Identification of DNA methylation biomarkers for prediction of response to neoadjuvant chemotherapy in triple-negative breast cancer [EPIC Array]
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ABSTRACT: Response to neoadjuvant chemotherapy (NAC) in triple-negative breast cancer is linked to long-term patient survival. However, response to NAC is highly variable and cannot reliably be predicted by clinical or other current methods. This study aims to address this problem by utilising the stable, yet dynamic marker known as DNA methylation. By defining the methylation differences at diagnosis in patients that achieve a pathological complete remission against those that do not respond, we can identify a marker that can potentially predict chemotherapy response and help further personalise the chemotherapy decision making in the clinic.
Project description:Neoadjuvant chemotherapy (NAC) has been of recent interest as an alternative to upfront surgery followed by adjuvant chemotherapy in patients with pancreatic ductal adenocarcinoma (PDAC). However, a subset of patients does not respond to NAC and may have been better managed by upfront surgery. Hence, there is an unmet need for accurate biomarkers for predicting NAC response in PDAC. This project aimed to identify upregulated proteins in tumor tissue from poor- and good-NAC responders.
Project description:Methylome-wide DNA methylation profiling of spatially separated breast tumor samples pre- and post-neoadjuvant chemotherapy (NAC) to characterize methylation heterogeneity alteration by NAC. The Illumina Infinium HumanMethylation450K Beadchip v1.2 was used to obtain DNA methylation profiles across approximately 485,000 CpGs in the 47 samples derived from 8 breast cancer patients.
Project description:<p>Neoadjuvant chemotherapy (NAC) for breast cancer is widely employed. We performed genome-wide association studies (GWAS) to determine if germline genetic variability was associated with benefits, in terms of pathological complete response (pCR), disease-free survival (DFS), and overall survival (OS), in patients entered on the NSABP B-40 NAC (National Surgical Adjuvant Breast and Bowel Project, B-40, Neoadjuvant Chemotherapy) trial where some patients were randomized to receive bevacizumab, in addition to chemotherapy. </p>
Project description:Triple-negative breast cancer (TNBC) is the most aggressive subtype, typically requiring neoadjuvant chemotherapy (NAC) as an obligatory component of the treatment regimen. Achieving a pathological complete response to NAC is associated with improved long-term outcomes for patients with TNBC. The functional status of the immune system plays a critical role in NAC efficacy. Herein, we presented the first investigation of systemic and local immune landscape during the initial course of NAC treatment and identify factors that contribute to chemotherapy resistance of TNBC. Using single-cell RNA sequencing, we demonstrated that the transcriptional profile remained stable in a patient who responded to NAC, while a non-responder exhibited significant dysregulation in the expression of genes involved in stress response, apoptosis, immune cell proliferation, and differentiation within lymphocyte and monocyte populations. During the first course of NAC, circulating cytotoxic CD8 T cells in the non-responder patient overexpressed granzymes B and H, granulysin, and perforin. In contrast, expression of these factors decreased in CD8 T cells within the tumor. Finally, we identified for a first time a signature of myeloid-derived suppressor cells (MDSC) within the S100АhighMHClow monocyte population and calculated an MDSC score for both the responder and the non-responder TNBC patients. An elevated MDSC score in the non-responder was validated using data from an independent cohort of patients with poor NAC response. Our data underscores the importance of immune system functionality in determining chemotherapy efficacy in TNBC. Keywords: triple-negative breast cancer, immune cell, cytotoxic CD8 T cell, chemotherapy, myeloid-derived suppressor cell, single-cell RNA sequencing.
Project description:In this study, we have analyzed the transcriptional patterns of breast cancer cell lines and tumors of NAC resistant patients evaluated by GGI, and screened potential genes associated with chemoresistance. Furthermore, we have constructed a neoadjuvant chemotherapy response risk model and examined the evaluation accuracy of the risk score for NAC response. We conducted molecular bioinformatics analysis of the genes that constitute the chemotherapy resistance risk score, and explored potential drugs to reverse breast cancer chemotherapy resistance. Finally, we have examined the the risk score for predicting prognosis in breast cancer. In all, we have reported a novel signature to evaluate neoadjuvant chemotherapy response and predicts prognosis in breast cancer, and screened out potential drugs to reverse chemotherapy resistance in breast cancer.
Project description:In this study, we comprehensively investigated the impact of neoadjuvant chemotherapy (NAC) on immune cells in the tumor microenvironment (TME) of esophageal squamous cell carcinoma (ESCC) using single cell RNA sequence. CD8+ T cells, CD4+ T cells, dendritic cells, and macrophages in TME of ESCC all showed higher levels of anti-tumor immune response in the NAC(+) group than in the NAC(-) group. Furthermore, the immune cells in the TME of the NAC(+) group interacted with each other to enhance the anti-tumor immune response. Our results suggest that NAC potentially enhance the anti-tumor immune response of immune cells in the TME.
Project description:In this study, a total of 300 patients with MIBC receiving chemotherapy were included; 62 received NAC before cystectomy and 245 received first-line chemotherapy upon detection of locally-advanced (T4b) or metastatic disease. Treatment response, defined as pathological downstaging (< pTa,CIS,N0) after NAC or complete or partial response after first-line treatment (RECIST criteria). DNA methylation analysis was performed using DNA from 72 patients. We used 500 ng genomic DNA for bisulfite conversion followed by whole-genome amplification prior to hybridization to EPIC BeadChip (Illumina, San Diego, CA) overnight as described by the manufacturer and then scanned with the Illumina iSCAN system. Data provided here consist of 144 idat files.
Project description:Neoadjuvant chemotherapy (NAC) followed by surgery is one of the standard therapeutic approaches for patients with locally advanced esophageal carcinoma in Japan. Recently, JCOG1109 study revealed that NAC with docetaxel, cisplatin and 5-fluorouracil (5-FU) (DCF-NAC) is superior to NAC with cisplatin and 5-FU, and has become the standard preoperative chemotherapy. By using microarray, we have previously investigated expression profiles of endoscopic biopsies of patients with esophageal squamous cell carcinoma (ESCC) before DCF-NAC (preNAC) and identified 17 molecules as predictive biomarkers for pathologically complete response to DCF-NAC. Here, we re-grouped our previous dataset based on the histopathological response grade with an addition of several microarray profiles (altogether 5 non-tumors, 12 highly resistant cancers and 27 sensitive cancers) and re-analyzed by bioinformatic web tools, including DAVID, GSEA, UALCAN and CIBERSORTx. We identified 204 genes as differentially expressed genes (DEGs) between highly resistant and sensitive groups. A number of DEGs were related to immune response and expressed higher in sensitive group. By UALCAN, 28 of the top 50 DEGs showed that their high expression were associated with favorable prognosis (p<0.25). Among them, 18 DEGs reached significance (p<0.05), suggesting that patients with high expression of these genes might have benefited from chemotherapy and thus had better outcome. We further showed distribution of the cells expressing CXCL9 mRNA, one of the prognosis related DEGs, in preNAC biopsy tissues of DCF-sensitive case. In conclusion, our data may provide useful information to establish predictive and effective methods for DCF-NAC in ESCC.
Project description:Identification of DNA methylation biomarkers for prediction of response to neoadjuvant chemotherapy in triple-negative breast cancer [EPIC Array]
Project description:In a cohort study of 7 women with primary invasive breast cancer, we obtained a tumor specimen before (biopsy) and after (tumorectomy) 4 cycles of NAC with epirubicine and cyclophosphamide, followed by 4 cycles of taxanes. Total RNA was extracted from tumor specimens and the whole transcriptome was quantified with Affymetrix HuGene1.1ST. Molecular functions changing during chemotherapy were searched. Whole genome expression of triple negative breast cancer tissues were measured before and after four cycles neoadjuvant chemotherapy