Premalignant Clonal Hematopoiesis (Clonal Hematopoiesis of Indeterminate Potential and Clonal Cytopenia of Undetermined Significance).

Premalignant clonal hematopoiesis is the presence of somatic alterations in the blood of otherwise healthy individuals. Although the condition is not considered as a cancer, it carries an increased risk of developing a hematologic malignancy, particularly in those with large neoplastic clones, multiple pathogenic mutations, and high-risk mutations. In addition to the increased risk of malignancy, clonal hematopoiesis carries a markedly increased risk of cardiovascular events and death.

Optimizing Insertion and Deletion Detection Using Next-Generation Sequencing in the Clinical Laboratory.

Detection of insertions and deletions (InDels) by short-read next-generation sequencing (NGS) technology can be challenging because of frequent misaligned reads. A systematic analysis of short InDels (1 to 30 bases) and fms-related receptor tyrosine kinase 3 (FLT3) internal tandem duplications (ITDs; 6 to 183 bases) from 46 clinical cases of solid or hematologic malignancy processed with a clinical NGS assay identified misaligned reads in every case, ranging from 3% to 100% of reads with the InDel showing mismapped bases. Mismaps also increased with InDel size.

CIBERSORT analysis of TCGA and METABRIC identifies subgroups with better outcomes in triple negative breast cancer.

Studies have shown that the presence of tumor infiltrating lymphocytes (TILs) in Triple Negative Breast Cancer (TNBC) is associated with better prognosis. However, the molecular mechanisms underlying these immune cell differences are not well delineated. In this study, analysis of hematoxylin and eosin images from The Cancer Genome Atlas (TCGA) breast cancer cohort failed to show a prognostic benefit of TILs in TNBC, whereas CIBERSORT analysis, which quantifies the proportion of each immune cell type, demonstrated improved overall survival in TCGA TNBC samples with increased CD8 T cells or CD8 plus CD4 memory activated T cells and in Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) TNBC samples with increased gamma delta T cells.

Rapidly progressive metastatic cholangiocarcinoma in a postpartum patient with cystic fibrosis: a case report.

Background: Cholangiocarcinoma is a rare gastrointestinal malignancy that arises within the intrahepatic, perihilar, and/or extrahepatic bile ducts. Individuals with cystic fibrosis are at increased risk for gastrointestinal malignancies. The most common gastrointestinal malignancy in cystic fibrosis is colon cancer, but other gastrointestinal malignancies also occur at greater rates than the general population.

Combined targeting of TGF-β, EGFR and HER2 suppresses lymphangiogenesis and metastasis in a pancreatic cancer model.

Pancreatic ductal adenocarcinomas (PDACs) are aggressive with frequent lymphatic spread. By analysis of data from The Cancer Genome Atlas, we determined that ~35% of PDACs have a pro-angiogenic gene signature. We now show that the same PDACs exhibit increased expression of lymphangiogenic genes and lymphatic endothelial cell (LEC) markers, and that LEC abundance in human PDACs correlates with endothelial cell microvessel density.

Overview of pre-clinical and clinical studies targeting angiogenesis in pancreatic ductal adenocarcinoma.

The importance of angiogenesis in pancreatic ductal adenocarcinoma (PDAC) and its therapeutic potential have been explored in both pre-clinical and clinical studies. Human PDACs overexpress a number of angiogenic factors and their cognate high-affinity receptors, and anti-angiogenic agents reduce tumor volume, metastasis, and microvessel density (MVD), and improve survival in subcutaneous and orthotopic pre-clinical models. Nonetheless, clinical trials using anti-angiogenic therapy have been overwhelmingly unsuccessful.

Angiogenic gene signature in human pancreatic cancer correlates with TGF-beta and inflammatory transcriptomes.

Pancreatic ductal adenocarcinomas (PDACs) are hypovascular, but overexpress pro-angiogenic factors and exhibit regions of microvasculature. Using RNA-seq data from The Cancer Genome Atlas (TCGA), we previously reported that ~12% of PDACs have an angiogenesis gene signature with increased expression of multiple pro-angiogenic genes. By analyzing the recently expanded TCGA dataset, we now report that this signature is present in ~35% of PDACs but that it is mostly distinct from an angiogenesis signature present in pancreatic neuroendocrine tumors (PNETs).

Organ-specific adaptive signaling pathway activation in metastatic breast cancer cells.

Breast cancer metastasizes to bone, visceral organs, and/or brain depending on the subtype, which may involve activation of a host organ-specific signaling network in metastatic cells. To test this possibility, we determined gene expression patterns in MDA-MB-231 cells and its mammary fat pad tumor (TMD-231), lung-metastasis (LMD-231), bone-metastasis (BMD-231), adrenal-metastasis (ADMD-231) and brain-metastasis (231-BR) variants. When gene expression between metastases was compared, 231-BR cells showed the highest gene expression difference followed by ADMD-231, LMD-231, and BMD-231 cells.

TCGA data and patient-derived orthotopic xenografts highlight pancreatic cancer-associated angiogenesis.

Pancreatic ductal adenocarcinomas (PDACs) overexpress pro-angiogenic factors but are not viewed as vascular. Using data from The Cancer Genome Atlas we demonstrate that a subset of PDACs exhibits a strong pro-angiogenic signature that includes 37 genes, such as HDAC9, that are overexpressed in PDAC arising in KRC mice, which express mutated Kras and lack RB. Moreover, patient-derived orthotopic xenografts can exhibit tumor angiogenesis, whereas conditioned media (CM) from KRC-derived pancreatic cancer cells (PCCs) enhance endothelial cell (EC) growth and migration, and activate canonical TGF-β signaling and STAT3.

Pancreatic cancer-associated retinoblastoma 1 dysfunction enables TGF-β to promote proliferation.

Pancreatic ductal adenocarcinoma (PDAC) is often associated with overexpression of TGF-β. Given its tumor suppressor functions, it is unclear whether TGF-β is a valid therapeutic target for PDAC. Here, we found that proliferating pancreatic cancer cells (PCCs) from human PDAC patients and multiple murine models of PDAC (mPDAC) often exhibit abundant levels of phosphorylated retinoblastoma 1 (RB) and Smad2.