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HER2-positive breast cancers that achieve pathological complete response (pCR) after HER2-directed therapy consistently have good survival. We previously identified  HSD17B4  methylation as a marker for pCR by methylation screening. Here, we aimed to identify a new marker by conducting a multi-omics analysis of materials prepared by laser capture microdissection, and adding 71 new samples. In the screening set (n = 36), mutations, methylation, and expression were analyzed by targeted sequencing, Infinium 450 K, and expression microarray, respectively, and 15 genes were identified as differentially expressed and eight genomic regions as differentially methylated between cancer samples with and without pCR. In a validation set (n = 47), one gene showed differential expression, and one region had differential methylation. Further, in the re-validation set (n = 55), all new samples, only  HSD17B4  methylation was significantly different. The  HSD17B4  methylation was at the transcriptional start site of its major variant, and was associated with its silencing.  HSD17B4  was highly expressed in the vast majority of human cancers, and its methylation was present only in breast cancers and one lymphoblastic leukemia cell line. A combination of estrogen receptor-negative status and  HSD17B4  methylation showed a positive predictive value of 80.0%. During HER2-directed neoadjuvant therapy,  HSD17B4  methylation was the most reliable marker to monitor response to the therapy. These results showed that  HSD17B4  methylation is a candidate predictive and response marker of HER2-positive breast cancer to HER2-directed therapy.

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Multi-omics analyses identify HSD17B4 methylation-silencing as a predictive and response marker of HER2-positive breast cancer to HER2-directed therapy