Impedance-Based Miniaturized Biosensor for Ultrasensitive and Fast Prostate-Specific Antigen Detection

This paper reports the successful fabrication of an impedance-based miniaturized biosensor and its application for ultrasensitive Prostate-Specific Antigen (PSA) detection in standard and real human plasma solution, spiked with different PSA concentrations. The sensor was fabricated using photolithographic techniques, while monoclonal antibodies specific to human PSA were used as primary capture antibodies. Electrochemical impedance spectroscopy (EIS) was employed as a detection technique. The sensor exhibited a detection limit of 1 pg/ml for PSA with minimal nonspecific binding (NSB). This detection limit is an order of magnitude lower than commercial PSA ELISA assays available on the market. The sensor can be easily modified into an array for the detection of other biomolecules of interest, enabling accurate, ultrasensitive, and inexpensive point-of-care sensing technologies

A novel genomic alteration of LSAMP associates with aggressive prostate cancer in African American men

Evaluation of cancer genomes in global context is of great interest in light of changing ethnic distribution of the world population. We focused our study on men of African ancestry because of their disproportionately higher rate of prostate cancer (CaP) incidence and mortality. We present a systematic whole genome analyses, revealing alterations that differentiate African American (AA) and Caucasian American (CA) CaP genomes. We discovered a recurrent deletion on chromosome 3q13.31 centering on the LSAMP locus that was prevalent in tumors from AA men (cumulative analyses of 435 patients: whole genome sequence, 14; FISH evaluations, 101; and SNP array, 320 patients). Notably, carriers of this deletion experienced more rapid disease progression. In contrast, PTEN and ERG common driver alterations in CaP were significantly lower in AA prostate tumors compared to prostate tumors from CA. Moreover, the frequency of inter-chromosomal rearrangements was significantly higher in AA than CA tumors. These findings reveal differentially distributed somaticmutations in CaP across ancestral groups, which have implications for precision medicine strategies. (C) 2015 The Authors. Published by Elsevier B.V

Hyperglycemia and prostate cancer recurrence in men treated for localized prostate cancer.

Background:Obesity is consistently linked with prostate cancer (PCa) recurrence and mortality, though the mechanism is unknown. Impaired glucose regulation, which is common among obese individuals, has been hypothesized as a potential mechanism for PCa tumor growth. In this study, we explore the relationship between serum glucose at time of treatment and risk of PCa recurrence following initial therapy.Methods:The study group comprised 1734 men treated with radical prostatectomy (RP) or radiation therapy (RT) for localized PCa between 2001-2010. Serum glucose levels closest to date of diagnosis were determined. PCa recurrence was determined based on PSA progression (nadir PSA+2 for RT; PSA0.2 for RP) or secondary therapy. Multivariate Cox regression was performed to determine whether glucose level was associated with biochemical recurrence after adjusting for age, race, body mass index, comorbidity, diagnosis of diabetes, Gleason Sum, PSA, treatment and treatment year.Results:Recurrence was identified in 16% of men over a mean follow-up period of 41 months (range 1-121 months). Those with elevated glucose (100 mg/dl) had a 50% increased risk of recurrence (HR 1.5, 95% CI: 1.1-2.0) compared with those with a normal glucose level (<100 mg/dl). This effect was seen in both those undergoing RP (HR 1.9, 95% CI: 1.0-3.6) and those treated with RT (HR 1.4, 95% CI: 1.0-2.0).Conclusions:Glucose levels at the time of PCa diagnosis are an independent predictor of PCa recurrence for men undergoing treatment for localized disease

A multi-center population-based case–control study of ovarian cancer in African-American women: the African American Cancer Epidemiology Study (AACES)

Abstract: Background: Ovarian cancer (OVCA) is the leading cause of death from gynecological cancer, with poorer survival for African American (AA) women compared to whites. However, little is known about risk factors for OVCA in AA. To study the epidemiology of OVCA in this population, we started a collaborative effort in 10 sites in the US. Here we describe the study and highlight the challenges of conducting a study of a lethal disease in a minority population. Methods: The African American Cancer Epidemiology Study (AACES) is an ongoing, population-based case–control study of OVCA in AA in 10 geographic locations, aiming to recruit 850 women with invasive epithelial OVCA and 850 controls age- and geographically-matched to cases. Rapid case ascertainment and random-digit-dialing systems are in place to ascertain cases and controls, respectively. A telephone survey focuses on risk factors as well as factors of particular relevance for AAs. Food-frequency questionnaires, follow-up surveys, biospecimens and medical records are also obtained. Results: Current accrual of 403 AA OVCA cases and 639 controls exceeds that of any existing study to date. We observed a high proportion (15%) of deceased non-responders among the cases that in part is explained by advanced stage at diagnosis. A logistic regression model did not support that socio-economic status was a factor in advanced stage at diagnosis. Most risk factor associations were in the expected direction and magnitude. High BMI was associated with ovarian cancer risk, with multivariable adjusted ORs and 95% CIs of 1.50 (0.99-2.27) for obese and 1.27 (0.85- 1.91) for morbidly obese women compared to normal/underweight women. Conclusions: AACES targets a rare tumor in AAs and addresses issues most relevant to this population. The importance of the study is accentuated by the high proportion of OVCA cases ascertained as deceased. Our analyses indicated that obesity, highly prevalent in this population (>60% of the cases), was associated with increased OVCA risk. While these findings need to be replicated, they suggest the potential for an effective intervention on the risk in AAs. Upon completion of enrollment, AACES will be the largest epidemiologic study of OVCA in AA women

Inclusion of diverse populations in genomic research and health services: Genomix workshop report

Clinical genetic services and genomic research are rapidly developing but, historically, those with the greatest need are the least to benefit from these advances. This encompasses low-income communities, including those from ethnic minority and indigenous backgrounds. The “Genomix” workshop at the European Society of Human Genetics (ESHG) 2016 conference offered the opportunity to consider possible solutions for these disparities from the experiences of researchers and genetic healthcare practitioners working with underserved communities in the USA, UK and Australia. Evident from the workshop and corresponding literature is that a multi-faceted approach to engaging communities is essential. This needs to be complemented by redesigning healthcare systems that improves access and raises awareness of the needs of these communities. At a more strategic level, institutions involved in funding research, commissioning and redesigning genetic health services also need to be adequately represented by underserved populations with intrinsic mechanisms to disseminate good practice and monitor participation. Further, as genomic medicine is mainstreamed, educational programmes developed for clinicians should incorporate approaches to alleviate disparities in accessing genetic services and improving study participation

Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk

Background Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk. Methods In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons. Results The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4). Conclusion These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes

miRNAs associated with prostate cancer risk and progression

Prostate cancer is the most common malignancy among men in the US. Though considerable improvement in the diagnosis of prostate cancer has been achieved in the past decade, predicting disease outcome remains a major clinical challenge. Recent expression profiling studies in prostate cancer suggest microRNAs (miRNAs) may serve as potential biomarkers for prostate cancer risk and disease progression. miRNAs comprise a large family of about 22-nucleotide-long non-protein coding RNAs, regulate gene expression post-transcriptionally and participate in the regulation of numerous cellular processes. In this review, we discuss the current status of miRNA in studies evaluating the disease progression of prostate cancer. The discussion highlights key findings from previous studies, which reported the role of miRNAs in risk and progression of prostate cancer, providing an understanding of the influence of miRNA on prostate cancer. Our review indicates that somewhat consistent results exist between these studies and reports on several prostate cancer related miRNAs. Present promising candidates are miR-1, −21, 106b, 141, −145, −205, −221, and −375, which are the most frequently studied and seem to be the most promising for diagnosis and prognosis for prostate cancer. Nevertheless, the findings from previous studies suggest miRNAs may play an important role in the risk and progression of prostate cancer as promising biomarkers

Variants in genes encoding small GTPases and association with epithelial ovarian cancer susceptibility

Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality in American women. Normal ovarian physiology is intricately connected to small GTP binding proteins of the Ras superfamily (Ras, Rho, Rab, Arf, and Ran) which govern processes such as signal transduction, cell proliferation, cell motility, and vesicle transport. We hypothesized that common germline variation in genes encoding small GTPases is associated with EOC risk. We investigated 322 variants in 88 small GTPase genes in germline DNA of 18,736 EOC patients and 26,138 controls of European ancestry using a custom genotype array and logistic regression fitting log-additive models. Functional annotation was used to identify biofeatures and expression quantitative trait loci that intersect with risk variants. One variant, ARHGEF10L (Rho guanine nucleotide exchange factor 10 like) rs2256787, was associated with increased endometrioid EOC risk (OR=1.33, p=4.46 x 10-6). Other variants of interest included another in ARHGEF10L, rs10788679, which was associated with invasive serous EOC risk (OR=1.07, p=0.00026) and two variants in AKAP6 (A-kinase anchoring protein 6) which were associated with risk of invasive EOC (rs1955513, OR=0.90, p=0.00033; rs927062, OR =0.94, p=0.00059). Functional annotation revealed that the two ARHGEF10L variants were located in super-enhancer regions and that AKAP6 rs927062 was associated with expression of GTPase gene ARHGAP5 (Rho GTPase activating protein 5). Inherited variants in ARHGEF10L and AKAP6, with potential transcriptional regulatory function and association with EOC risk, warrant investigation in independent EOC study populations

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC