Tumor suppressor DEAR1 regulates mammary epithelial cell fate and predicts early onset and metastasis in triple negative breast cancer.

Triple negative breast cancer (TNBC) is a disease of poor prognosis, with the majority classified as the basal-like subtype associated with epithelial-mesenchymal transition and metastasis. Because basal breast cancers originate from proliferative luminal progenitor-like cells upon dysregulation of proper luminal differentiation, genes regulating luminal-basal transition are critical to elucidate novel therapeutic targets to improve TNBC outcomes. Herein we demonstrate that the tumor suppressor DEAR1/TRIM62 is a critical regulator of luminal cell fate.

Hyperpolarized Magnetic Resonance and Artificial Intelligence: Frontiers of Imaging in Pancreatic Cancer.

Background: There is an unmet need for noninvasive imaging markers that can help identify the aggressive subtype(s) of pancreatic ductal adenocarcinoma (PDAC) at diagnosis and at an earlier time point, and evaluate the efficacy of therapy prior to tumor reduction. In the past few years, there have been two major developments with potential for a significant impact in establishing imaging biomarkers for PDAC and pancreatic cancer premalignancy: (1) hyperpolarized metabolic (HP)-magnetic resonance (MR), which increases the sensitivity of conventional MR by over 10,000-fold, enabling real-time metabolic measurements; and (2) applications of artificial intelligence (AI).

Objective: Our objective of this review was to discuss these two exciting but independent developments (HP-MR and AI) in the realm of PDAC imaging and detection from the available literature to date.

Plasma miRNA Biomarkers in Limited Volume Samples for Detection of Early-stage Pancreatic Cancer.

Early detection of pancreatic ductal adenocarcinoma (PDAC) is key to improving patient outcomes; however, PDAC is usually diagnosed late. Therefore, blood-based minimally invasive biomarker assays for limited volume clinical samples are urgently needed. A novel miRNA profiling platform (Abcam Fireplex-Oncology Panel) was used to investigate the feasibility of developing early detection miRNA biomarkers with 20 μL plasma from a training set (58 stage II PDAC cases and 30 controls) and two validation sets (34 stage II PDAC cases and 25 controls; 44 stage II PDAC cases and 18 controls).

Identification of genetic variants predictive of early onset pancreatic cancer through a population science analysis of functional genomic datasets.

Biomarkers are critically needed for the early detection of pancreatic cancer (PC) are urgently needed. Our purpose was to identify a panel of genetic variants that, combined, can predict increased risk for early-onset PC and thereby identify individuals who should begin screening at an early age. Previously, we identified genes using a functional genomic approach that were aberrantly expressed in early pathways to PC tumorigenesis.

Definitive Characterization of CA 19-9 in Resectable Pancreatic Cancer Using a Reference Set of Serum and Plasma Specimens.

The validation of candidate biomarkers often is hampered by the lack of a reliable means of assessing and comparing performance. We present here a reference set of serum and plasma samples to facilitate the validation of biomarkers for resectable pancreatic cancer. The reference set includes a large cohort of stage I-II pancreatic cancer patients, recruited from 5 different institutions, and relevant control groups.

Next generation sequencing of pancreatic cyst fluid microRNAs from low grade-benign and high grade-invasive lesions.

Intraductal papillary mucinous neoplasm (IPMN) is a precursor cystic lesion to pancreatic cancer. With the goal of classifying IPMN cases by risk of progression to pancreatic cancer, we undertook an exploratory next generation sequencing (NGS) based profiling study of miRNAs (miRNome) in the cyst fluids from low grade-benign and high grade-invasive pancreatic cystic lesions. Thirteen miRNAs (miR-138, miR-195, miR-204, miR-216a, miR-217, miR-218, miR-802, miR-155, miR-214, miR-26a, miR-30b, miR-31, and miR-125) were enriched and two miRNAs (miR-451a and miR-4284) were depleted in the cyst fluids derived from invasive carcinomas.

DEAR1, a novel tumor suppressor that regulates cell polarity and epithelial plasticity.

Elucidation of the regulatory controls on epithelial plasticity is pivotal not only to better understand the nature of metastasis but also for the design of targeted therapies to prevent the earliest steps in migration and invasion from the primary tumor. This review will highlight the role of the novel TRIM protein DEAR1 (annotated as TRIM62) in the regulation of apical-basal polarity and acinar morphogenesis as well as its function as a chromosome 1p35 tumor suppressor and negative regulator of TGFβ-driven epithelial-mesenchymal transition (EMT). DEAR1 binds to and promotes the ubiquitination of SMAD3, the major effector of TGFβ-mediated EMT, as well as downregulates SMAD3 targets SNAIL1/2, master transcriptional regulators of EMT.

Circulating microRNAs in Pancreatic Juice as Candidate Biomarkers of Pancreatic Cancer.

Development of sensitive and specific biomarkers, preferably those circulating in body fluids is critical for early diagnosis of cancer. This study performed profiling of microRNAs (miRNAs) in exocrine pancreatic secretions (pancreatic juice) by microarray analysis utilizing pancreatic juice from 6 pancreatic ductal adenocarcinoma (PDAC) patients and two pooled samples from 6 non-pancreatic, non-healthy (NPNH) as controls. Differentially circulating miRNAs were subsequently validated in 88 pancreatic juice samples from 50 PDAC, 19 chronic pancreatitis (CP) patients and 19 NPNH controls.

Loss of the novel tumour suppressor and polarity gene Trim62 (Dear1) synergizes with oncogenic Ras in invasive lung cancer.

Deregulation of cell polarity proteins has been linked to the processes of invasion and metastasis. TRIM62 is a regulator of cell polarity and a tumour suppressor in breast cancer. Here, we demonstrate that human non-small cell lung cancer lesions show a step-wise loss of TRIM62 levels during disease progression, which was associated with poor clinical outcomes.

DEAR1 is a chromosome 1p35 tumor suppressor and master regulator of TGF-β-driven epithelial-mesenchymal transition.

Unlabelled: Deletion of chromosome 1p35 is a common event in epithelial malignancies. We report that DEAR1 (annotated as TRIM62) is a chromosome 1p35 tumor suppressor that undergoes mutation, copy number variation, and loss of expression in human tumors. Targeted disruption in the mouse recapitulates this human tumor spectrum, with both Dear1(-/-) and Dear1(+/-) mice developing primarily epithelial adenocarcinomas and lymphoma with evidence of metastasis in a subset of mice.

Putative tumor suppressor gene SEL1L was downregulated by aberrantly upregulated hsa-mir-155 in human pancreatic ductal adenocarcinoma.

Sel-1-like (SEL1L) is a putative tumor suppressor gene that is significantly downregulated in human pancreatic ductal adenocarcinoma (PDA). The mechanism of the downregulation is unclear. Here, we investigated whether aberrantly upregulated microRNAs (miRNAs) repressed the expression of SEL1L.

VGLL3 expression is associated with a tumor suppressor phenotype in epithelial ovarian cancer.

Previous studies have implicated vestigial like 3 (VGLL3), a chromosome 3p12.3 gene that encodes a putative transcription co-factor, as a candidate tumor suppressor gene (TSG) in high-grade serous ovarian carcinomas (HGSC), the most common type of epithelial ovarian cancer. A complementation analysis based on microcell-mediated chromosome transfer (MMCT) using a centric fragment of chromosome 3 (der3p12-q12.

Susceptibility locus for lung cancer at 15q25.1 is not associated with risk of pancreatic cancer.

Objectives: Four genome-wide association (GWA) studies have found that variation in a region of strong linkage disequilibrium on the long arm of chromosome 15 (15q24-25.1) containing nicotinic acetylcholine receptor genes contributes to lung cancer risk. Because cigarette smoking is a major risk factor for developing both lung cancer and pancreatic cancer, we hypothesized that variation in this region may also modify individual susceptibility to pancreatic cancer.

A single-nucleotide polymorphism in tumor suppressor gene SEL1L as a predictive and prognostic marker for pancreatic ductal adenocarcinoma in Caucasians.

SEL1L is a putative tumor suppressor gene that is frequently down-regulated in pancreatic ductal adenocarcinoma (PDA). A single-nucleotide polymorphism (SNP) rs12435998 in intron3 of SEL1L has previously been reported to be associated with susceptibility to Alzheimer's disease. We hypothesized that this SNP may influence clinical outcomes of patients with PDA.

A migration signature and plasma biomarker panel for pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma is a disease of extremely poor prognosis for which there are no reliable markers of asymptomatic disease. To identify pancreatic cancer biomarkers, we focused on a genomic interval proximal to the most common fragile site in the human genome, chromosome 3p12, which undergoes smoking-related breakage, loss of heterozygosity, and homozygous deletion as an early event in many epithelial tumors, including pancreatic cancers. Using a functional genomic approach, we identified a seven-gene panel (TNC, TFPI, TGFBI, SEL-1L, L1CAM, WWTR1, and CDC42BPA) that was differentially expressed across three different expression platforms, including pancreatic tumor/normal samples.

Genetic variations of the PI3K-AKT-mTOR pathway and clinical outcome in muscle invasive and metastatic bladder cancer patients.

The phosphoinositide-3 kinase (PI3K)-AKT- mammalian target of rapamycin (mTOR) pathway is an important cellular pathway controlling cell growth, tumorigenesis, cell invasion and drug response. We hypothesized that genetic variations in the PI3K-AKT-mTOR pathway may affect the survival in muscle invasive and metastatic bladder cancer (MiM-BC) patients. We conducted a follow-up study of 319 MiM-BC patients to systematically evaluate 289 single-nucleotide polymorphisms (SNPs) of 20 genes in the PI3K-AKT-mTOR pathway as predicators of survival.

Genetic variants of p21 and p27 and pancreatic cancer risk in non-Hispanic Whites: a case-control study.

Objectives: p21 (WAF1/Cip1/CDKN1A) and p27 (Kip1/CDKN1B) are members of the Cip/Kip family of cyclin-dependent kinase inhibitors, which can induce cell cycle arrest and serve as tumor suppressors. We hypothesized that genetic variants in p21 and p27 may modify individual susceptibility to pancreatic cancer.

Methods: To test this hypothesis, we evaluated the associations of the Ser31Arg polymorphism in p21 and the Gly109Val polymorphism in p27, and their combinations, with pancreatic cancer risk in a case-control study of 509 pathologically confirmed pancreatic adenocarcinoma patients and 462 age- and sex-matched cancer-free controls in non-Hispanic whites.

MicroRNAs in plasma of pancreatic ductal adenocarcinoma patients as novel blood-based biomarkers of disease.

Development of minimally invasive biomarker assays for early detection and effective clinical management of pancreatic cancer is urgently needed to reduce high morbidity and mortality associated with this malignancy. We hypothesized that if aberrantly expressing microRNAs (miRNA) in pancreatic adenocarcinoma tissues are detected in blood plasma, then plasma profiling of these miRNAs might serve as a minimally invasive early detection biomarker assay for this malignancy. By using a modified protocol to isolate and quantify plasma miRNAs from heparin-treated blood, we show that miRNA profiling in plasma can differentiate pancreatic adenocarcinoma patients from healthy controls.

DEAR1 is a dominant regulator of acinar morphogenesis and an independent predictor of local recurrence-free survival in early-onset breast cancer.

Background: Breast cancer in young women tends to have a natural history of aggressive disease for which rates of recurrence are higher than in breast cancers detected later in life. Little is known about the genetic pathways that underlie early-onset breast cancer. Here we report the discovery of DEAR1 (ductal epithelium-associated RING Chromosome 1), a novel gene encoding a member of the TRIM (tripartite motif) subfamily of RING finger proteins, and provide evidence for its role as a dominant regulator of acinar morphogenesis in the mammary gland and as an independent predictor of local recurrence-free survival in early-onset breast cancer.

Polymorphisms of p16, p27, p73, and MDM2 modulate response and survival of pancreatic cancer patients treated with preoperative chemoradiation.

Genetic polymorphisms play an important role in clinical response to cytotoxic therapies. We hypothesized that polymorphisms in cell cycle genes may modulate response to preoperative chemoradiation and survival of pancreatic cancer patients. We evaluated 12 single-nucleotide polymorphisms (SNPs) of ten cell cycle genes in 88 patients with resectable adenocarcinoma of the pancreatic head who were treated with neoadjuvant concurrent gemcitabine and radiotherapy.

Polymorphisms of p21 and p27 jointly contribute to an earlier age at diagnosis of pancreatic cancer.

p21 and p27, members of the kinase inhibitor protein (KIP) family, bind to cyclin-CDK complexes to inhibit their catalytic activity and induce cell cycle arrest. The purpose of our study was to identify whether the p21 (C-to-A), and p27 (T-to-G) polymorphisms were associated with age at diagnosis of pancreatic cancer, either independently or jointly. Two hundred and five patients with a diagnosis of pancreatic cancer were genotyped for the p21 and p27 polymorphisms.

Fine mapping of the NRC-1 tumor suppressor locus within chromosome 3p12.

Identification of tumor suppressor genes based on physical mapping exercises has proven to be a challenging endeavor, due to the difficulty of narrowing regions of loss of heterozygosity (LOH), infrequency of homozygous deletions, and the labor-intensive characterization process for screening candidates in a given genomic interval. We previously defined a chromosome 3p12 tumor suppressor locus NRC-1 (Nonpapillary Renal Carcinoma-1) by functional complementation experiments in which renal cell carcinoma microcell hybrids containing introduced normal chromosome 3p fragments were either suppressed or unsuppressed for tumorigenicity following injection into athymic nude mice. We now present the fine-scale physical mapping of NRC-1 using a QPCR-based approach for measuring copy number at sequence tagged sites (STS) which allowed a sub-exon mapping resolution.

Aurora-A and p16 polymorphisms contribute to an earlier age at diagnosis of pancreatic cancer in Caucasians.

Purpose: Aurora-A and p16 play a major role in cell cycle checkpoint regulation. Both of them are important in the maintenance of centrosome duplication. Therefore, we hypothesized that polymorphisms in the two genes may interact or work together to influence the finely tuned mechanisms of cell cycle regulation that these proteins regulate.

Characterization of 11 human sarcoma cell strains: evaluation of cytogenetics, tumorigenicity, metastasis, and production of angiogenic factors.

Background: Human sarcomas have a propensity for aggressive local invasion and early pulmonary metastasis. Frequently, deaths are due to uncontrolled pulmonary metastases. The purpose of the current study was to evaluate cytogenetics, tumorigenicity, metastatic potential, and production of angiogenic factors in human sarcoma cell strains.