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

Abstract

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.

Effects of Semaglutide on Cardiac Protein Expression and Cardiac Function of Obese Mice

“…37 Hsd17b4 is involved in the catabolism of fatty acids and steroid hormones, and various studies have revealed Hsdl7b4 to be implicated in the development of prostate and breast cancer. 38 , 39 Hsd17b4 is linked to the peroxisome, which catalyzes many critical metabolic activities, primarily related to lipid metabolism. Obesity alters peroxisome function, resulting in aberrant lipid metabolism.…”

Cost-effectiveness of pertuzumab and trastuzumab as a first-line treatment of HER2-positive metastatic breast cancer in China

“…About 15-30% of breast cancer patients suffer from human epidermal growth factor receptor 2 (HER2)-positive breast cancer (6). Due to its poor prognosis, HER2 breast cancer has been described as the "most dangerous breast cancer."…”

“…Due to its poor prognosis, HER2 breast cancer has been described as the "most dangerous breast cancer." (6). HER2 breast cancer has a higher malignancy of tumor cells, faster disease progression (PD), and is more prone to metastasis and recurrence than other types of breast cancer (6).…”

“…(6). HER2 breast cancer has a higher malignancy of tumor cells, faster disease progression (PD), and is more prone to metastasis and recurrence than other types of breast cancer (6). With the advent of anti-HER2 breast cancer targeted drugs, trastuzumab has become the clinical gold standard for anti-HER2 breast cancer treatments.…”

Multi-Omic Approaches to Breast Cancer Metabolic Phenotyping: Applications in Diagnosis, Prognosis, and the Development of Novel Treatments

“…The majority of studies relied on the application of metabolomics-based approaches in BC tissue [141,143] and serum [140,142,144] samples, although groups have evaluated transcriptomic [33,45] and proteomic [146] profiles in tissue samples. Various studies have described how the combination of omics approaches could characterize specific targets and foster the development of novel therapeutic strategies for specific subgroups of BC patients [147][148][149]. In particular, multi-omics studies have focused on identifying and validating metabolic enzymes as promising therapeutic strategies for the treatment of different BC tumors (Table 4).…”