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Laga, Alvaro

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Laga

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Alvaro

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Laga, Alvaro
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    5-Hydroxymethylcytosine Expression in Metastatic Melanoma versus Nodal Nevus in Sentine Lymph Node Biopsies
    (2014) Lee, Jonathan J.; Granter, Scott; Laga, Alvaro; Saavedra, Arturo; Zhan, Qian; Guo, Weimin; Xu, Shuyun; Murphy, George; Lian, Christine
    Sentinel lymph node biopsies are conducted to stage patients with newly-diagnosed melanomas that have histopathologic attributes conferring defined levels of metastatic potential. Because benign nevic cells may also form ‘deposits’ in lymph nodes (nodal nevus), the pathologic evaluation for metastatic melanoma within sentinel lymph nodes can be challenging. 28 sentinel lymph node biopsy cases containing either metastatic melanoma (N=18) or nodal nevi (N=10) were retrieved from the archives of the Brigham and Women’s Hospital Department of Pathology (2011–2014). In addition, two sentinel lymph node cases that were favored to represent metastatic disease but whose histopathologic features were viewed as equivocal, with melanoma favored, were also included. Dual-labeling for the melanocyte lineage marker, MART-1, and the epigenetic marker 5-hydroxymethylcytosine, a functionally-significant indicator that has been shown to distinguish benign nevi from melanoma, was performed on all cases using immunohistochemistry and/or direct immunofluorescence. All (18 of 18) metastatic melanoma cases showed complete loss of 5-hydroxymethylcytosine nuclear staining in MART-1-positive cells and all (10 of 10) nodal nevus cases demonstrated 5-hydroxymethylcytosine nuclear staining in MART-1 positive cells. In addition, 5-hydroxymethylcytosine staining confirmed the favored diagnoses of metastatic melanoma in the two ‘equivocal’ cases. Thus, 5-hydroxymethylcytosine may be a useful adjunctive marker to distinguish between benign nodal nevi and metastatic melanoma during the evaluation of sentinel lymph node biopsies for metastatic melanoma.
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    Targeted next-generation sequencing reveals high frequency of mutations in epigenetic regulators across treatment-naïve patient melanomas
    (BioMed Central, 2015) Lee, Jonathan J.; Sholl, Lynette; Lindeman, Neal; Granter, Scott; Laga, Alvaro; Shivdasani, Priyanka; Chin, Gary; Luke, Jason J.; Ott, Patrick; Hodi, F. Stephen; Mihm, Martin; Lin, Jennifer; Werchniak, Andrew E.; Haynes, Harley; Bailey, Nancy; Liu, Robert; Murphy, George; Lian, Christine
    Background: 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. Results: 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. Conclusions: 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. Electronic supplementary material The online version of this article (doi:10.1186/s13148-015-0091-3) contains supplementary material, which is available to authorized users.