Dataset Information

Evaluating Clonal Hematopoiesis in Tumor-Infiltrating Leukocytes in Breast Cancer and Secondary Hematologic Malignancies.

ABSTRACT: Chemotherapy and radiation therapy are the foundations of adjuvant therapy for early-stage breast cancer. As a complication of cytotoxic regimens, breast cancer patients are at risk for therapy-related myeloid neoplasms (t-MNs). These t-MNs are commonly refractory to antileukemic therapies and result in poor patient outcomes. We previously demonstrated that somatic mutations in leukemia-related genes are present in the tumor-infiltrating leukocytes (TILeuks) of a subset of early breast cancers. Here, we performed genomic analysis of microdissected breast cancer tumor cells and TILeuks from seven breast cancer patients who subsequently developed leukemia. In four patients, mutations present in the leukemia were detected in breast cancer TILeuks. This finding suggests that TILeuks in the primary breast cancer may harbor the ancestor of the future leukemogenic clone. Additional research is warranted to ascertain whether infiltrating mutant TILeuks could constitute a biomarker for the development of t-MN and to determine the functional consequences of mutant TILeuks.

SUBMITTER: Comen EA

PROVIDER: S-EPMC7690564 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Evaluating Clonal Hematopoiesis in Tumor-Infiltrating Leukocytes in Breast Cancer and Secondary Hematologic Malignancies.

Comen Elizabeth A EA Bowman Robert L RL Selenica Pier P Kleppe Maria M Farnoud Noushin R NR Pareja Fresia F Weigelt Britta B Hill Corinne E CE Alon Abigail A Geyer Felipe C FC Akturk Guray G Reis-Filho Jorge S JS Norton Larry L Levine Ross L RL

Journal of the National Cancer Institute 20200101 1

Chemotherapy and radiation therapy are the foundations of adjuvant therapy for early-stage breast cancer. As a complication of cytotoxic regimens, breast cancer patients are at risk for therapy-related myeloid neoplasms (t-MNs). These t-MNs are commonly refractory to antileukemic therapies and result in poor patient outcomes. We previously demonstrated that somatic mutations in leukemia-related genes are present in the tumor-infiltrating leukocytes (TILeuks) of a subset of early breast cancers. ...[more]

PMID: 31504684

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Project description:BackgroundAssays of the abundance of immune cell populations in the tumor microenvironment promise to inform immune oncology research and the choice of immunotherapy for individual patients. We propose to measure the intratumoral abundance of various immune cell populations with gene expression. In contrast to IHC and flow cytometry, gene expression assays yield high information content from a clinically practical workflow. Previous studies of gene expression in purified immune cells have reported hundreds of genes showing enrichment in a single cell type, but the utility of these genes in tumor samples is unknown. We use co-expression patterns in large tumor gene expression datasets to evaluate previously reported candidate cell type marker genes lists, eliminate numerous false positives and identify a subset of high confidence marker genes.MethodsUsing a novel statistical tool, we use co-expression patterns in 9986 samples from The Cancer Genome Atlas (TCGA) to evaluate previously reported cell type marker genes. We compare immune cell scores derived from these genes to measurements from flow cytometry and immunohistochemistry. We characterize the reproducibility of our cell scores in replicate runs of RNA extracted from FFPE tumor tissue.ResultsWe identify a list of 60 marker genes whose expression levels measure 14 immune cell populations. Cell type scores calculated from these genes are concordant with flow cytometry and IHC readings, show high reproducibility in replicate RNA samples from FFPE tissue and enable detailed analyses of the anti-tumor immune response in TCGA. In an immunotherapy dataset, they separate responders and non-responders early on therapy and provide an intricate picture of the effects of checkpoint inhibition. Most genes previously reported to be enriched in a single cell type have co-expression patterns inconsistent with cell type specificity.ConclusionsDue to their concise gene set, computational simplicity and utility in tumor samples, these cell type gene signatures may be useful in future discovery research and clinical trials to understand how tumors and therapeutic intervention shape the immune response.

Dataset Information

Evaluating Clonal Hematopoiesis in Tumor-Infiltrating Leukocytes in Breast Cancer and Secondary Hematologic Malignancies.

Publications

Evaluating Clonal Hematopoiesis in Tumor-Infiltrating Leukocytes in Breast Cancer and Secondary Hematologic Malignancies.

Similar Datasets

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