Patterns of Structural Variation Define Prostate Cancer Across Disease States

The complex genomic landscape of prostate cancer evolves across disease states under therapeutic pressure directed toward inhibiting androgen receptor (AR) signaling. While significantly altered genes in prostate cancer have been extensively defined, there have been fewer systematic analyses of how structural variation reflects the genomic landscape of this disease. We comprehensively characterized structural alterations across 278 localized and 143 metastatic prostate cancers profiled by whole genome and transcriptome sequencing. We observed distinct significantly recurrent breakpoints in localized and metastatic castration-resistant prostate cancers (mCRPC), with pervasive alterations in noncoding regions flanking the AR, MYC, FOXA1, and LSAMP genes in mCRPC. We defined nine subclasses of mCRPC based on signatures of structural variation, each associated with distinct genetic features and clinical outcomes. Our results comprehensively define patterns of structural variation in prostate cancer and identify clinically actionable subgroups based on whole genome profiling.

Percutaneous CT-Guided Biopsy of the Craniovertebral Junction: Safety, Diagnostic Yield, and Technical Notes

The craniovertebral junction defined as the occiput, the atlas, and the axis is a complex bony region that contains vital neural and vascular structures. We report the experience of a single academic institution regarding CT-guided biopsy of this skeletal region. We reviewed all of the CT-guided biopsies performed in our department, completed in the craniovertebral junction. We collected data in regard to biopsy procedures, patients’ vital statistics, and histopathological diagnosis. In total, 16 patients (8M and 8F; mean age 52; range 16–86 years old) were included in this series. In eight patients, the lesions were located in the atlas vertebra (8/16—50%), in six patients in the axis (37.5%), and in two patients in the occiput (12.5%). No complications were observed during or after the procedures. All of the procedures were technically successful. The biopsy was diagnostic in 13/16 patients (81.3%): four metastatic lesions (25%—three breast and one prostate cancers), four multiple myeloma bone lesions (25%), three aneurismal bone cysts (18.8%), one aggressive hemangioma (6.3%), and one pseudogout (6.3%). Moreover, in two-thirds (66.6%) of non-diagnostic histological reports, malignancies were excluded. CT-guided percutaneous biopsy is a safe tool and allows obtaining a histological diagnosis, in most cases, even in the most delicate site of the human skeleton—the craniovertebral junction.

Disparities in Outcomes Among Patients Diagnosed With Cancer in Proximity to an Emergency Department Visit

A suspected diagnosis of cancer in the emergency department (ED) may be associated with poor outcomes, related to health disparities, however data are limited. This study is a case-control analysis of the Indiana State Department of Health Cancer Registry, and the Indiana Network for Patient Care. First time cancer diagnoses appearing in the registry between January 2013 and December 2017 were included. Cases were patients who had an ED visit in the 6 months before their cancer diagnosis; controls had no recent ED visits. The primary outcome was mortality, comparing ED-associated mortality to non-ED-associated. 134,761 first-time cancer patients were identified, including 15,432 (11.5%) cases. The mean age was same at 65, more of the cases were Black than the controls (12.4% vs 7.4%, P<.0001) and more were low income (36.4%. vs 29.3%). The top 3 ED-associated cancer diagnoses were lung (18.4%), breast (8.9%), and colorectal cancers (8.9%), whereas the controls were breast (17%), lung (14.9%), and prostate cancers (10.1%). Cases observed an over three-fold higher mortality, with cumulative death rate of 32.9% for cases vs 9.0% for controls (P<.0001). Regression analysis predicting mortality, controlling for many confounders produced an odds ratio of 4.12 (95% CI 3.72-4.56 for cases). This study found that an ED visit within 6 months prior to the first time of ICD-coded cancer is associated with Black race, low income and an overall three-fold increased adjusted risk of death. The mortality rates for ED-associated cancers are uniformly worse for all cancer types. These data suggest that additional work is needed to reduce disparities among ED-associated cancer diagnoses.

Fractal Dimension Analysis to Detect the Progress of Cancer Using Transmission Optical Microscopy

Fractal dimension, a measure of self-similarity in a structure, is a powerful physical parameter for the characterization of structural property of many partially filled disordered materials. Biological tissues are fractal in nature and reports show a change in self-similarity associated with the progress of cancer, resulting in changes in their fractal dimensions. Here, we report that fractal dimension measurement is a potential technique for the detection of different stages of cancer using transmission optical microscopy. Transmission optical microscopy of a thin tissue sample produces intensity distribution patterns proportional to its refractive index pattern, representing its mass density distribution. We measure fractal dimension detection of different cancer stages and find its universal feature. Many deadly cancers are difficult to detect in their early to different stages due to the hard-to-reach location of the organ and/or lack of symptoms until very late stages. To study these deadly cancers, tissue microarray (TMA) samples containing different stages of cancers are analyzed for pancreatic, breast, colon, and prostate cancers. The fractal dimension method correctly differentiates cancer stages in progressive cancer, raising possibilities for a physics-based accurate diagnosis method for cancer detection.

Role of Precision Oncology in Type II Endometrial and Prostate Cancers in the African Population: Global Cancer Genomics Disparities

Precision oncology can be defined as molecular profiling of tumors to identify targetable alterations. Emerging research reports the high mortality rates associated with type II endometrial cancer in black women and with prostate cancer in men of African ancestry. The lack of adequate genetic reference information from the African genome is one of the major obstacles in exploring the benefits of precision oncology in the African context. Whilst external factors such as the geography, environment, health-care access and socio-economic status may contribute greatly towards the disparities observed in type II endometrial and prostate cancers in black populations compared to Caucasians, the contribution of African ancestry to the contribution of genetics to the etiology of these cancers cannot be ignored. Non-coding RNAs (ncRNAs) continue to emerge as important regulators of gene expression and the key molecular pathways involved in tumorigenesis. Particular attention is focused on activated/repressed genes and associated pathways, while the redundant pathways (pathways that have the same outcome or activate the same downstream effectors) are often ignored. However, comprehensive evidence to understand the relationship between type II endometrial cancer, prostate cancer and African ancestry remains poorly understood. The sub-Saharan African (SSA) region has both the highest incidence and mortality of both type II endometrial and prostate cancers. Understanding how the entire transcriptomic landscape of these two reproductive cancers is regulated by ncRNAs in an African cohort may help elucidate the relationship between race and pathological disparities of these two diseases. This review focuses on global disparities in medicine, PCa and ECa. The role of precision oncology in PCa and ECa in the African population will also be discussed.

Novel insights into the consequences of obesity: a phenotype-wide Mendelian randomization study

Obesity is thought to significantly impact the quality of life. In this study, we sought to evaluate the health consequences of obesity on the risk of a broad spectrum of human diseases. The causal effects of exposing to obesity on health outcomes were inferred using Mendelian randomization (MR) analyses using a fixed effects inverse-variance weighted model. The instrumental variables were SNPs associated with obesity as measured by body mass index (BMI) reported by GIANT consortium. The spectrum of outcome consisted of the phenotypes from published GWAS and the UK Biobank. The MR-Egger intercept test was applied to estimate horizontal pleiotropic effects, along with Cochran’s Q test to assess heterogeneity among the causal effects of instrumental variables. Our MR results confirmed many putative disease risks due to obesity, such as diabetes, dyslipidemia, sleep disorder, gout, smoking behaviors, arthritis, myocardial infarction, and diabetes-related eye disease. The novel findings indicated that elevated red blood cell count was inferred as a mediator of BMI-induced type 2 diabetes in our bidirectional MR analysis. Intriguingly, the effects that higher BMI could decrease the risk of both skin and prostate cancers, reduce calorie intake, and increase the portion size warrant further studies. Our results shed light on a novel mechanism of the disease-causing roles of obesity.

The best prostate biopsy sampling system—fusion and systematic biopsy: A single center experience

Background: Prostate cancer is the second most commonly diagnosed cancer in men. The diagnostic accuracy in prostate cancer can be increased by employing a preliminary multiparametric MRI followed by a fusion-targeted biopsy. Methods: To compare the diagnostic accuracy of fusion-targeted biopsy with the standard systematic biopsy in prostate cancer patients, we enrolled 139 patients on which we performed 139 prostate biopsies consisting of three targeted samples followed by 12 regular systematic samples. Based on histology, we analyzed the diagnostic performance of the two methods. Results: Both methods were equally good at detecting clinically significant cancer (83.3%, 50/60), while systematic biopsy detected more clinically insignificant cancers. However, the best diagnostic performance is obtained by combining the two methods. Conclusion: The two methods are best seen as synergistic, and the addition of fusion biopsy can be used to detect more clinically significant prostate cancers than systematic biopsy alone.

Extent, impact, and mitigation of batch effects in tumor biomarker studies using tissue microarrays

Tissue microarrays (TMAs) have been used in thousands of cancer biomarker studies. To what extent batch effects, measurement error in biomarker levels between slides, affects TMA-based studies has not been assessed systematically. We evaluated 20 protein biomarkers on 14 TMAs with prospectively collected tumor tissue from 1,448 primary prostate cancers. In half of the biomarkers, more than 10% of biomarker variance was attributable to between-TMA differences (range, 1-48%). We implemented different methods to mitigate batch effects (R package batchtma), tested in plasmode simulation. Biomarker levels were more similar between mitigation approaches compared to uncorrected values. For some biomarkers, associations with clinical features changed substantially after addressing batch effects. Batch effects and resulting bias are not an error of an individual study but an inherent feature of TMA-based protein biomarker studies. They always need to be considered during study design and addressed analytically in studies using more than one TMA.