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Lynn Schoenfield, Paula Carver, Mary Beth Aronow, Arun Singh, Ray Tubbs, Yogen Saunthararajah; Immunohistochemical Evaluation Of the H3k9Trime repressive mark In Uveal Melanomas With Correlation To H3K4Me3, Monosomy 3 And Clinical Outcome. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5249.
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Aberrant histone modification patterns measured at the level of single nuclei have been shown to be predictive of cancer recurrence and poorer survival in multiple cancers. We recently reported that lower global levels of H3K4me1 (a chromatin activation mark) measured by immunohistochemistry are associated with death with metastases in a small group of uveal melanomas. This study was aimed at looking at a chromatin repressive mark, H3K9me3, to further our understanding of how these epigenetic events relate to uveal melanoma pathogenesis.
37 cases of enucleated globes for UVM from 2004-11 were examined by immunohistochemistry for H3K9me3[H3(trimethyl)K9 ab8898 by Abcam] using a red chromagen. Cases were interpreted as positive if in a significant area, at least 10% of the nuclei stained with the red chromagen. Results were compared to H3K4me1 data, patient outcome, and chromosome 3 or 3p26 status by FISH and SNP.
The study included 21 males and 16 females. Follow-up ranged from 19 mo.-6 yrs. 11 patients were DOD, 3 alive with metastasis, 3 dead without metastases, and 20 alive without metastases. H3K9me3 was positive in 28 cases and of these 11 were DOD (39%), 3 alive with metastasis (11%), 2 dead without metastases (7%), and 12 alive without metastases (43%). There was monosomy 3 by at least one of the above methods in 22 of the 28 H3K9me3 positive cases (79%). 9 cases were negative for H3K9me3 and of these 8 were alive without metastasis (89%) and 1 was dead without metastases (11%). Monosomy 3 was found in 1 of the 9 H3K9me3 negative cases (11%) and disomy in the other 8 cases (89%). Comparing the results of H3K9me3 to H3K4me1, 19/37 (51%) cases were positive for H3K9me3 and negative for H3K4me1; of these 19 cases, 16 (84%) had monosomy 3, 10 (53%) of whom were DOD and 1 (5%) alive with metastases. 5/37 cases (14%) were negative for H3K9me3 and positive for H3K4me1; all 5 cases (100%) were disomy for chromosome 3 and alive without metastasis. 24/37 (65%) showed the expected pattern of mutual exclusion of the repression and activation marks. 9 cases (24%) were positive for both marks and 4 cases (11%) were negative for both.
Patterns of histone modifications detected at the level of single nuclei in uveal melanoma suggest that an accumulation of chromatin repression marks and loss of activation marks correlates with more aggressive disease. In the next step, we are attempting to characterize the pathways that produce this epigenetic phenotype and the specific genes that are repressed to contribute to disease progression.
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