Epigenome analysis of pre- and post-neoadjuvant chemotherapy breast tumor samples
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ABSTRACT:
PROVIDER: PRJNA416463 | ENA |
REPOSITORIES: ENA
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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.
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Project description:When locally advanced breast cancer is treated with neoadjuvant chemotherapy, the recurrence risk is significantly higher if no complete pathologic response is achieved. Identification of the underlying resistance mechanisms is essential to select treatments with maximal efficacy and minimal toxicity. Here we employed gene expression profiles derived from 317 HER2-negative treatment-naïve breast cancer biopsies of patients who underwent neoadjuvant chemotherapy, deep whole exome and RNA-sequencing profiles of 22 matched pre- and post-treatment tumors, and treatment outcome data to identifiy biomarkers of response and resistance mechanims. Molecular profiling of treatment-naïve breast cancer samples revealed that expression levels of proliferation, immune response and extracellular matrix (ECM) organization combined predict response to chemotherapy. Triple negative patients with high proliferation, high immune response and low ECM expression had a significantly better treatment response and survival benefit (HR 0.29, 95% CI 0.10-0.85; p=0.02), while in ER+ patients the opposite was seen (HR 4.73, 95% CI 1.51-14.8; 0=0.008). The characterization of paired pre-and post-treatment samples revealed that aberrations of known cancer genes were either only present in the pre-treatmane sample (CDKN1B) or in the post-treatment sample(TP53, APC, CTNNB1). Proliferation-associated genes were frequently down-regulated in post-treatment ER+ tumors, but not in triple negative tumors. Genes involved in ECM were upregulated in the majority of post-chemotherapy samples. Genomic and transcriptomic differences between pre- and post-chemotherapy samples are common and may reveal potential mechanisms of therapy resistance. Our results show a wide range of distinct, but related mechanisms, with a prominent role for proliferation- and ECM-related genes.
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Project description:The high rate of recurrence and chemoresistance necessitates in ovarian cancer warrants further research into tumor markers characterizing the resistant population. The proportion of drug-resistant tissue cells in residual lesions after neoadjuvant chemotherapy increases, and drug-resistant markers are enriched. However, there is a lack of comprehensive understanding of tumor marker predoninance pre- and post- neoadjuvant chemotherapy. Here we performed quantitative proteomic analysis of TMT in three patients with matched pretreatment biopsies and post-NACT ovarian cancer tissues. This study highlights a dominant molecular subpopulation that persists in the ovary after neoadjuvant chemotherapy exposure in order to elucidate how it is involved in mediating chemotherapy response, which will lay the foundation for the development.
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Project description:PURPOSE: To develop a predictive test for response and survival following neoadjuvant taxane-anthracycline chemotherapy for HER2-negative invasive breast cancer. METHODS: We developed a microarray-based gene expression test from pre-treatment tumor biopsies (310 patients) to predict favorable outcome based on estrogen receptor (ER) status,pathologic response to chemotherapy, 3-year disease outcomes, and sensitivity to endocrine therapy. Tumors were classified as treatment-sensitive if predicted to have pathologic response (and not resistance) to chemotherapy, or sensitive to endocrine therapy. We tested predictive accuracy, with 95% confidence interval (CI), for pathologic response (PPV, positive predictive value), distant relapse-free survival (DRFS), and absolute risk reduction at median follow-up in 198 other patients. Independence from clinical-pathologic factors was assessed in a multivariate Cox regression analysis based on the likelihood ratio test. Other evaluable, published response predictors (genomic grade index (GGI), intrinsic subtype (PAM50), pCR predictor (DLDA30)) were compared. Neoadjuvant validation cohort of 198 HER2-negative breast cancer cases treated with taxane-anthracycline chemotherapy pre-operatively and endocrine therapy if ER-positive. Response was assessed at the end of neoadjuvant treatment and distant-relapse-free survival was followed for at least 3 years post-surgery.
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Project description:PURPOSE: To develop a predictive test for response and survival following neoadjuvant taxane-anthracycline chemotherapy for HER2-negative invasive breast cancer. METHODS: We developed a microarray-based gene expression test from pre-treatment tumor biopsies (310 patients) to predict favorable outcome based on estrogen receptor (ER) status,pathologic response to chemotherapy, 3-year disease outcomes, and sensitivity to endocrine therapy. Tumors were classified as treatment-sensitive if predicted to have pathologic response (and not resistance) to chemotherapy, or sensitive to endocrine therapy. We tested predictive accuracy, with 95% confidence interval (CI), for pathologic response (PPV, positive predictive value), distant relapse-free survival (DRFS), and absolute risk reduction at median follow-up in 198 other patients. Independence from clinical-pathologic factors was assessed in a multivariate Cox regression analysis based on the likelihood ratio test. Other evaluable, published response predictors (genomic grade index (GGI), intrinsic subtype (PAM50), pCR predictor (DLDA30)) were compared. Neoadjuvant study of 310 HER2-negative breast cancer cases treated with taxane-anthracycline chemotherapy pre-operatively and endocrine therapy if ER-positive. Response was assessed at the end of neoadjuvant treatment and distant-relapse-free survival was followed for at least 3 years post-surgery.
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Project description:In metastatic cancer, the degree of heterogeneity of the tumor-immune microenvironment and its molecular underpinnings remain largely unstudied. To characterize the tumor-immune interface at baseline and during neoadjuvant chemotherapy in high-grade serous ovarian cancer (HGSOC), we performed immunogenomics analysis of treatment-naive and paired pre/post-chemotherapy treated samples. In treatment-naive HGSOC, we find that immune cell-excluded and inflammatory microenvironments co-exist within the same individuals and within the same tumor sites, indicating ubiquitous variability in immune cell infiltration. Analysis of tumor microenvironment cell composition, DNA copy number, mutations and gene expression showed that immune cell exclusion was associated with amplification of Myc target genes and increased expression of canonical Wnt signaling in treatment-naive HGSOC. Following neoadjuvant chemotherapy, increased natural killer cell infiltration and oligoclonal expansion of T cells were detected. We demonstrate that the tumor-immune microenvironment of advanced HGSOC is intrinsically heterogeneous and that chemotherapy induces local immune activation, suggesting that chemotherapy can potentiate the immunogenicity of immune-excluded HGSOC tumors. The goal of this particular experiment was quantify RNA expression using microarray technology, and then evaluate differences in the trasncirptomic landscape of treatment naïve metastatic high grade serous ovarian cancer.
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