Carly A. Conran

Genetic variation in STAT4 predicts response to interferon‐α therapy for hepatitis B e antigen‐positive chronic hepatitis B

Interferon (IFN)‐α is a first‐line therapy for chronic hepatitis B (CHB) patients but only initiates a response in a minority of patients. A genetic variant, rs7574865 in STAT4, was recently reported to be associated with risk of developing CHB and hepatitis B virus‐related hepatocellular carcinoma. We aimed to determine whether this variant is associated with the response to IFNα treatment for hepatitis B e antigen (HBeAg)‐positive CHB patients. We studied 466 HBeAg‐positive CHB patients who received either IFNα‐2b (n = 224) or pegylated IFNα‐2a (n = 242) therapy for 48 weeks and were followed for an additional 24 weeks. The rate of sustained virologic response (SVR), defined as HBeAg seroconversion along with hepatitis B virus DNA level <2000 copies/mL at week 72, was compared among patients with different genotypes of rs7574865. After 48 weeks of treatment and 24 weeks off treatment, the SVR rates in the IFNα‐2b and pegylated IFNα‐2a therapy groups were 30.4% and 28.9%, respectively. Compared to the rs7574865 GT/TT genotype, the GG genotype (a risk factor of CHB and hepatitis B virus‐related hepatocellular carcinoma) was significantly associated with a reduced SVR rate in both patients who received IFNα‐2b therapy (21.1% versus 37.2%, P = 0.01) and those who received pegylated IFNα‐2a therapy (18.0% versus 41.2%, P = 9.74 × 10‐5). In joint analysis of the 466 patients, the GG genotype was associated with an approximately half SVR rate compared to the GT/TT genotype (19.3% versus 39.1%, P = 4.15 × 10‐6). A multivariate logistic regression model including rs7574865 and clinical variables showed that rs7574865 was the most significant factor for the prediction of SVR. Conclusion: STAT4 rs7574865 is a reliable predictor of response to IFNα therapy for HBeAg‐positive CHB patients and may be used for optimizing the treatment of CHB. (Hepatology 2016;63:1102–1111)

Clinical validity and utility of genetic risk scores in prostate cancer.

Current issues related to prostate cancer (PCa) clinical care (e.g., over-screening, over-diagnosis, and over-treatment of nonaggressive PCa) call for risk assessment tools that can be combined with family history (FH) to stratify disease risk among men in the general population. Since 2007, genome-wide association studies (GWASs) have identified more than 100 SNPs associated with PCa susceptibility. In this review, we discuss (1) the validity of these PCa risk-associated SNPs, individually and collectively; (2) the various methods used for measuring the cumulative effect of multiple SNPs, including genetic risk score (GRS); (3) the adequate number of SNPs needed for risk assessment; (4) reclassification of risk based on evolving numbers of SNPs used to calculate genetic risk, (5) risk assessment for men from various racial groups, and (6) the clinical utility of genetic risk assessment. In conclusion, data available to date support the clinical validity of PCa risk-associated SNPs and GRS in risk assessment among men with or without FH. PCa risk-associated SNPs are not intended for diagnostic use; rather, they should be used the same way as FH. Combining GRS and FH can significantly improve the performance of risk assessment. Improved risk assessment may have important clinical utility in targeted PCa testing. However, clinical trials are urgently needed to evaluate this clinical utility as well as the acceptance of GRS by patients and physicians.

A genetic variant near GATA3 implicated in inherited susceptibility and etiology of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS)

Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are common conditions. Little is known about their etiologies except that studies have suggested a substantial heritable component. Our objective is to provide a comprehensive, genome‐wide evaluation of inherited risks and possible mechanisms of etiology in BPH.

Prostate health index significantly reduced unnecessary prostate biopsies in patients with PSA 2-10 ng/mL and PSA >10 ng/mL: Results from a Multicenter Study in China

The performance of prostate health index (phi) in predicting prostate biopsy outcomes has been well established for patients with prostate‐specific antigen (PSA) values between 2 and 10 ng/mL. However, the performance of phi remains unknown in patients with PSA >10 ng/mL, the vast majority in Chinese biopsy patients. We aimed to assess the ability of phi to predict prostate cancer (PCa) and high‐grade disease (Gleason Score ≥7) on biopsy in a Chinese population.

Differences in inherited risk among relatives of hereditary prostate cancer patients using genetic risk score

Family history assigns equivalent risk to all relatives based upon the degree of relationship. Recent genetic studies have identified single nucleotide polymorphisms (SNPs) that can be used to calculate a genetic risk score (GRS) to determine prostate cancer (PCa) risk. We sought to determine whether GRS can stratify PCa risk among individuals in families considered to be at higher risk due their family history of PCa.

Germline mutations in DNA repair genes are associated with bladder cancer risk and unfavourable prognosis

To perform a systematic evaluation of whether germline DNA repair gene mutations in bladder cancer (BCa) are associated with increased risk of BCa and aggressive disease.

Reclassification of prostate cancer risk using sequentially identified SNPs: Results from the REDUCE trial

Although the clinical validity of risk‐associated single nucleotide polymorphisms (SNPs) for assessment of disease susceptibility has been consistently established, risk reclassification from increasing numbers of implicated risk‐associated SNPs raises concern that it is premature for clinical use. Our objective is to assess the degree and impact of risk reclassification with the increasing number of SNPs.

MP33-11 GENETIC RISK SCORE CAN DISTINGUISH RISK OF PROSTATE CANCER AMONG FAMILY MEMBERS WITH SIMILAR DEGREES OF RELATIONSHIP

INTRODUCTION AND OBJECTIVES: Background: Management of men at risk of prostate cancer (PCa), but with a cancer-negative index biopsy, remains a challenge. PCa diagnosis involves an invasive biopsy procedure that is subject to significant sampling errors, possible negative quality-of-life implications for the patient and high additional costs to the healthcare system. An epigenetic assay assessing PCaassociated DNA-methylation of GSTP1, RASSF1, and APC in histologically negative biopsies has previously been clinically validated to improve the negative predictive value (NPV) relative to standard of care (SOC), yielding a NPV of 90% for all PCa and 96% for high-grade PCa (Gleason Score 7 or higher). Examination of the repeat biopsy rate associated with the outcome of this epigenetic assay would provide further evidence of its clinical utility for improving urologists’ management of previously biopsied patients. Objective:The primary goal of this study was to determine the rate of repeat biopsy in relation to the epigenetic assay and how this impacted the management of patients. METHODS: Practicing urologists used the epigenetic assay to evaluate 986 men (680 in the case group and 306 in the control group) with a previous negative biopsy. Men in the Case group had an epigenetic assay-negative result and were prospectively followed for a minimum of 12 months from the date of epigenetic profiling. The Control group was managed under SOC. RESULTS: The two groups were balanced in terms of patient characteristics, except for median age, which was lower in the Case group compared to the Control group (62 vs. 66 years, p<0.001). Use of the epigenetic assay resulted in significantly fewer first repeat biopsies in the Case group compared to the Control group (7.8% vs. 15.4%, respectively; p1⁄40.004). There were also significantly fewer second repeat biopsies in the Case group compared to the Control group (12.1% vs. 26.1%, respectively; p<0.001) and significantly lower PCa detection upon repeat biopsy after a negative epigenetic assay result in the Case group compared to the Control group (0.6% vs. 4.9%, respectively; p<0.001). CONCLUSIONS: In this real-world prospective study, the use of the epigenetic assay resulted in a significant reduction in the rate of excess repeat prostate biopsies.

Chapter 12 – Prostate Cancer

In personalized medicine (PM), the aim is to provide individual risk assessment for medical conditions, or to predict the efficacy of measures intended to monitor, prevent, or treat these conditions (http://www.personalizedmedicinecoalition.org). The approaches of PM could be important in addressing clinical and public health issues involved in a variety of diseases, including cancers that are detected via population-level screening. This is particularly relevant to prostate cancer (PCa), where concerns have been raised regarding prostate-specific antigen screening, subsequent overdiagnosis of low-grade diseases, and ultimately overtreatment of many indolent cancers. These interrelated issues have prompted a significant effort to identify markers that can effectively differentiate individuals who have different risks for PCa onset or progression. Improved risk estimation may help to address this major public health problem, as the prostate is the most common site of cancer diagnosis, accounting for approximately 26% of all new cancer diagnoses and 9% of cancer deaths in US men. This translates to an estimated 220,800 PCa diagnoses and 27,540 deaths in US men each year (Siegel et al., 2015. CA Cancer J Clin).

MP90-12 INHERITED RISK FOR OTHER TYPES OF CANCER AMONG MEN WITH OR WITHOUT PROSTATE CANCER BASED ON THE GENETIC RISK SCORE

(CWR22Rv1) and AR -ve cell line (DU145). Xenografted PC3 tumors in nude mice also showed NE differentiation when mice were treated with Dovitinib. The exact mechanistic underpinnings of this NE differentiation are unclear, but seem to be supported through MAPK and PI3K signaling pathways. CONCLUSIONS: Our study for the first time demonstrates that Dovitinib can induce neuroendocrine in AR +ve and AR eve PCa cell lines, both in vitro and in vivo. It provides a robust tool to study the NE differentiation process in vitro and identify vulnerabilities for therapeutic intervention. The NE differentiation might be a potential mechanism of resistance development to Dovitinib therapy, and thus could have critical clinical implications.