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Jurmeister, Philipp; Weber, Karsten; Villegas, Sonia; Karn, Thomas; Untch, Michael; Thieme, Anne; Mueller, Volkmar; Taube, Eliane; Fasching, Peter; Schmitt, Wolfgang D.; Marme, Frederik; Stickeler, Elmar; Sinn, Bruno V.; Jank, Paul; Schem, Christian; Klauschen, Frederick; Mackelenbergh, Marion van; Denkert, Carsten; Loibl, Sibylle and Capper, David (2021): DNA methylation profiling identifies two distinct subgroups in breast cancers with low hormone receptor expression, mainly associated with HER2 amplification status. In: Clinical Epigenetics, Vol. 13, No. 1, 184

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Background Current clinical guidelines suggest that breast cancers with low hormone receptor expression (LowHR) in 1-10% of tumor cells should be regarded as hormone receptor positive. However, clinical data show that these patients have worse outcome compared to patients with hormone receptor expression above 10%. We performed DNA methylation profiling on 23 LowHR breast cancer specimens, including 13 samples with HER2 amplification and compared our results with a reference breast cancer cohort from The Cancer Genome Atlas to clarify the status for this infrequent but important patient subgroup. Results In unsupervised clustering and dimensionality reduction, breast cancers with low hormone receptor expression that lacked HER2 amplification usually clustered with triple negative breast cancer (TNBC) reference samples (8/10;LowHR TNBC-like). In contrast, most specimens with low hormone receptor expression and HER2 amplification grouped with hormone receptor positive cancers (11/13;LowHR HRpos-like). We observed highly similar DNA methylation patterns of LowHR TNBC-like samples and true TNBCs. Furthermore, the Ki67 proliferation index of LowHR TNBC-like samples and clinical outcome parameters were more similar to TNBCs and differed from LowHR HRpos-like cases. Conclusions We here demonstrate that LowHR breast cancer comprises two epigenetically distinct groups. Our data strongly suggest that LowHR TNBC-like samples are molecularly, histologically and clinically closely related to TNBC, while LowHR HRpos-like specimens are closely related to hormone receptor positive tumors.

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