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Melanoma: HELP
Articles by Colleen M. Cebulla
Based on 22 articles published since 2010
(Why 22 articles?)
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Between 2010 and 2020, C. Cebulla wrote the following 22 articles about Melanoma.
 
+ Citations + Abstracts
1 Review Brachytherapy for patients with uveal melanoma: historical perspectives and future treatment directions. 2018

Brewington, Beatrice Y / Shao, Yusra F / Davidorf, Fredrick H / Cebulla, Colleen M. ·Havener Eye Institute, Department of Ophthalmology and Visual Science, Ohio State University. · Medical Student Research Program, The Ohio State University College of Medicine, Columbus, OH, USA. ·Clin Ophthalmol · Pubmed #29844657.

ABSTRACT: Surgical management with enucleation was the primary treatment for uveal melanoma (UM) for over 100 years. The Collaborative Ocular Melanoma Study confirmed in 2001 that globe-preserving episcleral brachytherapy for UM was safe and effective, demonstrating no survival difference with enucleation. Today, brachytherapy is the most common form of radiotherapy for UM. We review the history of brachytherapy in the treatment of UM and the evolution of the procedure to incorporate fine-needle-aspiration biopsy techniques with DNA-and RNA-based genetic prognostic testing.

2 Review Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases. 2016

Rai, K / Pilarski, R / Cebulla, C M / Abdel-Rahman, M H. ·Division of Human Genetics, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA. · Department of Ophthalmology and Visual Science, Havener Eye Institute, The Ohio State University, Columbus, OH, USA. · Department of Pathology, Menoufiya University, Shebin Elkoum, Egypt. ·Clin Genet · Pubmed #26096145.

ABSTRACT: The BRCA1-associated protein-1 (BAP1) tumor predisposition syndrome (BAP1-TPDS) is a recently identified hereditary cancer syndrome. Germline mutations in this tumor suppressor gene predispose families to the development of various malignancies. The molecular functions of the gene as well as the clinical phenotype of the syndrome are still being clarified. We sought to conduct a comprehensive review of published research into BAP1-TPDS to more thoroughly delineate the clinical implications of germline BAP1 mutations. We also report two additional families with germline BAP1 mutations. Current evidence demonstrates that germline BAP1 mutations predispose families to uveal melanoma, renal cell carcinoma, malignant mesothelioma, cutaneous melanoma, and possibly to a range of other cancers as well. Some of these cancers tend to be more aggressive, have a propensity to metastasize, and onset earlier in life in patients with BAP1 mutations as compared to non-predisposed patients with equivalent cancers. Although further research is necessary, this information can aid in the management, diagnosis, and therapy of these patients and their families, and highlights the importance of genetic counseling.

3 Review Ocular melanoma and the BAP1 hereditary cancer syndrome: implications for the dermatologist. 2014

Martorano, Lisa M / Winkelmann, Richard R / Cebulla, Colleen M / Abdel-Rahman, Mohamed H / Campbell, Shannon M. ·Richmond Medical Center, University Hospitals, Cleveland, OH, USA. ·Int J Dermatol · Pubmed #24697775.

ABSTRACT: Ocular melanoma is a rare subtype of melanoma, which includes uveal melanoma (UM) and conjunctival melanoma. UM is associated with an increased risk of cutaneous melanoma (CM) in addition to mesothelioma, skin lesions such as epithelioid atypical Spitz tumors, and other internal malignancies due to a germline mutation of the BRCA1-associated protein 1 (BAP1) gene. Such familial risks are important for dermatologists to recognize when screening patients with a history of UM for CM and other malignancies. Molecular genetics further help to elucidate the connections between UM and CM by revealing similarities and differences in important mutations among the melanoma subtypes. Both UM and CM have been shown to harbor germline mutation of BAP1. However, somatic mutations in either GNAQ or GNA11 are unique to UM tumors and could be used as potential markers to differentiate UM from metastatic CM and act as direct therapeutic targets. However, CM-associated BRAF and CDKN2A mutations are rare in UM. This review addresses the clinical features, pathogenesis, and current treatment options of UM, focusing on UM and the BAP1 cancer syndrome to raise awareness of ocular melanoma and its greater role in the predisposition to a hereditary cancer syndrome.

4 Article Heterogeneity in Mitogen-Activated Protein Kinase (MAPK) Pathway Activation in Uveal Melanoma With Somatic GNAQ and GNA11 Mutations. 2019

Boru, Getachew / Cebulla, Colleen M / Sample, Klarke M / Massengill, James B / Davidorf, Frederick H / Abdel-Rahman, Mohamed H. ·Department of Ophthalmology, the Ohio State University, Columbus, Ohio, Unites States. · Division of Human Genetics, the Ohio State University, Columbus, Ohio, United States. ·Invest Ophthalmol Vis Sci · Pubmed #31173078.

ABSTRACT: Purpose: The activation of the mitogen-activated protein kinase (MAPK) pathway has been suggested as the major downstream target when GNAQ and GNA11 (GNAQ/11) are mutated in uveal melanoma (UM). However, clinical trials with single agent MEK inhibitor showed no clinical significance in altering the overall outcome of the disease in UM; therefore, we investigated the correlation between naturally occurring mutations in GNAQ/11 and activation of MAPK pathway in vivo in primary UM. Methods: Screening for activating mutations in codons 183 and 209 of GNAQ/11 was carried out by sequencing and restriction fragment length polymorphism (RFLP) in a cohort of 42 primary UM. Activation of the MAPK pathway and other potential downstream signals was assessed by immunohistochemistry and/or Western blot analysis. Potential downstream signaling of mutant and wild type GNAQ/11 was studied by transient transfection assay in nonmutant cell lines. Results: Somatic mutations in GNAQ/11 were observed in 35/42 (83.3%) of primary UM. Tumors with GNAQ/11 mutations showed variations in the activation of ERK1/2 with significant tumor heterogeneity. Weak and undetectable ERK1/2 activation was observed in 4/35 (11.4%) and 8/35 (22.9%) of the GNAQ/11 mutant UM, respectively. Tumor heterogeneity of GNAQ/11 mutations was also observed in a subset of tumors. Conclusions: Our results indicate that there is marked variation in MAPK activation in UM with GNAQ/11 mutations. Thus, GNAQ/11 mutational status is not a sufficient biomarker to adequately predict UM patient responses to single-agent selective MEK inhibitor therapy.

5 Article Germline large deletion of BAP1 and decreased expression in non-tumor choroid in uveal melanoma patients with high risk for inherited cancer. 2019

Boru, Getachew / Grosel, Timothy W / Pilarski, Robert / Stautberg, Meredith / Massengill, James B / Jeter, Joanne / Singh, Arun / Marino, Meghan J / McElroy, Joseph P / Davidorf, Frederick H / Cebulla, Colleen M / Abdel-Rahman, Mohamed H. ·Department of Ophthalmology and Visual Science, Havener Eye Institute, The Ohio State University Columbus, Columbus, Ohio. · Division of Human Genetics, Department of Internal Medicine, The Ohio State University Columbus, Columbus, Ohio. · Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio. · Cole Eye Institute, Department of Ophthalmic Oncology, Cleveland Clinic, Cleveland, Ohio. · Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio. ·Genes Chromosomes Cancer · Pubmed #30883995.

ABSTRACT: Uveal melanoma (UM) is the most common phenotype in patients with germline BAP1 mutation. This study aimed to identify selection criteria for BAP1 germline testing and assessed the role of large deletion/duplication and epigenetic inactivation. One hundred seventy-two UM patients with high risk of hereditary cancer were included. Germline variants in BAP1 were assessed by direct sequencing and large deletion/duplication by multiplex ligation-dependent probe amplification. BAP1 expression in unaffected choroid tissue from a patient with UM was assessed by quantitative RT-PCR and methylation by pyrosequencing. Twenty-eight patients had one or more germline sequence variants in BAP1; seven of these were pathogenic. One hundred forty patients were assessed for large deletion/duplication and in one BAP1 whole gene deletion was detected. In total, eight patients (4.7%) had pathogenic alterations in BAP1 with the highest frequencies of in patients with a personal/family history of ≥2 BAP1-related cancers 6/16 (38%), age of onset <35 years 4/21 (19%) and familial UM 6/34 (18%). One of 19 non-tumor choroid tissues tested showed uncharacteristically low expression as compared to the controls decrease in BAP1 RNA expression but no evidence of constitutional promotor hypermethylation was detected. UM patients with a strong personal or family history of cancers associated with BAP1, early age of onset and familial UM should be assessed for germline variants in BAP1, including large deletions.

6 Article BAP1 expression is prognostic in breast and uveal melanoma but not colon cancer and is highly positively correlated with RBM15B and USP19. 2019

Shahriyari, Leili / Abdel-Rahman, Mohamed / Cebulla, Colleen. ·Department of Mathematics, University of Texas Arlington, Arlington, Texas, United States of America. · Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, United States of America. · Havener Eye Institute, Department of Ophthalmology and Visual Science, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America. ·PLoS One · Pubmed #30716094.

ABSTRACT: BAP1 is a tumor suppressor gene important to the development and prognosis of many cancers, especially uveal melanoma (UM). Its role in more common cancers such as breast and colon cancer is largely unknown. We collected the transcriptome profiling data sets from the TCGA uveal melanoma (TCGA-UVM), breast cancer (TCGA-BRCA), and colon cancer (TCGA-COAD) projects to analyze the expression of BAP1. We found that patients with UM and breast cancer, but not colon cancer, who died had a lower level of BAP1 gene expression compared to surviving patients. Importantly, in breast cancer patients, the lowest BAP1 expression levels corresponded to the dead young patients (age at diagnosis < 46). Since the number of cases in TCGA-BRCA was much higher than TCGA-UVM, we obtained highly correlated genes with BAP1 in invasive breast carcinomas. Then, we tested if these genes are also highly correlated with BAP1 in UM and colon cancer. We found that BAP1 is highly positively correlated with RBM15B and USP19 expression in invasive breast carcinoma, UM, and colon adenocarcinoma. All three genes are located in close proximity on the 3p21 tumor suppressor region that is commonly altered in many cancers.

7 Article Trends in Radiation Practices for Female Ocular Oncologists in North America: A Collaborative Study of the International Society of Ocular Oncology. 2019

Shah, Sona N / Kogachi, Kaitlin / Correa, Zelia M / Schefler, Amy C / Aronow, Mary E / Callejo, Sonia A / Cebulla, Colleen M / Day-Ghafoori, Shelley / Francis, Jasmine H / Lally, Sara / McCannel, Tara A / Paton, Katherine E / Phan, Isabella T / Pointdujour-Lim, Renelle / Ramasubramanian, Aparna / Rath, Pamela / Shields, Carol L / Skalet, Alison H / Wells, Jill R / Jennelle, Richard L / Berry, Jesse L. ·USC Roski Eye Institute, University of Southern California, Los Angeles, California, USA. · Children's Hospital Los Angeles, Los Angeles, California, USA. · University of Cincinnati, Cincinnati, Ohio, USA. · Retina Consultants of Houston, Houston, Texas, USA. · Massachusetts Eye and Ear, Retina Service, Harvard Medical School, Boston, Massachusetts, USA. · University of Montreal, Montreal, Québec, Canada. · Ohio State University, Columbus, Ohio, USA. · Austin Retina Associates, Austin, Texas, USA. · Memorial Sloan Kettering Cancer Center, New York City, New York, USA. · Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. · University of California, Los Angeles, Los Angeles, California, USA. · University of British Columbia, Vancouver, British Columbia, Canada. · Kaiser Permanente, Northern California, San Francisco, California, USA. · Yale University, New Haven, Connecticut, USA. · University of Louisville, Louisville, Kentucky, USA. · Everett and Hurite Ophthalmic Association, Pittsburgh, Pennsylvania, USA. · Casey Eye Institute, Oregon Health & Science University, Portland, Oregon, USA. · Department of Radiation Oncology, Oregon Health & Science University, Portland, Oregon, USA. · Emory Eye Center, Emory University, Atlanta, Georgia, USA. · Department of Radiation Oncology, University of Southern California, Los Angeles, California, USA. ·Ocul Oncol Pathol · Pubmed #30675478.

ABSTRACT: Background: The aim of this study was to determine the known radiation exposure, attitudes, and consequent risk modifications among female ocular oncologists in North America who routinely administer radioactive plaque brachytherapy treatment and are members of the International Society of Ocular Oncology. Methods: Nineteen female ocular oncologists completed an anonymous 17-question radiation exposure survey. Results: Eleven of the participants chose to routinely wear lead protection during surgery; 8 did not. Fifteen of 19 participants reported using an unloaded "nonactive" template to prepare for plaque implantation. During pregnancy, 11 of 13 participants continued to perform plaque brachytherapy. Eight of these 11 undertook measures to decrease radiation exposure self-reported as lead wear and other. The average reported anxiety regarding fertility was 2.1 (SD, 2.2) on a scale from 1 to 10. Conclusion: This study corroborates prior literature that surgeons' exposure to radiation during plaque brachytherapy is minimal. Nonetheless, there remains some anxiety regarding exposure risk to women, due to potential effects on fertility and fetal health. We found variability in exposure monitoring, required training, and precautions during pregnancy amongst this group of surgeons. Improved education and clearer pregnancy guidelines may equip female ocular oncologists with optimal knowledge regarding risk of radiation exposure.

8 Article Patterns of BAP1 protein expression provide insights into prognostic significance and the biology of uveal melanoma. 2018

Farquhar, Neil / Thornton, Sophie / Coupland, Sarah E / Coulson, Judy M / Sacco, Joseph J / Krishna, Yamini / Heimann, Heinrich / Taktak, Azzam / Cebulla, Colleen M / Abdel-Rahman, Mohamed H / Kalirai, Helen. ·Liverpool Ocular Oncology Research Group, Department of Molecular and Clinical Cancer MedicineInstitute of Translational Medicine, University of LiverpoolLiverpoolUK. · Department of Cellular PathologyRoyal Liverpool University HospitalLiverpoolUK. · Department of Cellular and Molecular PhysiologyInstitute of Translational Medicine, University of LiverpoolLiverpoolUK. · Department of Medical OncologyClatterbridge Cancer CentreClatterbridgeUK. · Liverpool Ocular Oncology CentreRoyal Liverpool University HospitalLiverpoolUK. · Department of Medical Physics & Clinical EngineeringRoyal Liverpool University HospitalLiverpoolUK. · Department of Ophthalmology and Visual ScienceHavener Eye Institute, The Ohio State UniversityColumbusOHUSA. · Division of Human Genetics, Department of Internal MedicineThe Ohio State UniversityColumbusOHUSA. ·J Pathol Clin Res · Pubmed #29416875.

ABSTRACT: Uveal melanoma (UM) is a rare aggressive intraocular tumour with a propensity for liver metastases, occurring in ∼50% of patients. The tumour suppressor

9 Article Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma. 2017

Robertson, A Gordon / Shih, Juliann / Yau, Christina / Gibb, Ewan A / Oba, Junna / Mungall, Karen L / Hess, Julian M / Uzunangelov, Vladislav / Walter, Vonn / Danilova, Ludmila / Lichtenberg, Tara M / Kucherlapati, Melanie / Kimes, Patrick K / Tang, Ming / Penson, Alexander / Babur, Ozgun / Akbani, Rehan / Bristow, Christopher A / Hoadley, Katherine A / Iype, Lisa / Chang, Matthew T / Anonymous1140916 / Cherniack, Andrew D / Benz, Christopher / Mills, Gordon B / Verhaak, Roel G W / Griewank, Klaus G / Felau, Ina / Zenklusen, Jean C / Gershenwald, Jeffrey E / Schoenfield, Lynn / Lazar, Alexander J / Abdel-Rahman, Mohamed H / Roman-Roman, Sergio / Stern, Marc-Henri / Cebulla, Colleen M / Williams, Michelle D / Jager, Martine J / Coupland, Sarah E / Esmaeli, Bita / Kandoth, Cyriac / Woodman, Scott E. ·Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada. · The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. · Buck Institute for Research on Aging, Novato, CA 94945, USA. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · The Eli and Edythe L. Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02142, USA. · Department of Biomolecular Engineering, Center for Biomolecular Sciences and Engineering, University of California, Santa Cruz, CA 95064, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Public Health Sciences, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA. · The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD 21287, USA. · The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA. · Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Human Oncology and Pathogenesis Program, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA. · Molecular and Medical Genetics, Computational Biology, Oregon Health and Science University, Portland, OR 97239, USA. · Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Institute for Applied Cancer Science, Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. · Institute for Systems Biology, Seattle, WA 98109, USA. · Human Oncology and Pathogenesis Program, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA; Departments of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94122, USA. · Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Dermatology, University Hospital Essen, 45157 Essen, Germany. · Center for Cancer Genomics, National Cancer Institute, Bethesda, MD 20892, USA. · Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Department of Pathology, The Ohio State University, Wexner Medical Center, Columbus, OH 43210, USA. · Department of Pathology, Dermatology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. · Departments of Ophthalmology and Internal Medicine, Division of Human Genetics, The Ohio State University, Columbus, OH 43210, USA. · Department of Translational Research, Institut Curie, PSL Research University, Paris 75248, France. · Havener Eye Institute, The Ohio State University Wexner Medical Center, Columbus, OH 43212, USA. · Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands. · Department of Molecular & Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool L7 8TX, UK; Department of Cellular Pathology, Royal Liverpool University Hospital, Liverpool, L69 3GA, UK. · Orbital Oncology & Ophthalmic Plastic Surgery, Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: besmaeli@mdanderson.org. · Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA. Electronic address: kandothc@mskcc.org. · Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: swoodman@mdanderson.org. ·Cancer Cell · Pubmed #28810145.

ABSTRACT: Comprehensive multiplatform analysis of 80 uveal melanomas (UM) identifies four molecularly distinct, clinically relevant subtypes: two associated with poor-prognosis monosomy 3 (M3) and two with better-prognosis disomy 3 (D3). We show that BAP1 loss follows M3 occurrence and correlates with a global DNA methylation state that is distinct from D3-UM. Poor-prognosis M3-UM divide into subsets with divergent genomic aberrations, transcriptional features, and clinical outcomes. We report change-of-function SRSF2 mutations. Within D3-UM, EIF1AX- and SRSF2/SF3B1-mutant tumors have distinct somatic copy number alterations and DNA methylation profiles, providing insight into the biology of these low- versus intermediate-risk clinical mutation subtypes.

10 Article Germline BAP1 alterations in familial uveal melanoma. 2017

Rai, Karan / Pilarski, Robert / Boru, Getachew / Rehman, Muneeb / Saqr, Ahmad H / Massengill, James B / Singh, Arun / Marino, Meghan J / Davidorf, Frederick H / Cebulla, Colleen M / H Abdel-Rahman, Mohamed. ·Division of Human Genetics, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio. · Department of Ophthalmology and Visual Science, Havener Eye Institute, The Ohio State University, Columbus, Ohio. · Cole Eye Institute, Department of Ophthalmic Oncology, Cleveland Clinic, Cleveland, Ohio. ·Genes Chromosomes Cancer · Pubmed #27718540.

ABSTRACT: Uveal melanoma (UM) is the most commonly diagnosed primary intraocular tumor in adults. Familial UM (FUM), defined as two or more family members diagnosed with UM, is rare and estimated at less than 1% of all UM. Currently, BAP1 is the only gene known to contribute significant risk for UM. In this study we aimed to estimate the frequency of BAP1 mutation in FUM and to characterize the family and personal histories of other cancers in these families. We identified 32 families with FUM, including seven families previously reported by our group. BAP1 mutation testing was carried out by direct sequencing of the coding exons and the adjacent untranslated regions of the gene. Germline deletion and duplication analysis of BAP1 was assessed by multiplex ligation-dependent probe amplification (MLPA). Germline BAP1 mutations were found in 6/32 (19%) families. No deletions or duplications were identified in any of the 24 samples tested by MLPA. Combined with published studies, the frequency of BAP1 mutations was 14/64 (22%) in FUM. FUM families without BAP1 mutations have distinct family histories with high rates of prostate cancer in first- and second-degree relatives. It is likely that additional genes conferring risk for FUM exist. It is important to understand key shared features of FUM to focus future research on identifying these additional tumor predisposition syndromes. Though BAP1 should be tested first in these families, FUM families without BAP1 mutation should be explored for additional predisposition genes. © 2016 Wiley Periodicals, Inc.

11 Article Genetic markers of pigmentation are novel risk loci for uveal melanoma. 2016

Ferguson, Robert / Vogelsang, Matjaz / Ucisik-Akkaya, Esma / Rai, Karan / Pilarski, Robert / Martinez, Carlos N / Rendleman, Justin / Kazlow, Esther / Nagdimov, Khagay / Osman, Iman / Klein, Robert J / Davidorf, Frederick H / Cebulla, Colleen M / Abdel-Rahman, Mohamed H / Kirchhoff, Tomas. ·Perlmutter Cancer Center, New York University School of Medicine, New York, USA. · Departments of Population Health and Environmental Medicine, New York University School of Medicine, New York, USA. · The Interdisciplinary Melanoma Cooperative Group, New York University School of Medicine, New York, USA. · Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA. · Department of Medicine, New York University School of Medicine, New York, USA. · Ronald O. Perelman, Department of Dermatology, New York University, New York, USA. · Department of Genetic and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, USA. · Havener Eye Institute, Department of Ophthalmology and Visual Science, The Ohio State University, Columbus, OH USA. ·Sci Rep · Pubmed #27499155.

ABSTRACT: While the role of genetic risk factors in the etiology of uveal melanoma (UM) has been strongly suggested, the genetic susceptibility to UM is currently vastly unexplored. Due to shared epidemiological risk factors between cutaneous melanoma (CM) and UM, in this study we have selected 28 SNPs identified as risk variants in previous genome-wide association studies on CM or CM-related host phenotypes (such as pigmentation and eye color) and tested them for association with UM risk. By logistic regression analysis of 272 UM cases and 1782 controls using an additive model, we identified five variants significantly associated with UM risk, all passing adjustment for multiple testing. The three most significantly associated variants rs12913832 (OR = 0.529, 95% CI 0.415-0.673; p = 8.47E-08), rs1129038 (OR = 0.533, 95% CI 0.419-0.678; p = 1.19E-07) and rs916977 (OR = 0.465, 95% CI 0.339-0.637; p = 3.04E-07) are correlated (r(2) > 0.5) and map at 15q12 in the region of HERC2/OCA2, which determines eye-color in the human population. Our data provides first evidence that the genetic factors associated with pigmentation traits are risk loci of UM susceptibility.

12 Article Germline BAP1 mutations misreported as somatic based on tumor-only testing. 2016

Abdel-Rahman, Mohamed H / Rai, Karan / Pilarski, Robert / Davidorf, Frederick H / Cebulla, Colleen M. ·Department of Ophthalmology and Visual Science, The Ohio State University, Columbus, OH, USA. mohamed.abdel-rahman@osumc.edu. · Division of Human Genetics, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA. mohamed.abdel-rahman@osumc.edu. · Department of Pathology, Menoufiya University, Shebin El-Kom, Egypt. mohamed.abdel-rahman@osumc.edu. · Division of Human Genetics, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA. · Department of Ophthalmology and Visual Science, The Ohio State University, Columbus, OH, USA. ·Fam Cancer · Pubmed #26748926.

ABSTRACT: We present three unrelated patients with germline mutations in BAP1 misreported as somatic mutations. All had strong family histories of cancer. One of these patients presented with an invasive breast cancer with the tumor tissue showing partial loss of the mutant rather than the wild type allele, suggesting that the germline BAP1 mutation didn't contribute to breast cancer development in this patient. This data highlights the importance of sequencing matching germline and tumor DNA for proper assessment of somatic versus germline mutation status. In patients with somatic mutations reported from laboratories carrying out tumor-only genomic testing, the possibility that a variant may be a germline mutation should be considered, especially if the personal and/or family history suggests hereditary cancer predisposition. Since tumor-only testing can reveal germline mutations, ethical issues for patients being tested should be considered including proper consent and genetic counseling.

13 Article Long-term visual acuity outcomes in patients with uveal melanoma treated with 125I episcleral OSU-Nag plaque brachytherapy. 2016

Wisely, C Ellis / Hadziahmetovic, Mersiha / Reem, Rachel E / Hade, Erinn M / Nag, Subir / Davidorf, Frederick H / Martin, Douglas / Cebulla, Colleen M. ·Department of Ophthalmology and Visual Science, Havener Eye Institute, The Ohio State University Wexner Medical Center, Columbus, OH. · Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH. · Center for Biostatistics, Department of Bioinformatics, The Ohio State University Wexner Medical Center, Columbus, OH. · Department of Radiation Oncology, Northern California Kaiser Permanente, Santa Clara, CA. · Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH. Electronic address: Douglas.Martin@osumc.edu. ·Brachytherapy · Pubmed #26525215.

ABSTRACT: PURPOSE: To report our experience in long-term follow-up of ocular melanoma patients treated with custom OSU-Nag eye plaques using (125)I sources. METHODS: A retrospective chart review was conducted for 113 consecutive ocular melanoma patients with follow-up visual acuity data who were treated with OSU-Nag plaque episcleral brachytherapy at The Ohio State University Medical Center from 1994 to 2009. Visual acuity, complication data, and recurrence rates were recorded up to 120 months after brachytherapy. RESULTS: Median age at presentation was 63.0 years (range, 22-93). Median follow-up was 65.5 months (range, 2-180). Median radiation dose at the prescription point was 85.8 Gy (range, 51.8-103.7). Preservation of useful visual acuity, defined as better than 20/200, was noted in 43 of 74 (58%) of patients in the present study at 36 months compared with 50.1% of Collaborative Ocular Melanoma Study participants. By 120 months, 17 of 30 (57%; 95% confidence interval, 45-69%) progressed to visual acuity worse than 20/200, whereas 9 of 30 (30%) retained visual acuity of 20/40 or better, and 4 of 30 (13%) were 20/50-20/200. The rate of retinopathy after radiation was approximately 40% of all those observed by 60 months. Baseline visual acuity, apical tumor height, American Joint Committee on Cancer tumor category, and distance between the tumor and the fovea were all significantly associated with loss of visual acuity. The local tumor control rate by 60 months of follow-up was 93% (95% confidence interval, 85-97%). CONCLUSIONS: The OSU-Nag custom (125)I plaque is an effective treatment for uveal melanoma, with preservation of useful visual acuity in 58% of eyes 3 years after treatment and 43% of eyes 10 years after treatment.

14 Article Bilateral Choroidopathy and Serous Retinal Detachments During Ipilimumab Treatment for Cutaneous Melanoma. 2015

Mantopoulos, Dimosthenis / Kendra, Kari L / Letson, Alan D / Cebulla, Colleen M. ·Havener Eye Institute, Department of Ophthalmology and Visual Science, The Ohio State University, Wexner Medical Center, Columbus. · Department of Internal Medicine, Division of Medical Oncology, The Ohio State University, Wexner Medical Center, Columbus. ·JAMA Ophthalmol · Pubmed #25974108.

ABSTRACT: -- No abstract --

15 Article Analysis of BAP1 Germline Gene Mutation in Young Uveal Melanoma Patients. 2015

Cebulla, Colleen M / Binkley, Elaine M / Pilarski, Robert / Massengill, James B / Rai, Karan / Liebner, David A / Marino, Meghan J / Singh, Arun D / Abdel-Rahman, Mohamed H. ·Havener Eye Institute, Department of Ophthalmology and Visual Science . ·Ophthalmic Genet · Pubmed #25687217.

ABSTRACT: BACKGROUND: To evaluate the prevalence of BAP1 germline mutations in a series of young patients with uveal melanoma (UM), diagnosed before age 30. MATERIALS AND METHODS: The study was carried out on 14 young uveal melanoma patients (average age 21.4 years, range 3 months to 29 years). Germline DNA was extracted from peripheral blood. BAP1 sequencing was carried out using direct sequencing of all exons and adjacent intronic sequences. We also tested for germline mutations in additional melanoma-associated candidate genes CDKN2A and CDK4 (exon 4). RESULTS: We identified one patient with a pathogenic mutation (c. 1717delC, p.L573fs*3) in BAP1. This patient was diagnosed with UM at age 18 years and had a family history of a father with UM and a paternal grandfather with cancer of unknown origin. One additional patient had an intronic variant of uncertain significance (c.123-48T > G) in BAP1 while the remaining 12 patients had no alteration. None of the patients had CDKN2A or CDK4 (Exon 4) mutations. Family history was positive for a number of additional malignancies in this series, in particular for cutaneous melanoma, prostate, breast and colon cancers. There were no families with a history of mesothelioma or renal cell carcinoma. CONCLUSIONS: This study suggests that a small subset of patients with early onset UM has germline mutation in BAP1. While young patients with UM should be screened for germline BAP1 mutations, our results suggest that there is a need to identify other candidate genes which are responsible for UM in young patients.

16 Article Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases. 2014

Pilarski, Robert / Cebulla, Colleen M / Massengill, James B / Rai, Karan / Rich, Thereasa / Strong, Louise / McGillivray, Barbara / Asrat, Mary-Jill / Davidorf, Frederick H / Abdel-Rahman, Mohamed H. ·Division of Human Genetics, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio. ·Genes Chromosomes Cancer · Pubmed #24243779.

ABSTRACT: The clinical phenotype of BAP1 hereditary cancer predisposition syndrome (MIM 614327) includes uveal melanoma (UM), cutaneous melanoma (CM), renal cell carcinoma (RCC), and mesothelioma. However, the frequency of the syndrome in patients with UM and the association with other cancers are still not clear. In this study, we screened 46 previously untested, unrelated UM patients with high risk for hereditary cancer for germline mutation in BAP1. We also studied four additional patients with a personal or family history suggestive of BAP1 hereditary cancer syndrome. We identified three patients with germline pathogenic mutations (c.2050 C>T, pGln684*; c.1182C>G, p.Tyr394*, and c.1882_1885delTCAC, p. Ser628Profs*8) in BAP1. Two of these three patients presented with UM and the third with a metastatic adenocarcinoma likely from a hepatic cholangiocarcinoma. Reported family histories included UM, mesothelioma, RCC, CM, and several other internal malignancies. The results of this study confirm the association between germline BAP1 mutation and predisposition to UM, mesothelioma, CM and RCC. However, other cancers, such as cholangiocarcinoma and breast carcinoma may be part of the phenotype of this hereditary cancer predisposition syndrome. In addition, the results support the existence of other candidate genes in addition to BAP1 contributing to hereditary predisposition to UM.

17 Article Long-term survivors with metastatic uveal melanoma. 2012

Buzzacco, Dominic M / Abdel-Rahman, Mohamed H / Park, Stanley / Davidorf, Frederick / Olencki, Thomas / Cebulla, Colleen M. ·Department of Ophthalmology and Vision Science, The Ohio State University, Columbus, Ohio, USA. ·Open Ophthalmol J · Pubmed #22798969.

ABSTRACT: BACKGROUND: To report the tumor, patient, and treatment characteristics of long-term metastatic uveal melanoma survivors. METHODS: A non-comparative, retrospective case series of patients from a single institution surviving >24 months with metastatic uveal melanoma (UM). RESULTS: Nine patients met the study criteria and their charts were reviewed. The mean age at diagnosis of UM was 44.1 years (SD +/- 14.4 years). Initial treatment modalities included enucleation (67%), brachytherapy (22%), and proton beam radiation (11%). The average time from primary tumor diagnosis to detection of metastasis was 125.9 months (SD +/- 95 months). The most common location for initial metastasis was the liver. All patients underwent treatment for metastatic disease including systemic therapy, surgical resection, and isolated hepatic perfusion. The majority of patients received treatment with a tyrosine kinase inhibitor (sorafenib, sunitinib, and/or imatinib). The median survival with metastasis was 51 months (range 27-123 months). Patients had a long disease-free interval before presentation of metastatic disease. CONCLUSIONS: A small subset of patients with metastatic UM has prolonged survival. Identification of these patients may be helpful for future clinical trial design.

18 Article Monosomy 3 status of uveal melanoma metastases is associated with rapidly progressive tumors and short survival. 2012

Abdel-Rahman, Mohamed H / Cebulla, Colleen M / Verma, Vishal / Christopher, Benjamin N / Carson, William E / Olencki, Thomas / Davidorf, Frederick H. ·Department of Ophthalmology, The Ohio State University, Columbus, OH 43210, USA. Mohamed.abdel-rahman@osumc.edu ·Exp Eye Res · Pubmed #22569040.

ABSTRACT: The aim of the study was to investigate the molecular genetics of uveal melanoma (UM) metastases and correlate it with disease progression. Twelve pathologically confirmed UM metastases from 11 patients were included. Molecular genetic alterations in chromosomes 3 (including the BAP1 region), 8q, 6p, and 1p were investigated by microsatellite genotyping. Mutations in codon 209 of GNAQ and GNA11 genes were studied by restriction-fragment length polymorphism (RFLP). We identified monosomy of chromosome 3 in tumors from four patients with an average survival of 5 months (range 1-8 months) from time of diagnosis of metastatic disease. In contrast, tumors with either disomy or partial chromosome 3 alterations showed significantly slower metastatic disease progression with an average survival of 69 months (range 40-123 months, p = 0.003). Alterations in chromosomal arms 1p, 6p, and 8q and mutations in either GNAQ or GNA11 showed no association with disease progression. Prominent mononuclear inflammatory infiltrate was observed in tumors from patients with slowly progressive disease. In conclusion, in UM metastases, monosomy 3 is associated with highly aggressive, rapidly progressive disease while disomy or partial change of 3 and prominent mononuclear inflammatory infiltrate in the tumor is associated with better prognosis. These findings should be considered when designing clinical trials testing effectiveness of various therapies of metastatic UM.

19 Article Molecular genetic testing of uveal melanoma from routinely processed and stained cytology specimens. 2011

Christopher, Benjamin N / Cebulla, Colleen M / Wakely, Paul E / Davidorf, Frederick H / Abdel-Rahman, Mohamed H. ·Department of Ophthalmology, The Ohio State University, Columbus, OH, USA. ·Exp Eye Res · Pubmed #21945171.

ABSTRACT: In the following study we investigated the utility of molecular genetic testing of the DNA extracted from routinely stained and processed smears from uveal melanoma (UM). Smears from five uveal melanoma cell lines and 12 primary tumors were prepared and stained with Papanicolaou and Romanowsky stains. Genotyping was carried out utilizing 14 microsatellite markers on chromosomes 3, 6 and 8. Mutational screening for alterations in GNAQ and GNA11 genes was carried out by restriction fragment length polymorphism. The results were compared to those obtained through direct sequencing of frozen tumor tissues. High quality DNA was extracted from the stained slides with no difference in the efficiency of DNA extraction between the two staining techniques. The extracted DNA was of adequate quality for genotyping and mutational screening. DNA extracted from approximately 200 tumor cells is sufficient for reproducible testing of allelic imbalances and for studying the common somatic mutations in GNAQ and GNA11 genes. In conclusion, we presented the feasibility of utilizing routinely stained cytology smears from UM for molecular genetic testing. The DNA obtained is of sufficient quality to carry out genotyping for markers on chromosome 3, 6 and 8, as well as screening for somatic mutations in GNAQ and GNA11 genes.

20 Article Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. 2011

Abdel-Rahman, Mohamed H / Pilarski, Robert / Cebulla, Colleen M / Massengill, James B / Christopher, Benjamin N / Boru, Getachew / Hovland, Peter / Davidorf, Frederick H. ·Department of Ophthalmology, The Ohio State University, Columbus, Ohio, USA. mohamed.abdel-rahman@osumc.edu ·J Med Genet · Pubmed #21941004.

ABSTRACT: OBJECTIVE: To investigate the potential contribution of germline sequence alterations in the BAP1 gene in uveal melanoma (UM) patients with possible predisposition to hereditary cancer. DESIGN: A total of 53 unrelated UM patients with high risk for hereditary cancer and five additional family members of one proband were studied. Mutational screening was carried out by direct sequencing. RESULTS: Of the 53 UM patients studied, a single patient was identified with a germline BAP1 truncating mutation, c. 799 C→T (p.Q267X), which segregated in several family members and was associated with UM and other cancers. Biallelic inactivation of BAP1 and decreased BAP1 expression were identified in the UM, lung adenocarcinoma and meningioma tumours from three family members with this germline BAP1 mutation. Germline BAP1 variants of uncertain significance, likely non-pathogenic, were also identified in two additional UM patients. CONCLUSION: This study reports a novel hereditary cancer syndrome caused by a germline BAP1 mutation that predisposes patients to UM, lung carcinoma, meningioma, and possibly other cancers. The results indicate that BAP1 is the candidate gene in only a small subset of hereditary UM, suggesting the contribution of other candidate genes.

21 Unspecified Uveal Melanoma Mimicking Advanced Coats' Disease in a Young Patient. 2016

Gupta, Naina / Terrell, William / Schoenfield, Lynn / Kirsch, Claudia / Cebulla, Colleen M. ·Havener Eye Institute, Department of Ophthalmology and Visual Science, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA. · Havener Eye Institute, Department of Ophthalmology and Visual Science, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA; Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA. · Department of Radiology, North Shore Long Island Jewish Health System, Hofstra Medical School, Manhasset, N.Y., USA. ·Ocul Oncol Pathol · Pubmed #27239453.

ABSTRACT: BACKGROUND/AIMS: To report a case and the unique histopathology of a necrotic uveal melanoma mimicking advanced Coats' disease in a young adult. METHOD: A 26-year-old male presented with a blind, painful eye, total exudative retinal detachment, and bulbous aneurysms consistent with Coats' disease. No masses were visualized on ultrasound or CT scan, and the patient underwent enucleation of the eye. RESULTS: Histopathology of the involved eye confirmed a necrotic uveal melanoma with persistent spindle cells forming a collar around residual tumor vessels. CONCLUSION: Careful consideration is needed in approaching any patient with a blind, painful eye and opaque media, even in younger populations.

22 Minor Optic disc edema from remote uveal melanoma. 2013

Clark, Sireesha A / Lubow, Martin / Ray-Chaudhury, Abhik / Davidorf, Frederick H / Abdel-Rahman, Mohamed H / Cebulla, Colleen M. · ·JAMA Ophthalmol · Pubmed #23307225.

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