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ABSTRACT: BAP1 has been shown to be a target of both somatic alteration in high-risk ocular melanomas (OM) and germline inactivation in a few individuals from cancer-prone families. These findings suggest that constitutional BAP1 changes may predispose individuals to metastatic OM and that familial permeation of deleterious alleles could delineate a new cancer syndrome.
To characterize BAP1's contribution to melanoma risk, we sequenced BAP1 in a set of 100 patients with OM, including 50 metastatic OM cases and 50 matched non-metastatic OM controls, and 200 individuals with cutaneous melanoma (CM) including 7 CM patients from CM-OM families and 193 CM patients from CM-non-OM kindreds.
Germline BAP1 mutations were detected in 4/50 patients with metastatic OM and 0/50 cases of non-metastatic OM (8% vs. 0%, p = 0.059). Since 2/4 of the BAP1 carriers reported a family history of CM, we analyzed 200 additional hereditary CM patients and found mutations in 2/7 CM probands from CM-OM families and 1/193 probands from CM-non-OM kindreds (29% vs. 0.52%, p = .003). Germline mutations co-segregated with both CM and OM phenotypes and were associated with the presence of unique nevoid melanomas and highly atypical nevoid melanoma-like melanocytic proliferations (NEMMPs). Interestingly, 7/14 germline variants identified to date reside in C-terminus suggesting that the BRCA1 binding domain is important in cancer predisposition.
Germline BAP1 mutations are associated with a more aggressive OM phenotype and a recurrent phenotypic complex of cutaneous/ocular melanoma, atypical melanocytic proliferations and other internal neoplasms (ie. COMMON syndrome), which could be a useful clinical marker for constitutive BAP1 inactivation.
PLoS ONE 01/2012; 7(4):e35295. · 4.09 Impact Factor
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ABSTRACT: To describe the in vivo evolution of laser-induced choroidal neovascularization (CNV) in mice using spectral domain optical coherence tomography (SD-OCT).
Laser photocoagulation was applied to the mouse fundus using a 532-nm diode laser (100, 150, and 200 mW; 100-μm diameter, 0.1-second duration). SD-OCT examination was performed immediately after laser application and at days 3, 5, 7, 14, 21, and 28 after laser. Fluorescein angiography (FA) was performed at day 5, 7, 14, and 28. Acquired SD-OCT images were analyzed to describe morphologic features, measure CNV size and retinal thickness, and assess the frequency of lesions resulting in fluid accumulation. Finally, SD-OCT images were compared to fluorescein angiograms and histologic sections with immunostaining at similar time points.
SD-OCT allowed visualization of the initial laser damage and the subsequent stages of the injury response. CNV formation reached its maximum size at day 5. By day 7, significant size reduction was observed (P < 0.001), continuing through days 14 and 28. Exudation signs, such as fluid accumulation and increase in retinal thickness, followed the same time course, with a peak at day 5 and a decrease by day 7. Delivery of higher laser energy levels to the RPE/choroid complex resulted in a significant percentage of lesions demonstrating excessive chorioretinal damage without CNV formation.
SD-OCT is a fast and reliable tool for the in vivo evaluation of laser-induced CNV, allowing quantification of lesion size and exudation parameters. Moreover, it provides morphologic information that correlates with histologic findings.
Investigative ophthalmology & visual science 02/2011; 52(6):3880-7. · 3.43 Impact Factor
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Michael Lukason,
Elizabeth DuFresne,
Hillard Rubin,
Peter Pechan,
Qiuhong Li, Ivana Kim,
Szilard Kiss,
Christina Flaxel,
Margaret Collins,
Joan Miller,
William Hauswirth,
Timothy Maclachlan,
Samuel Wadsworth,
Abraham Scaria
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ABSTRACT: Inhibition of vascular endothelial growth factor (VEGF) for the management of the pathological ocular neovascularization associated with diseases such as neovascular age-related macular degeneration is a proven paradigm; however, monthly intravitreal injections are required for optimal treatment. We have previously shown that a novel, secreted anti-VEGF molecule sFLT01 delivered by intravitreal injection of an AAV2 vector (AAV2-sFLT01) gives persistent expression and is efficacious in a murine model of retinal neovascularization. In the present study, we investigate transduction and efficacy of an intravitreally administered AAV2-sFLT01 in a nonhuman primate (NHP) model of choroidal neovascularization (CNV). A dose-dependent and persistent expression of sFLT01 was observed by collecting samples of aqueous humor at different time points over 5 months. The location of transduction as elucidated by in situ hybridization was in the transitional epithelial cells of the pars plana and in retinal ganglion cells. AAV2-sFLT01 was able to effectively inhibit laser-induced CNV in a dose-dependent manner as determined by comparing the number of leaking CNV lesions in the treated versus control eyes using fluorescein angiography. Our data suggest that intravitreal delivery of AAV2-sFLT01 may be an effective long-term treatment for diseases caused by ocular neovascularization.
Molecular Therapy 10/2010; 19(2):260-5. · 6.87 Impact Factor
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ABSTRACT: The purpose was to study the clinical profile and prognosis of young patients with uveal melanoma treated by proton beam irradiation.
A retrospective case-control series was studied. Seventeen patients aged <or=20 years with uveal melanoma and 51 risk factor-matched control subjects aged >20 years were treated for posterior uveal melanoma between 1975 and 2004. All patients were treated with proton beam irradiation at Harvard Cyclotron. Metastasis and survival of patients were the main outcome measures.
Of a total of 3,207 patients with uveal melanoma, 17 patients were <or=20 years of age at the time of diagnosis. No metastatic deaths were observed (median follow-up, 16 years). Among the control group, there were 7 of 50 metastasis-related deaths.
There was an excellent outcome regarding metastasis in a cohort of young patients with posterior uveal melanoma treated with proton beam irradiation.
Retina (Philadelphia, Pa.) 03/2010; 30(8):1267-71. · 2.93 Impact Factor
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Bao Jian Fan,
Louis Pasquale,
Cynthia L Grosskreutz,
Douglas Rhee,
Teresa Chen,
Margaret M DeAngelis, Ivana Kim,
Elizabeth del Bono,
Joan W Miller,
Tiansen Li,
Jonathan L Haines,
Janey L Wiggs
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ABSTRACT: Pseudoexfoliation syndrome is a major risk factor for glaucoma in many populations throughout the world. Using a U.S. clinic-based case control sample with broad ethnic diversity, we show that three common SNPs in LOXL1 previously associated with pseudoexfoliation in Nordic populations are significantly associated with pseudoexfoliation syndrome and pseudoexfoliation glaucoma.
Three LOXL1 SNPs were genotyped in a patient sample (206 pseudoexfoliation, 331 primary open angle glaucoma, and 88 controls) from the Glaucoma Consultation Service at the Massachusetts Eye and Ear Infirmary. The SNPs were evaluation for association with pseudeoexfoliation syndrome, pseudoexfoliation glaucoma, and primary open angle glaucoma.
The strongest association was found for the G allele of marker rs3825942 (G153D) with a frequency of 99% in pseudoexfoliation patients (with and without glaucoma) compared with 79% in controls (p = 1.6 x 10-15; OR = 20.93, 95%CI: 8.06, 54.39). The homozygous GG genotype is also associated with pseudoexfoliation when compared to controls (p = 1.2 x 10-12; OR = 23.57, 95%CI: 7.95, 69.85). None of the SNPs were significantly associated with primary open angle glaucoma.
The pseudoexfoliation syndrome is a common cause of glaucoma. These results indicate that the G153D LOXL1 variant is significantly associated with an increased risk of pseudoexfoliation and pseudoexfoliation glaucoma in an ethnically diverse patient population from the Northeastern United States. Given the high prevalence of pseudooexfoliation in this geographic region, these results also indicate that the G153D LOXL1 variant is a significant risk factor for adult-onset glaucoma in this clinic based population.
BMC Medical Genetics 02/2008; 9:5. · 2.33 Impact Factor
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ABSTRACT: Endostatin, a fragment of the basement membrane component collagen XVIII, exhibits antiangiogenic properties in vitro and in vivo when high doses are administered. It is not known whether endogenous endostatin at physiological levels has a protective role as an inhibitor of pathological angiogenesis, such as choroidal neovascularization (CNV) in age-related macular degeneration. Using a laser injury model, we induced CNV in mice lacking collagen XVIII/endostatin and in control mice. CNV lesions in mutant mice were approximately 3-fold larger than in control mice and showed increased vascular leakage. These differences were independent of age-related changes at the choroid-retina interface. Ultrastructural analysis of the choroidal vasculature in mutant mice excluded morphological vascular abnormalities as a cause for the larger CNV lesions. When recombinant endostatin was administered to collagen XVIII/endostatin-deficient mice, CNV lesions were similar to those seen in control mice. In control mice treated with recombinant endostatin, CNV lesions were almost undetectable. These findings demonstrate that endogenous endostatin is an inhibitor of induced angiogenesis and that administration of endostatin potently inhibits CNV growth and vascular leakage. Endostatin may have a regulatory role in the pathogenesis of CNV and could be used therapeutically to inhibit growth and leakage of CNV lesions.
The FASEB Journal 01/2008; 21(14):3809-18. · 5.71 Impact Factor
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Bao Fan,
Louis Pasquale,
Cynthia Grosskreutz,
Douglas Rhee,
Teresa Chen,
Margaret DeAngelis, Ivana Kim,
del Bono Elizabeth,
Joan Miller,
Tiansen Li,
Jonathan Haines,
Janey Wiggs
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ABSTRACT: Abstract
Background
Pseudoexfoliation syndrome is a major risk factor for glaucoma in many populations throughout the world. Using a U.S. clinic-based case control sample with broad ethnic diversity, we show that three common SNPs in LOXL1 previously associated with pseudoexfoliation in Nordic populations are significantly associated with pseudoexfoliation syndrome and pseudoexfoliation glaucoma.
Methods
Three LOXL1 SNPs were genotyped in a patient sample (206 pseudoexfoliation, 331 primary open angle glaucoma, and 88 controls) from the Glaucoma Consultation Service at the Massachusetts Eye and Ear Infirmary. The SNPs were evaluation for association with pseudeoexfoliation syndrome, pseudoexfoliation glaucoma, and primary open angle glaucoma.
Results
The strongest association was found for the G allele of marker rs3825942 (G153D) with a frequency of 99% in pseudoexfoliation patients (with and without glaucoma) compared with 79% in controls (p = 1.6 × 10<sup>-15</sup>; OR = 20.93, 95%CI: 8.06, 54.39). The homozygous GG genotype is also associated with pseudoexfoliation when compared to controls (p = 1.2 × 10<sup>-12</sup>; OR = 23.57, 95%CI: 7.95, 69.85). None of the SNPs were significantly associated with primary open angle glaucoma.
Conclusion
The pseudoexfoliation syndrome is a common cause of glaucoma. These results indicate that the G153D LOXL1 variant is significantly associated with an increased risk of pseudoexfoliation and pseudoexfoliation glaucoma in an ethnically diverse patient population from the Northeastern United States. Given the high prevalence of pseudooexfoliation in this geographic region, these results also indicate that the G153D LOXL1 variant is a significant risk factor for adult-onset glaucoma in this clinic based population.
BMC Medical Genetics. 01/2008;
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Hong Zhang,
Margaux Morrison,
Andy DeWan,
Scott Adams,
Michael Andreoli,
Nancy Huynh,
Maureen Regan,
Alison Brown,
Joan Miller, Ivana Kim,
Josephine Hoh,
Margaret DeAngelis
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ABSTRACT: Abstract
Background
To examine if the significantly associated SNPs derived from the genome wide allelic association study on the AREDS cohort at the NEI (dbGAP) specifically confer risk for neovascular age-related macular degeneration (AMD). We ascertained 134 unrelated patients with AMD who had one sibling with an AREDS classification 1 or less and was past the age at which the affected sibling was diagnosed (268 subjects). Genotyping was performed by both direct sequencing and Sequenom iPLEX system technology. Single SNP analyses were conducted with McNemar's Test (both 2 × 2 and 3 × 3 tests) and likelihood ratio tests (LRT). Conditional logistic regression was used to determine significant gene-gene interactions. LRT was used to determine the best fit for each genotypic model tested (additive, dominant or recessive).
Results
Before release of individual data, p -value information was obtained directly from the AREDS dbGAP website. Of the 35 variants with P < 10<sup>-6 </sup>examined, 23 significantly modified risk of neovascular AMD. Many variants located in tandem on 1q32-q22 including those in CFH , CFHR4 , CFHR2 , CFHR5 , F13B , ASPM and ZBTB were significantly associated with AMD risk. Of these variants, single SNP analysis revealed that CFH rs572515 was the most significantly associated with AMD risk (P < 10<sup>-6</sup>). Haplotype analysis supported our findings of single SNP association, demonstrating that the most significant haplotype, GATAGTTCTC, spanning CFH , CFHR4 , and CFHR2 was associated with the greatest risk of developing neovascular AMD ( P < 10<sup>-6</sup>). Other than variants on 1q32-q22, only two SNPs, rs9288410 ( MAP2 ) on 2q34-q35 and rs2014307 ( PLEKHA1 / HTRA1 ) on 10q26 were significantly associated with AMD status ( P = .03 and P < 10<sup>-6 </sup>respectively). After controlling for smoking history, gender and age, the most significant gene-gene interaction appears to be between rs10801575 ( CFH ) and rs2014307 ( PLEKHA1 / HTRA1 ) ( P < 10<sup>-11</sup>). The best genotypic fit for rs10801575 and rs2014307 was an additive model based on LRT. After applying a Bonferonni correction, no other significant interactions were identified between any other SNPs.
Conclusion
This is the first replication study on the NEI dbGAP SNPs, demonstrating that alleles on 1q, 2q and 10q may predispose an individual to AMD.
BMC Medical Genetics. 01/2008;
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Retina 10/2006; 26(7):818-22. · 2.81 Impact Factor
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Deeba Husain, Ivana Kim,
Danny Gauthier,
Anne Marie Lane,
Miltiadis K Tsilimbaris,
Eric Ezra,
Edward J Connolly,
Norman Michaud,
Evangelos S Gragoudas,
Charles A O'Neill,
Joseph C Beyer,
Joan W Miller
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ABSTRACT: To study the safety and efficacy of intravitreal injections of anti-vascular endothelial growth factor antibody fragment (ranibizumab [formerly known as rhuFabV2], Lucentis; Genentech, South San Francisco, Calif) in combination with intravenous verteporfin (Visudyne; Novartis, East Hanover, NJ) photodynamic therapy (PDT) on experimental choroidal neovascularization in the monkey eye.
Choroidal neovascularization was induced by laser injury in both eyes of cynomolgus monkeys and followed with weekly fundus photography and fluorescein angiography. Two weeks after induction, weekly treatments were initiated. These treatments included using either an intravitreal injection of ranibizumab (previously known as rhuFabV2) in combination with verteporfin PDT or a ranibizumab vehicle (placebo) in combination with verteporfin PDT (PDT only). Six animals (group 1) initially received intravitreal injections followed 1 week later by PDT. Four animals (group 2) initially received PDT followed 1 week later by intravitreal injection. Two animals (group 3) received injections and PDT on the same day at 2-week intervals. Photodynamic therapy was applied in all 3 groups every 2 weeks for 3 treatments with follow-up through 2 weeks after the last PDT treatment. Fluorescein angiograms were graded using a masked standardized protocol. The data were analyzed using the McNemar chi(2) test for matched pairs.
No choroidal neovascularization leakage was observed in the eyes of animals treated with ranibizumab and PDT at day 21 or 42 after the start of the first treatment. Leakage persisted in eyes treated with PDT alone at 21 days (3 of 12 eyes) and 42 days (2 of 12 eyes). At all time points studied, the ranibizumab and PDT-treated eyes experienced better angiographic outcomes than the eyes receiving PDT alone.
These preliminary data indicate that an intravitreal ranibizumab injection in combination with verteporfin PDT (ranibizumab and PDT) causes a greater reduction in angiographic leakage than PDT and intravitreal vehicle injection (PDT only) in experimental choroidal neovascularization.
This combination therapy can potentially offer a new treatment modality for choroidal neovascularization in patients with macular degeneration and other diseases.
Archives of Ophthalmology 05/2005; 123(4):509-16. · 3.71 Impact Factor
