Abstract 869: Breast tumor gene expression in the mTOR pathway and clinicopathological characteristics in Black women and White women

3588 Background: Tumor gene expression signatures have been used to predict drug response, and we have previously reported drug-induced signatures to be more informative than the untreated baseline signatures. However, repeated tumor sampling during treatment is not feasible for most patients. We studied peripheral mononuclear cell (PBMC) gene expression levels in association with tumor gene expression levels in an attempt to identify peripheral blood markers that may serve as more accessible surrogates to predict drug treatment and response. Methods: Chemonaive breast cancer patients were treated with an alternating sequential regimen of doxorubicin and docetaxel and randomized to start with either drug. RNA from primary tumor before and 3 weeks, and from PBMC before and 24 hours after the first cycle of each drug was hybridized on the Affymetrix HG-U133+2 array containing 54,675 probe sets. Results: Pre- and post-treatment tumors from 47 patients were studied, including 35 with paired PBMC samples. 230 pre- and 85 posttreatment PBMC probe sets showed strong correlation in expression level (Pearson correlation coefficient >0.9) with the corresponding pre- and posttreatment tumor probe set, and included genes involved in transcription regulation and binding. Of the 975 tumor probe sets whose changes distinguished doxorubicin from docetaxel treatment, 12 corresponding PBMC probe sets were identified (p < 0.001) whose changes at 24 hours distinguished the two treatments with 77% accuracy. Of the 1,081 and 1,526 tumor probe sets whose changes predicted treatment response to doxorubicin and docetaxel, 19 and 15 informative PBMC probe sets predicted response to each drug with 100% and 80% accuracy, and included TNF receptor associated protein 1 and trefoil factor 1 for doxorubicin-, and folliculin and dynein for docetaxel-response. When the PBMC probe sets were validated in an independent test set treated with docetaxel (n = 23), 87% was correctly classified as docetaxel-treated, while 89% of non-responders clustered together. Conclusions: Peripheral blood contains genomic markers whose expression levels closely reflect that of breast tumor markers, and may be promising as surrogates to predict drug treatment and sensitivity. No significant financial relationships to disclose.

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Dual Hypergraph Regularized PCA for Biclustering of Tumor Gene Expression Data

IEEE Transactions on Knowledge and Data Engineering ◽

10.1109/tkde.2018.2874881 ◽

2019 ◽

Vol 31 (12) ◽

pp. 2292-2303 ◽

Cited By ~ 1

Author(s):

Xuesong Wang ◽

Jian Liu ◽

Yuhu Cheng ◽

Aiping Liu ◽

Enhong Chen

Keyword(s):

Gene Expression ◽

Gene Expression Data ◽

Expression Data ◽

Tumor Gene Expression ◽

Tumor Gene

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Clinicopathological significance and prognostic value of Wilms' tumor gene expression in colorectal cancer

Cancer Biomarkers ◽

10.3233/cbm-150521 ◽

2015 ◽

Vol 15 (6) ◽

pp. 789-797 ◽

Cited By ~ 13

Author(s):

Yukinaga Miyata ◽

Kenichi Kumagai ◽

Tomoko Nagaoka ◽

Kazutaka Kitaura ◽

Goro Kaneda ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Prognostic Value ◽

Wilms Tumor ◽

Wilms Tumor Gene ◽

Clinicopathological Significance ◽

Tumor Gene Expression ◽

Tumor Gene

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Investigating survivin as a novel target in black women with breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.594 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 594-594

Author(s):

Andrea Walens ◽

Linnea T Olsson ◽

Sarah Van Alsten ◽

Lisa A. Carey ◽

Melissa A. Troester ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Black Women ◽

White Women ◽

Tumor Biology ◽

Survivin Expression ◽

Breast Tumors ◽

The Cancer Genome Atlas ◽

Molecular Features ◽

Apoptosis Protein

594 Background: Black women with breast cancer have higher mortality than White women. Differences in tumor biology contribute to racial disparities in breast cancer outcomes. BIRC5 gene encodes survivin, an inhibitor of apoptosis protein, and an independent marker of poor prognosis in breast cancer. Cancer patients have anti-survivin antibodies and circulating survivin-specific T cells, suggesting that survivin may be targetable. Several ongoing antibody-mediated, vaccine strategies that target survivin are being developed. Nevertheless, most survivin studies were conducted in cohorts of White women. To date, the prevalence and/or role of survivin expression in breast tumors from Black women has not been studied. Methods: Associations between BIRC5 expression, clinicopathological and molecular features were measured in the population-based Carolina Breast Cancer Study (CBCS) and The Cancer Genome Atlas (TCGA) breast cancer cohort. Gene expression was measured by Nanostring RNA counting and split into BIRC5 high (4th quartile) and low categories based on log2 gene expression values. Relative frequency differences (RFD) for the association between BIRC5 high and clinicopathologic features were estimated. RNA based p53 mutant status and homologous recombination deficiency (HRD) status were included in RFD analysis. Receiver operating characteristic (ROC) curves were used to illustrate the potential of BIRC5 expression to distinguish patients who achieved pathological complete response (pCR) after receiving neoadjuvant chemotherapy in CBCS (133 Black, 49 non-Black). Results: BIRC5 gene expression was significantly increased in tumors from 966 Black patients compared to 1,497 non-Black (p < 0.00001), adjusting for stage and subtype. BIRC5 high tumors were significantly more expressed in higher stage and basal-like breast cancer subtypes. BIRC5 high tumors were also significantly enriched for expression of genes involved in p53 loss and HRD. Furthermore, in an analysis of 182 CBCS patients, BIRC5 gene expression alone predicted pCR with similar overall AUC to ROR-PT multigene signatures (AUC 0.62 vs 0.64). Conclusions: Our study shows that survivin expression is particularly high in breast tumors from Black women. This was associated with more aggressive clinicopathological features in addition to p53 mutant and HRD status. Black women with breast cancer represent an area of unmet clinical need and could potentially benefit from anti-survivin targetable treatment strategies. Further studies are needed to help close this gap which constitutes the largest disparity among cancer-specific diseases.[Table: see text]

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Simultaneous enumeration of cancer and immune cell types from bulk tumor gene expression data

eLife ◽

10.7554/elife.26476 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 107

Author(s):

Julien Racle ◽

Kaat de Jonge ◽

Petra Baumgaertner ◽

Daniel E Speiser ◽

David Gfeller

Keyword(s):

Gene Expression ◽

Gene Expression Data ◽

Immune Cell ◽

Expression Profiles ◽

Cell Types ◽

Response To Therapy ◽

Expression Data ◽

Cell Type ◽

Tumor Gene Expression ◽

Tumor Gene

Immune cells infiltrating tumors can have important impact on tumor progression and response to therapy. We present an efficient algorithm to simultaneously estimate the fraction of cancer and immune cell types from bulk tumor gene expression data. Our method integrates novel gene expression profiles from each major non-malignant cell type found in tumors, renormalization based on cell-type-specific mRNA content, and the ability to consider uncharacterized and possibly highly variable cell types. Feasibility is demonstrated by validation with flow cytometry, immunohistochemistry and single-cell RNA-Seq analyses of human melanoma and colorectal tumor specimens. Altogether, our work not only improves accuracy but also broadens the scope of absolute cell fraction predictions from tumor gene expression data, and provides a unique novel experimental benchmark for immunogenomics analyses in cancer research (http://epic.gfellerlab.org).

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Biological Insights into Chemotherapy Resistance in Ovarian Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20092131 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2131 ◽

Cited By ~ 2

Author(s):

Michelle A. Glasgow ◽

Peter Argenta ◽

Juan E. Abrahante ◽

Mihir Shetty ◽

Shobhana Talukdar ◽

...

Keyword(s):

Gene Expression ◽

Ovarian Cancer ◽

Expression Profiles ◽

Rna Extraction ◽

Chemotherapy Resistance ◽

Gene Expression Profiles ◽

Gene Set Enrichment Analysis ◽

Before And After ◽

Tumor Gene Expression ◽

Tumor Gene

The majority of patients with high-grade serous ovarian cancer (HGSOC) initially respond to chemotherapy; however, most will develop chemotherapy resistance. Gene signatures may change with the development of chemotherapy resistance in this population, which is important as it may lead to tailored therapies. The objective of this study was to compare tumor gene expression profiles in patients before and after treatment with neoadjuvant chemotherapy (NACT). Tumor samples were collected from six patients diagnosed with HGSOC before and after administration of NACT. RNA extraction and whole transcriptome sequencing was performed. Differential gene expression, hierarchical clustering, gene set enrichment analysis, and pathway analysis were examined in all of the samples. Tumor samples clustered based on exposure to chemotherapy as opposed to patient source. Pre-NACT samples were enriched for multiple pathways involving cell cycle growth. Post-NACT samples were enriched for drug transport and peroxisome pathways. Molecular subtypes based on the pre-NACT sample (differentiated, mesenchymal, proliferative and immunoreactive) changed in four patients after administration of NACT. Multiple changes in tumor gene expression profiles after exposure to NACT were identified from this pilot study and warrant further attention as they may indicate early changes in the development of chemotherapy resistance.

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