementation of the new guidelines. This article is protected by copyright. All rights reserved.
    Journal of Cutaneous Pathology 04/2015; 42(8). DOI:10.1111/cup.12517 · 1.58 Impact Factor

  • Plastic &amp Reconstructive Surgery 04/2015; 135(4):1219. DOI:10.1097/01.prs.0000463989.07184.1d · 2.99 Impact Factor
  • Leigh A. Compton · George F. Murphy · Christine G. Lian ·
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    ABSTRACT: Immunohistochemistry (IHC) is an important adjunct in the diagnosis of neoplastic skin diseases. In addition to the many established IHC markers currently in use, new markers continue to emerge, although their general acceptance and routine application requires robust validation. Here, we summarize the most well-established and commonly used biomarkers along with an array of newer ones reported in the past several decades that either demonstrate or hold high clinical promise in the field of cutaneous pathology. We also highlight recent applications of novel IHC markers in melanoma diagnosis including genetic mutation status markers [e.g. BRAF (v-raf murine sarcoma viral oncogene homolog B) and NRAS (neuroblastoma RAS viral oncogene homolog)] and an epigenetic alteration marker (e.g. 5-hydroxymethylcytosine). We specifically focus on the role of IHC in the differential diagnosis of cutaneous lesions that fall under the following categories: melanoma, epidermal tumors with an intraepidermal epitheliomatous pattern, spindle cell lesions of the dermis, small round blue cell tumors of the dermis, and cutaneous adnexal tumors. While IHC is a valuable tool in diagnostic dermatopathology, marker selection and interpretation must be highly informed by clinical context and the histologic differential diagnosis. With rapid progress in our understanding of the genetic and epigenetic mechanisms of tumorigenesis, new IHC markers will continue to emerge in the field of diagnostic dermatopathology.
    03/2015; 2(1):15-42. DOI:10.1159/000377698
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    ABSTRACT: Metastatic melanoma is a highly aggressive skin cancer with a poor prognosis. Despite a complete response in fewer than 5% of patients, the chemotherapeutic agent dacarbazine (DTIC) remains the reference drug after almost 40 years. More recently, FDA-approved drugs have shown promise but patient outcome remains modest, predominantly due to drug resistance. As such, combinatorial targeting has received increased attention, and will advance with the identification of new molecular targets. One attractive target for improving melanoma therapy is the growth factor Nodal, whose normal expression is largely restricted to embryonic development, but is reactivated in metastatic melanoma. In this study, we sought to determine how Nodal-positive human melanoma cells respond to DTIC treatment and to ascertain whether targeting Nodal in combination with DTIC would be more effective than monotherapy. A single treatment with DTIC inhibited cell growth but did not induce apoptosis. Rather than reducing Nodal expression, DTIC increased the size of the Nodal-positive subpopulation, an observation coincident with increased cellular invasion. Importantly, clinical tissue specimens from patients with melanomas refractory to DTIC therapy stained positive for Nodal expression, both in pre- and post-DTIC tumors, underscoring the value of targeting Nodal. In vitro, anti-Nodal antibodies alone had some adverse effects on proliferation and apoptosis, but combining DTIC treatment with anti-Nodal antibodies decreased cell growth and increased apoptosis synergistically, at concentrations incapable of producing meaningful effects as monotherapy. Targeting Nodal in combination with DTIC therapy holds promise for the treatment of metastatic melanoma. Mol Cancer Res; 1-11. ©2015 AACR. ©2015 American Association for Cancer Research.
    Molecular Cancer Research 03/2015; 13(4). DOI:10.1158/1541-7786.MCR-14-0077 · 4.38 Impact Factor
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    ABSTRACT: Galectin-1 (Gal-1)-binding to Gal-1 ligands on immune and endothelial cells can influence melanoma development through dampening anti-tumor immune responses and promoting angiogenesis. However, whether Gal-1 ligands are functionally expressed on melanoma cells to help control intrinsic malignant features remains poorly understood. Here, we analyzed expression, identity and function of Gal-1 ligands in melanoma progression. Immunofluorescent analysis of benign and malignant human melanocytic neoplasms revealed that Gal-1 ligands were abundant in severely-dysplastic nevi as well as in primary and metastatic melanomas. Biochemical assessments indicated that melanoma cell adhesion molecule (MCAM) was a major Gal-1 ligand on melanoma cells that was largely dependent on its N-glycans. Other melanoma cell Gal-1 ligand activity conferred by O-glycans was negatively regulated by α2,6 sialyltransferase ST6GalNAc2. In Gal-1-deficient mice, MCAM-silenced (MCAM(KD)) or ST6GalNAc2-overexpressing (ST6(O/E)) melanoma cells exhibited slower growth rates, underscoring a key role for melanoma cell Gal-1 ligands and host Gal-1 in melanoma growth. Further analysis of MCAM(KD) or ST6(O/E) melanoma cells in cell migration assays indicated that Gal-1 ligand-dependent melanoma cell migration was severely inhibited. These findings provide a refined perspective on Gal-1 - melanoma cell Gal-1 ligand interactions as contributors to melanoma malignancy.Journal of Investigative Dermatology accepted article preview online, 10 March 2015. doi:10.1038/jid.2015.95.
    Journal of Investigative Dermatology 03/2015; 135(7). DOI:10.1038/jid.2015.95 · 7.22 Impact Factor

  • Plastic &amp Reconstructive Surgery 01/2015; 135:1219. DOI:10.1097/01.prs.0000463340.84041.3a · 2.99 Impact Factor
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    ABSTRACT: Background: Severe facial injuries can compromise the upper airway by reducing airway volume, obstructing or obliterating the nasal passage, and interfering with oral airflow. Besides the significant impact on quality of life, upper airway impairments can have life-threatening or life-altering consequences. The authors evaluated improvements in functional airway after face transplantation. Methods: Between 2009 and 2011, four patients underwent face transplantation at the authors' institution, the Brigham and Women's Hospital. Patients were examined preoperatively and postoperatively and their records reviewed for upper airway infections and sleeping disorders. The nasal mucosa was biopsied after face transplantation and analyzed using scanning electron microscopy. Volumetric imaging software was used to evaluate computed tomographic scans of the upper airway and assess airway volume changes before and after transplantation. Results: Before transplantation, two patients presented an exposed naked nasal cavity and two suffered from occlusion of the nasal passage. Two patients required tracheostomy tubes and one had a prosthetic nose. Sleeping disorders were seen in three patients, and chronic cough was diagnosed in one. After transplantation, there was no significant improvement in sleeping disorders. The incidence of sinusitis increased because of mechanical interference of the donor septum and disappeared after surgical correction. All patients were decannulated after transplantation and were capable of nose breathing. Scanning electron micrographs of the respiratory mucosa revealed viable tissue capable of mucin production. Airway volume significantly increased in all patients. Conclusions: Face transplantation successfully restored the upper airway in four patients. Unhindered nasal breathing, viable respiratory mucosa, and a significant increase in airway volume contributed to tracheostomy decannulation.
    Plastic &amp Reconstructive Surgery 12/2014; 134:946e-54e. DOI:10.1097/PRS.0000000000000752 · 2.99 Impact Factor
  • Maria Koulmanda · Bohdan Pomahac · Zhigang Fan · George F Murphy · Terry B Strom ·
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    ABSTRACT: Purpose of review: The field of vascularized composite allograft (VCA) to achieve its full potential will require induction of tolerance. This review will introduce a new method of potential inducing tolerance in hand transplantation. Recent findings: Hand transplantation is never a life-extending transplant. This fact resulted in considerable debate both for and against the use of immunosuppression for nonlife-extending transplants. There is considerable debate about the ethics of hand transplantation. There is now consensus that nonlife-extending transplants are acceptable in properly selected patients. However, ideally, hand transplants should not receive life-long immunosuppression. Therefore, attempts to achieve drug-free tolerance through nonlife-endangering therapies are warranted. To this end, we propose implementation of tolerizing therapy long after periinflammation has subsided and drug minimization has proven successful. Evidence that short-term treatment with low doses of IL-2 or a long-lived IL-2 immunoglobulin (Ig) can tilt the balance of immunity from tissue destructive to tolerance come from preclinical demonstrations in mouse and nonhuman primate models of autoimmunity and/or transplantation and even more recent clinical trials. Summary: We believe that with the proper use of low-dose IL-2 given at an opportune time in the inflammatory process of transplant that reduce immunosuppression and even tolerance can be induced in hand transplantation. We propose that tolerance can be inducted after a long period of conventional treatment to avoid 'tolerance-hindering' adverse inflammation that occurs in the posttransplant period. With abatement of posttransplant inflammation and with time, we will institute low-dose IL-2-based therapy to support the proliferation, viability and functional phenotype of regulatory T cells.
    Current Opinion in Organ Transplantation 12/2014; 19(6):545-51. DOI:10.1097/MOT.0000000000000138 · 2.88 Impact Factor
  • Nicole Gunasekera · George F Murphy · Vaneeta M Sheth ·
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    ABSTRACT: Inflammatory vitiligo with raised borders (IVRB) is a rare subtype of vitiligo described as having a rim of raised erythema at the periphery of the depigmented patches. The etiology is poorly understood, and there are few reports of successful treatment of the condition in the literature. We report a 38-year-old South Asian male who presented with diffuse depigmented macules and patches surrounded by blue-gray rims involving a large body surface area. Light microscopy revealed inflammatory vitiligo. He was treated with 2 courses of oral prednisone and whole-body narrow-band ultraviolet B (NB-UVB) therapy, which resulted in cessation of disease spread as well as substantial repigmentation. Our observation suggests that early and aggressive treatment can lead to significant and rapid improvement in patients with IVRB. © 2014 S. Karger AG, Basel.
    Dermatology 11/2014; 230(1). DOI:10.1159/000366197 · 1.57 Impact Factor
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    ABSTRACT: Matrix metalloproteinases (MMPs) are key biological mediators of processes as diverse as wound healing, embryogenesis, and cancer progression. Although MMPs may be induced through multiple signaling pathways, the precise mechanisms for their regulation in cancer are incompletely understood. Because cytoskeletal changes are known to accompany MMP expression, we sought to examine the potential role of the poorly understood cytoskeletal protein, nestin, in modulating melanoma MMPs. Nestin knockdown (KD) upregulated the expression of specific MMPs and MMP-dependent invasion both through extracellular matrix barriers in vitro and in peritumoral connective tissue of xenografts in vivo. The development of three-dimensional melanospheres that in vitro partially recapitulate noninvasive tumorigenic melanoma growth was inhibited by nestin KD, although ECM invasion by aberrant melanospheres that did form was enhanced. Mechanistically, nestin KD-dependent melanoma invasion was associated with intracellular redistribution of phosphorylated focal adhesion kinase and increased melanoma cell responsiveness to transforming growth factor-beta, both implicated in pathways of melanoma invasion. The results suggest that the heretofore poorly understood intermediate filament, nestin, may serve as a novel mediator of MMPs critical to melanoma virulence.Laboratory Investigation advance online publication, 3 November 2014; doi:10.1038/labinvest.2014.130.
    Laboratory Investigation 11/2014; 94(12). DOI:10.1038/labinvest.2014.130 · 3.68 Impact Factor
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    ABSTRACT: Purpose of review: Acute rejection is the most common complication after vascularized composite allotransplantation (VCA). This review provides a state-of-the-art analysis of prevention, diagnosis and treatment of acute rejection episodes and highlights recent findings with the potential to improve patient care and enhance understanding of the underlying biologic processes. Recent findings: Recent reports suggest that maintenance immunosuppression dose reduction and steroid withdrawal are realistic goals in VCA, despite the known high immunogenicity of the skin component. It appears that utilization of sentinel flaps, in-depth histological analyses and application of novel biomarkers have facilitated early diagnosis and characterization of acute rejection episodes, leading to timely institution of appropriate therapy. The successful management of the first highly sensitized face transplant recipient suggests the possibility of carefully considering these high-risk VCA candidates for transplantation. Summary: Acute rejection is higher in VCA than in any other organ in the field of transplantation, although most episodes are controlled by high-dose steroids and optimization of maintenance immunosuppression. Because of limitations in patient number and the duration of follow-up, the long-term safety and effectiveness of VCA remain unclear. Moreover, the tests currently used to diagnose acute rejection are of limited value. Better diagnostic tools and a better understanding of the immunologic events during acute rejection are therefore needed to improve diagnosis, treatment and outcomes of this life-changing restorative surgery.
    Current Opinion in Organ Transplantation 10/2014; DOI:10.1097/MOT.0000000000000140 · 2.88 Impact Factor
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    ABSTRACT: Atg16L1 mediates the cellular degradative process of autophagy and is considered a critical regulator of inflammation based on its genetic association with inflammatory bowel disease. Here we find that Atg16L1 deficiency leads to an exacerbated graft-versus-host disease (GVHD) in a mouse model of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Atg16L1-deficient allo-HSCT recipients with GVHD displayed increased T cell proliferation due to increased dendritic cell (DC) numbers and costimulatory molecule expression. Reduced autophagy within DCs was associated with lysosomal abnormalities and decreased amounts of A20, a negative regulator of DC activation. These results broaden the function of Atg16L1 and the autophagy pathway to include a role in limiting a DC-mediated response during inflammatory disease, such as GVHD.
    Immunity 10/2014; 41(4). DOI:10.1016/j.immuni.2014.09.011 · 21.56 Impact Factor
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    ABSTRACT: Skin biopsies are critical for histological evaluation of rejection and proper treatment after facial allotransplantation (FAT). Many facial allografts provide only limited skin area and frequent biopsies may additionally compromise aesthetic outcome. Sentinel flaps (SFs), recovered as free fasciocutanous radial forearm flaps, have been employed for remote site rejection monitoring. They maintain their axial blood supply similar to facial allografts. The correlation between FAT and SF in cases of rejection is presented.
    Plastic &amp Reconstructive Surgery 09/2014; DOI:10.1097/PRS.0000000000000797 · 2.99 Impact Factor
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    ABSTRACT: Importance Port-wine stains (PWSs) are common congenital cutaneous capillary malformations. A somatic GNAQ mutation was recently identified in patients with sporadic PWSs and Sturge-Weber syndrome. However, subsequent studies to confirm or extend this observation are lacking.Observations We report a long-standing, unilateral facial PWS of a man in his early 70s confirmed by histopathological analysis. Staged surgical excision of the vascular malformation was performed, and genomic DNA was extracted from the vascular malformation specimen and normal skin. Targeted next-generation sequencing of the coding sequence of 275 known cancer genes including GNAQ was performed in both specimens. A single-nucleotide variant (c.548G>A, p.Arg183Gln) in GNAQ was identified in the PWS-affected tissue but not in the normal skin sample. In addition, this sequencing approach uncovered several additional novel somatic mutations in the genes SMARCA4, EPHA3, MYB, PDGFR-β, and PIK3CA.Conclusions and Relevance Our findings confirm the presence of somatic mutations in GNAQ in the affected skin of a patient with congenital PWS, as well as alterations in several other novel genes of possible importance in the pathogenesis of PWS that may also offer substantial therapeutic targets.
    JAMA Dermatology 09/2014; 150(12). DOI:10.1001/jamadermatol.2014.1244 · 4.43 Impact Factor
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    ABSTRACT: Merkel cell carcinoma (MCC) is a highly virulent cutaneous neoplasm that, like melanoma, is a frequent cause of patient morbidity and mortality. The cellular mechanisms responsible for the aggressive behavior of MCC remain unknown. Vasculogenic mimicry (VM) is a phenomenon associated with cancer virulence, including in melanoma, whereby anastomosing laminin networks form in association with tumor cells that express certain endothelial genes. To determine whether VM is a factor in MCC, we employed a relevant xenograft model using two independent human MCC lines. Experimentally induced tumors were remarkably similar histologically to patient MCC, and both contained laminin networks associated with vascular endothelial-cadherin (CD144) and vascular endothelial growth factor receptor 1, as well as Nodal expression typical of VM in melanoma. Moreover, two established chemotherapeutic agents utilized for human MCC, etoposide and carboplatin, induced necrosis in xenografts on systemic administration while enriching for laminin networks in apparently resistant viable tumor regions that persisted. These findings for the first time establish VM-like laminin networks as a biomarker in MCC, demonstrate the experimental utility of the MCC xenograft model, and suggest that VM-rich regions of MCC may be refractory to conventional chemotherapeutic agents.Laboratory Investigation advance online publication, 11 August 2014; doi:10.1038/labinvest.2014.99.
    Laboratory Investigation 08/2014; 94(10). DOI:10.1038/labinvest.2014.99 · 3.68 Impact Factor

Publication Stats

6k Citations
1,291.15 Total Impact Points


  • 1983-2015
    • Brigham and Women's Hospital
      • • Department of Pathology
      • • Division of Genetics
      Boston, Massachusetts, United States
  • 1982-2015
    • Harvard Medical School
      • • Department of Pathology
      • • Department of Dermatology
      Boston, Massachusetts, United States
    • Beth Israel Deaconess Medical Center
      • Department of Dermatology
      Boston, Massachusetts, United States
  • 2014
    • Ruhr-Universität Bochum
      Bochum, North Rhine-Westphalia, Germany
  • 1981-2014
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2013
    • Stanford University
      • Division of Plastic and Reconstructive Surgery
      Palo Alto, California, United States
  • 1983-2013
    • Massachusetts General Hospital
      • • Transplantation Biology Research Center
      • • Department of Pathology
      Boston, Massachusetts, United States
  • 2012
    • Fudan University
      • Department of Immunology
      Shanghai, Shanghai Shi, China
  • 1986-2012
    • Dana-Farber Cancer Institute
      • • Center for Melanoma Oncology
      • • Department of Pediatric Oncology
      Boston, Massachusetts, United States
  • 2003-2011
    • Memorial Sloan-Kettering Cancer Center
      • • Department of Medicine
      • • Department of Pediatrics
      New York City, NY, United States
    • Cornell University
      Итак, New York, United States
  • 1998-2004
    • Thomas Jefferson University
      • • Department of Pathology, Anatomy & Cell Biology
      • • Department of Microbiology & Immunology
      Philadelphia, Pennsylvania, United States
  • 1997-2004
    • Jefferson College
      Хиллсборо, Missouri, United States
  • 2002
    • Johns Hopkins Medicine
      • Department of Dermatology
      Baltimore, Maryland, United States
  • 1997-1999
    • Thomas Jefferson University Hospitals
      • Department of Pathology, Anatomy and Cell Biology
      Philadelphia, Pennsylvania, United States
  • 1989-1996
    • University of Pennsylvania
      • Department of Dermatology
      Philadelphia, Pennsylvania, United States
    • William Penn University
      Filadelfia, Pennsylvania, United States
  • 1995
    • Hospital of the University of Pennsylvania
      • Department of Dermatology
      Philadelphia, Pennsylvania, United States
  • 1993
    • Showa University
      Shinagawa, Tōkyō, Japan
    • Wistar Institute
      Philadelphia, Pennsylvania, United States
  • 1992
    • Philadelphia University
      Philadelphia, Pennsylvania, United States
  • 1981-1986
    • Beverly Hospital, Boston MA
      BVY, Massachusetts, United States
  • 1975-1980
    • University of Vermont
      • Department of Pathology
      Burlington, Vermont, United States