Showing papers by "Keith A. Baggerly published in 2018"

FABP4 as a key determinant of metastatic potential of ovarian cancer

Abstract: The standard treatment for high-grade serous ovarian cancer is primary debulking surgery followed by chemotherapy. The extent of metastasis and invasive potential of lesions can influence the outcome of these primary surgeries. Here, we explored the underlying mechanisms that could increase metastatic potential in ovarian cancer. We discovered that FABP4 (fatty acid binding protein) can substantially increase the metastatic potential of cancer cells. We also found that miR-409-3p regulates FABP4 in ovarian cancer cells and that hypoxia decreases miR-409-3p levels. Treatment with DOPC nanoliposomes containing either miR-409-3p mimic or FABP4 siRNA inhibited tumor progression in mouse models. With RPPA and metabolite arrays, we found that FABP4 regulates pathways associated with metastasis and affects metabolic pathways in ovarian cancer cells. Collectively, these findings demonstrate that FABP4 is functionally responsible for aggressive patterns of disease that likely contribute to poor prognosis in ovarian cancer.

Cholangiocarcinoma With FGFR Genetic Aberrations: A Unique Clinical Phenotype

Abstract: PurposeFGFR genetic aberrations (GAs) occur in an estimated 10% to 16% of intrahepatic cholangiocarcinomas (CCAs). The natural history of CCA with FGFR GAs, the prognostic role of coexisting GAs, and the outcome with FGFR-targeted inhibitors are unknown.Patients and MethodsPatients with CCA with FGFR GAs were identified using next-generation sequencing or fluorescence in situ hybridization from four tertiary cancer centers and compared with FGFR wild-type counterparts. Data reviewed included demographic, treatment, overall survival (OS), and GA data. Fisher’s exact test, Kaplan-Meier plots, and log-rank tests were used for statistical analysis.ResultsThree hundred seventy-seven patients with CCA were identified, and 95 had FGFR GAs. FGFR2 GA was most common (n = 74, with 63 fusions) and seen in intrahepatic CCA. In patients with CCA, FGFR GAs occurred more frequently in younger patients (≤ 40 years; 20%) compared with older patients (> 40 years; 6.7%; P < .001), presented at an earlier stage (TNM stage I/...

Defining Survivorship Trajectories Across Patients With Solid Tumors: An Evidence-Based Approach

Abstract: Importance Survivorship involves a multidisciplinary approach to surveillance and management of comorbidities and secondary cancers, overseen by oncologists, surgeons, and primary care physicians. Optimal timing and coordination of care, however, is unclear and often based on arbitrary 5-year cutoffs. Objective To determine high- and low-risk periods for all tumor types that could define when survivorship care might best be overseen by oncologists and when to transition to primary care physicians. Design, Setting, and Participants In this pan-cancer, longitudinal, observational study, excess mortality hazard, calculated as an annualized mortality risk above a baseline population, was plotted over time. The time this hazard took to stabilize defined a high-risk period. The percent morality elevation above age- and sex-matched controls in the latter low-risk period was reported as a mortality gap. The US population–based Surveillance, Epidemiology, and End Results database defined the cancer population, and the US Census life tables defined controls. Incident cases of patients with cancer were separated into tumor types based on International Classification of Diseases for Oncology definitions. Exposures Population-level data on incident cancer cases was compared with the general US population. Main Outcomes and Measures Overall mortality and cause of death were reported on observed cancer cases. Results A total of 2 317 185 patients (median age, 63 years; 49.8% female) with 66 primary tumor types were evaluated. High-risk surveillance period durations ranged from less than 1 year (breast, prostate, lip, ocular, and parathyroid cancers) up to 19 years (unspecified gastrointestinal cancers). The annualized mortality gap, representing the excess mortality in the stable period, ranged from a median 0.26% to 9.33% excess annual mortality (thyroid and hypopharyngeal cancer populations, respectively). Cluster analysis produced 6 risk cluster groups: group 1, with median survival of 16.2 (5th to 95th percentile range [PR], 10.7-40.2) years and median high-risk period of 2.5 (PR, 0-5.0) years; group 2, 8.3 (PR, 5.1-23.3) and 2.5 (PR, 4.0-8.0) years; group 3, 2.8 (PR, 1.4-3.7) and 7.0 (PR, 6.0-11.1) years; group 4, 1.6 (PR, 1.5-1.8) and 6.0 (PR, 5.1-11.4) years; group 5, 0.8 (PR, 0.5-1.2) and 0.8 (PR, 0.5-1.2) years; and group 6, 0.5 (PR, 0.4-0.8) and 12.0 (PR, 9.3-12.9) years, respectively. Subanalyses of selected tumor types in these groups revealed that stratifying on stage and histologic type can change the risk cluster and guidance for care. Conclusions and Relevance These findings indicate that a standardized 5-year surveillance period is inadequate for some cancers while excessive for others. High-risk cancers require the most resources with the longest high-risk period, highest persistent baseline mortality risk, and longest period of primary cancer mortality, all arguing for longer follow-up with an oncologist in these cancers.

A survey on data reproducibility and the effect of publication process on the ethical reporting of laboratory research

Abstract: Purpose: The successful translation of laboratory research into effective therapies is dependent upon the validity of peer-reviewed publications. However, several publications in recent years suggested that published scientific findings could be reproduced only 11% to 45% of the time. Multiple surveys attempted to elucidate the fundamental causes of data irreproducibility and underscored potential solutions, more robust experimental designs, better statistics, and better mentorship. However, no prior survey has addressed the role of the review and publication process on honest reporting.Experimental Design: We developed an anonymous online survey intended for trainees involved in bench research. The survey included questions related to mentoring/career development, research practice, integrity, and transparency, and how the pressure to publish and the publication process itself influence their reporting practices.Results: Responses to questions related to mentoring and training practices were largely positive, although an average of approximately 25% did not seem to receive optimal mentoring. A total of 39.2% revealed having been pressured by a principle investigator or collaborator to produce "positive" data. About 62.8% admitted that the pressure to publish influences the way they report data. The majority of respondents did not believe that extensive revisions significantly improved the manuscript while adding to the cost and time invested.Conclusions: This survey indicates that trainees believe that the pressure to publish affects honest reporting, mostly emanating from our system of rewards and advancement. The publication process itself affects faculty and trainees and appears to influence a shift in their ethics from honest reporting ("negative data") to selective reporting, data falsification, or even fabrication. Clin Cancer Res; 24(14); 3447-55. ©2018 AACR.

ADH1B promotes mesothelial clearance and ovarian cancer infiltration

Abstract: Primary debulking surgery followed by adjuvant chemotherapy is the standard treatment for ovarian cancer. Residual disease after primary surgery is associated with poor patient outcome. Previously, we discovered ADH1B to be a molecular biomarker of residual disease. In the current study, we investigated the functional role of ADH1B in promoting ovarian cancer cell invasiveness and contributing to residual disease. We discovered that ADH1B overexpression leads to a more infiltrative cancer cell phenotype, promotes metastasis, increases the adhesion of cancer cells to mesothelial cells, and increases extracellular matrix degradation. Live cell imaging revealed that ADH1B-overexpressing cancer cells efficiently cleared the mesothelial cell layer compared to control cells. Moreover, gene array analysis revealed that ADH1B affects several pathways related to the migration and invasion of cancer cells. We also discovered that hypoxia increases ADH1B expression in ovarian cancer cells. Collectively, these findings indicate that ADH1B plays an important role in the pathways that promote ovarian cancer cell infiltration and may increase the likelihood of residual disease following surgery.

Prevalence of aflatoxin-associated TP53R249S mutation in hepatocellular carcinoma in Hispanics in South Texas

Abstract: We aimed to determine whether aflatoxin dietary exposure plays a role in the high incidence of hepatocellular carcinoma (HCC) observed among Hispanics in South Texas.We measured TP53R249S somatic mutation, hallmark of aflatoxin etiology in HCC, using droplet digital PCR and restriction fragment length polymorphism. TP53R249S mutation was detected in 3 out of 41 HCC tumors from Hispanics in South Texas (7.3%). We also measured TP53R249S mutation in plasma cell free DNA (cfDNA) from 218 HCC patients and 96 Hispanic subjects with advanced fibrosis or cirrhosis, from South Texas. The mutation was detected only in Hispanic and Asian HCC patients and patients harboring TP53R249S mutation were significantly younger and had a shorter overall survival. The mutation was not detected in any Hispanic subject with advanced fibrosis or cirrhosis. Genes involved in cell cycle control of chromosomal replication and in BRCA1-dependent DNA damage response were enriched in HCCs with TP53R249S mutation. The E2F1 family members, E2F1 and E2F4, were identified as upstream regulators. TP53R249S mutation was detected in 5.7%-7.3% of Hispanics with HCC in South Texas. This mutation was associated with a younger age and worse prognosis. TP53R249S was however not detected in Hispanics in South Texas with cirrhosis or advanced fibrosis. Aflatoxin exposure may contribute to a small number of HCCs in Hispanics in South Texas but the detection of TP53R249S mutation in plasma cfDNA is not a promising biomarker of risk assessment for HCC in subjects with cirrhosis or advanced fibrosis in this population.

Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer

Abstract: The sarcomatoid variant of urothelial bladder cancer (SARC) displays a high propensity for distant metastasis and is associated with short survival. We report a comprehensive genomic analysis of 28 cases of SARCs and 84 cases of conventional urothelial carcinomas (UCs), with the TCGA cohort of 408 muscle-invasive bladder cancers serving as the reference. SARCs showed a distinct mutational landscape with enrichment of TP53, RB1, and PIK3CA mutations. They were related to the basal molecular subtype of conventional UCs and could be divided into epithelial/basal and more clinically aggressive mesenchymal subsets based on TP63 and its target genes expression levels. Other analyses revealed that SARCs are driven by downregulation of homotypic adherence genes and dysregulation of cell cycle and EMT networks, and nearly half exhibited a heavily infiltrated immune phenotype. Our observations have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer.

Dissecting Pathway Disturbances Using Network Topology and Multi-platform Genomics Data

Abstract: Complex diseases such as cancers usually result from accumulated disturbance of pathways instead of the disruptions of one or a few major genes. As opposed to single-platform analyses, it is likely that integrating diverse molecular regulatory elements and their interactions can lead to more insights on pathway-level disturbances of biological systems and their potential consequences in disease development and progression. To explore the benefit of pathway-based analysis, we focus on multi-platform genomics, epigenomics, and transcriptomics (-omics, for short) from 11 cancer types collected by The Cancer Genome Atlas project. Specifically, we use a well-studied oncogenic pathway, the BRAF pathway, to investigate the relevant copy number variants (CNVs), methylations, and gene expressions, and quantify their effects on discovering tumor-specific aberrations across multiple tumor lineages. We also perform simulation studies to further investigate the effects of network topology and multiple omics on dissecting pathway disturbances. Our analysis shows that adding molecular regulatory elements such as CNVs and/or methylations to the baseline mRNA molecules can improve our power of discovering tumorous aberrances. Also, incorporating CNVs with the baseline mRNA molecules can be more beneficial than incorporating methylations. Moreover, employing regulatory topologies can improve the discoveries of tumorous aberrances. Finally, our analysis reveals similarities and differences among diverse cancer types based on disturbance of the BRAF pathway.

Detection of Bladder Cancer in Urine Sediments by a Novel Multicolor Fluorescence In Situ Hybridization (Quartet) Test.

Abstract: Background Bladder cancer is among the common human malignancies that show a heavy mutational load and copy number variations of numerous chromosomes, which makes them a target for diagnostic explorations Objective We aimed to design a multicolor fluorescence in situ hybridization (FISH) test referred to as the quartet test for the detection of bladder cancer in urine Design, setting, and participants We performed genome-wide copy number variation analysis on cohorts from the University of Texas MD Anderson Cancer Center ( n =40) and The Cancer Genome Atlas ( n =129), and identified the most frequently amplified chromosomal regions These data were used to select four of the amplified regions to design a multicolor FISH test, referred to as the quartet test Assay validation was performed on urine samples from 98 patients with bladder cancer: 56 with low-grade papillary, 42 with high-grade invasive disease, and 48 benign controls Intervention The quartet test can be used in clinical practice for noninvasive detection of bladder cancer Outcome measurements and statistical analysis We initially analyzed samples using a fraction of abnormal cell scores and then by the quantitative score, which included not only the proportion of cells with abnormal copy numbers, but also the proportion of cells with numbers of altered copies and degree of amplification We used receiver operator characteristic (ROC) curves to identify cutoff values for the scores at which performances of sensitivity and specificity were maximized Results and limitations The copy number status assessed by probes detected in voided urine reflected the amplification status of the primary tumor An ROC curve summarizing the proportion of assayed cells with any abnormal copy numbers gave specificity of 938% and sensitivity of 786% using the proportion of cells with abnormal copy numbers The quantitative score giving extra weight to cells with multiple simultaneous amplifications provided 958% specificity and 768% sensitivity Both percentage of abnormal cells and quantitative scores were highly effective for assessing the grade of the tumor The full spectrum of potential clinical applications was not explored in the current study, and further validation studies are needed Conclusions The quartet test shows promising specificity and sensitivity results, but it requires validation on a larger multi-institutional cohort of samples Patient summary The quartet test can be used for noninvasive detection of bladder cancer in voided urine It can also be used to assess the grade of the tumor and tumor recurrence as well as post-treatment effects

Defining survivorship and surveillance with evidence.

Abstract: 6528Background: Survivorship involves a multidisciplinary approach to surveillance and management of comorbidities and secondary cancers, however timing is based on arbitrary 5 year cutoffs Here,

Experimental Design, Randomization, and Validation.

Abstract: Featured Article: Baggerly KA, Morris JS, Coombes KR. Reproducibility of SELDI-TOF protein patterns in serum: comparing datasets from different experiments. Bioinformatics 2004;20:777–85.2 Before our article discussed here appeared in 2004, one might have thought a golden age in proteomic diagnostics was at hand. The good news began in 2002 (1), when National Cancer Institute (NCI)3/Food and Drug Administration (FDA) researchers claimed to have processed high-throughput measurements of easy-to-get samples with machine learning algorithms to extract previously elusive diagnoses. The high-throughput measurements were from mass spectrometry, specifically surface-enhanced laser desorption and ionization (SELDI) assays. The samples were minimally processed serum. The machine learning algorithms were, broadly, black boxes taking peak intensities (nominally peptide abundances) and producing categorical calls: “disease,” “no disease,” or “something else.” The diagnosis was whether a woman had ovarian cancer. The numbers looked impressive. Starting with 216 samples (100 women with ovarian cancer, 100 healthy controls, and 16 women with …