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Your search keyword '"Markus Ringnér"' showing total 2 results
Start Over Author "Markus Ringnér" Journal molecular oncology
2 results on '"Markus Ringnér"'

1. Analysis of DNA methylation patterns in the tumor immune microenvironment of metastatic melanoma

Author

Shamik Mitra, Martin Lauss, Rita Cabrita, Jiyeon Choi, Tongwu Zhang, Karolin Isaksson, Håkan Olsson, Christian Ingvar, Ana Carneiro, Johan Staaf, Markus Ringnér, Kari Nielsen, Kevin M. Brown, and Göran Jönsson

Subjects
DNA methylation, immune cells, melanoma, pan‐cancer, tumor microenvironment, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

The presence of immune cells in the tumor microenvironment has been associated with response to immunotherapies across several cancer types, including melanoma. Despite its therapeutic relevance, characterization of the melanoma immune microenvironments remains insufficiently explored. To distinguish the immune microenvironment in a cohort of 180 metastatic melanoma clinical specimens, we developed a method using promoter CpG methylation of immune cell type‐specific genes extracted from genome‐wide methylation arrays. Unsupervised clustering identified three immune methylation clusters with varying levels of immune CpG methylation that are related to patient survival. Matching protein and gene expression data further corroborated the identified epigenetic characterization. Exploration of the possible immune exclusion mechanisms at play revealed likely dependency on MITF protein level and PTEN loss‐of‐function events for melanomas unresponsive to immunotherapies (immune‐low). To understand whether melanoma tumors resemble other solid tumors in terms of immune methylation characteristics, we explored 15 different solid tumor cohorts from TCGA. Low‐dimensional projection based on immune cell type‐specific methylation revealed grouping of the solid tumors in line with melanoma immune methylation clusters rather than tumor types. Association of survival outcome with immune cell type‐specific methylation differed across tumor and cell types. However, in melanomas immune cell type‐specific methylation was associated with inferior patient survival. Exploration of the immune methylation patterns in a pan‐cancer context suggested that specific immune microenvironments might occur across the cancer spectrum. Together, our findings underscore the existence of diverse immune microenvironments, which may be informative for future immunotherapeutic applications.

Published
2020
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2. Global H3K27 trimethylation and EZH2 abundance in breast tumor subtypes

Author

Sofia K. Gruvberger-Saal, Stephen P. Ethier, Åke Borg, Cecilia Hegardt, Pär-Ola Bendahl, Dorthe Grabau, Mårten Fernö, Steina Aradottir, Karolina Holm, Kristina Lövgren, Per-Uno Malmström, Markus Ringnér, Jillian Howlin, Lisa Rydén, Olle Stål, and Lao H. Saal

Subjects
Cancer Research, Estrogen receptor, Breast Neoplasms, macromolecular substances, Biology, Methylation, Histones, Breast cancer, Cell Line, Tumor, Genetics, medicine, Humans, Gene silencing, Enhancer of Zeste Homolog 2 Protein, Breast, Epigenetics, skin and connective tissue diseases, Tissue microarray, EZH2, Polycomb Repressive Complex 2, Cancer, General Medicine, medicine.disease, Immunohistochemistry, Gene Expression Regulation, Neoplastic, Oncology, Papers, Mutation, Cancer research, biology.protein, Molecular Medicine, Female, PRC2
Abstract

Polycomb repressive complex 2 (PRC2) and its core member enhancer of zeste homolog 2 (EZH2) mediate the epigenetic gene silencing mark: trimethylation of lysine 27 on histone 3 (H3K27me3). H3K27me3 is characteristic of the chromatin at genes involved in developmental regulation in undifferentiated cells. Overexpression of EZH2 has been found in several cancer types such as breast, prostate, melanoma and bladder cancer. Moreover, overexpression is associated with highly proliferative and aggressive types of breast and prostate tumors. We have analyzed the abundance of EZH2 and H3K27me3 using immunohistochemistry in two large and well-characterized breast tumor data sets encompassing more than 400 tumors. The results have been analyzed in relation to the molecular subtypes of breast tumors (basal-like, luminal A, luminal B, HER2-enriched and normal-like), as well as in subtypes defined by clinical markers (triple negative, ER+/HER2-/Ki67low, ER+/HER2-/Ki67high and HER2+), and were validated in representative breast cancer cell lines by western blot. We found significantly different expression of both EZH2 and H3K27me3 across all subtypes with high abundance of EZH2 in basal-like, triple negative and HER2-enriched tumors, and high H3K27me3 in luminal A, HER2-enriched and normal-like tumors. Intriguingly, the two markers show an inverse correlation, particularly for the basal-like and triple negative tumors. Consequently, high expression of EZH2 was associated with poor distant disease-free survival whereas high expression of H3K27me3 was associated with better survival. Additionally, none of 182 breast tumors was found to carry a previously described EZH2 mutation affecting Tyr641. Our observation that increased expression of EZH2 does not necessarily correlate with increased abundance of H3K27me3 supports the idea that EZH2 can have effects beyond epigenetic silencing of target genes in breast cancer.

Published
2012
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