Qiaoyan Hu

A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer

In Western countries, prostate cancer is the most prevalent cancer of men and one of the leading causes of cancer-related death in men. Several genome-wide association studies have yielded numerous common variants conferring risk of prostate cancer. Here, we analyzed 32.5 million variants discovered by whole-genome sequencing 1,795 Icelanders. We identified a new low-frequency variant at 8q24 associated with prostate cancer in European populations, rs188140481[A] (odds ratio (OR) = 2.90; Pcombined = 6.2 × 10−34), with an average risk allele frequency in controls of 0.54%. This variant is only very weakly correlated (r2 ≤ 0.06) with previously reported risk variants at 8q24, and its association remains significant after adjustment for all known risk-associated variants. Carriers of rs188140481[A] were diagnosed with prostate cancer 1.26 years younger than non-carriers (P = 0.0059). We also report results for a previously described HOXB13 variant (rs138213197[T]), confirming it as a prostate cancer risk variant in populations from across Europe.

Personalized Prostate Specific Antigen Testing Using Genetic Variants May Reduce Unnecessary Prostate Biopsies

PURPOSE Recent studies have identified genetic variants associated with increased serum prostate specific antigen concentrations and prostate cancer risk, raising the possibility of diagnostic bias. By correcting for the effects of these variants on prostate specific antigen, it may be possible to create a personalized prostate specific antigen cutoff to more accurately identify individuals for whom biopsy is recommended. Therefore, we determined how many men would continue to meet common biopsy criteria after genetic correction of their measured prostate specific antigen concentrations. MATERIALS AND METHODS The genotypes of 4 single nucleotide polymorphisms previously associated with serum prostate specific antigen levels (rs2736098, rs10788160, rs11067228 and rs17632542) were determined in 964 healthy Caucasian volunteers without prostate cancer. Genetic correction of prostate specific antigen was performed by dividing an individuals prostate specific antigen value by his combined genetic risk. Analyses were used to compare the percentage of men who would meet commonly used biopsy thresholds (2.5 ng/ml or greater, or 4.0 ng/ml or greater) before and after genetic correction. RESULTS Genetic correction of serum prostate specific antigen results was associated with a significantly decreased percentage of men meeting biopsy thresholds. Genetic correction could lead to a 15% or 20% relative reduction in the total number of biopsies using a biopsy threshold of 2.5 ng/ml or greater, or 4.0 ng/ml or greater, respectively. In addition, genetic correction could result in an 18% to 22% reduction in the number of potentially unnecessary biopsies and a 3% decrease in potentially delayed diagnoses. CONCLUSIONS Our results suggest that 4 single nucleotide polymorphisms can be used to adjust a mans measured prostate specific antigen concentration and potentially delay or prevent unnecessary prostate biopsies in Caucasian men.

Outcomes in patients with Gleason score 8–10 prostate cancer: relation to preoperative PSA level

Study Type – Therapy (case series)

Association of prostate cancer risk alleles with unfavourable pathological characteristics in potential candidates for active surveillance.

Study Type – Prognosis (cohort)

Genetic sequence variants are associated with severity of lower urinary tract symptoms and prostate cancer susceptibility.

PURPOSE While a clear heritable component underlies lower urinary tract symptoms and benign prostatic hyperplasia, few studies have identified specific genetic factors. In contrast, recent genome-wide association studies identified single nucleotide polymorphisms that increase prostate cancer risk. Some of these single nucleotide polymorphisms may also predispose to surgical intervention for benign prostatic hyperplasia. We determined whether these single nucleotide polymorphisms are also associated with lower urinary tract symptom severity and benign prostatic hyperplasia medication use. MATERIALS AND METHODS The genotypes of 38 single nucleotide polymorphisms previously associated with prostate cancer risk were determined for 1,168 healthy white male volunteers. American Urological Association symptom index score and medication for benign prostatic hyperplasia were documented prospectively. Statistical analyses were done to compare the frequency of the single nucleotide polymorphisms with American Urological Association symptom index and benign prostatic hyperplasia medication use. RESULTS Several single nucleotide polymorphisms, including rs2736098 on chromosome 5p15, showed a significant relationship with benign prostatic hyperplasia medication. After adjusting for the other genetic variants, patient age and medication use, rs1571801 on chromosome 9q33.2 (OR 1.31, 95% CI 1.0-1.74) and rs5945572 on chromosome Xp11 (OR 1.28, 95% CI 1.04-1.59) were significantly associated with increased urinary symptoms. In contrast, rs445114 on chromosome 8q24 was marginally associated with decreased urinary symptoms (OR 0.83, 95% CI 0.66-1.01). CONCLUSIONS Of 38 single nucleotide polymorphisms that predispose to prostate cancer we identified 3 that are also associated with a well characterized lower urinary tract symptom phenotype. These single nucleotide polymorphisms may aid in the improved characterization of men with lower urinary tract symptoms/benign prostatic hyperplasia.

Prostate Cancer Risk Alleles and Their Associations with Other Malignancies

OBJECTIVE To determine whether certain risk alleles are responsible for the relationship between prostate cancer (CaP) and other malignancies. CaP has been associated with other common malignancies. Recently, numerous single nucleotide polymorphisms (SNPs) have been associated with CaP susceptibility. METHODS We genotyped 1121 patients with CaP for 36 risk alleles known to be significantly associated with CaP susceptibility and determined their relationships to other malignancies in CaP probands and their first-degree relatives. RESULTS The most common other malignancies in the CaP probands were nonmelanoma skin cancer (13.6%), leukemia (7.3%), melanoma (3.9%), non-Hodgkins lymphoma (0.7%), colorectal cancer (0.6%), and multiple myeloma (0.3%). Among the probands, a significantly increased frequency of leukemia was found in the carriers of SNP rs2736098 (5p15, P = .03) and melanoma in the carriers of either SNP rs1512268 (8p21, P = .006) or SNP rs5759167 (22q13, P = .02). Multiple myeloma was more common in carriers of SNP rs9364554 (6q25, P = .02). The probands who were carriers of SNP rs16901979 (8q24) were significantly more likely to report a family history of melanoma (P = .03), and the probands with a family history of multiple myeloma and non-Hodgkins disease were significantly more likely to be carriers of SNP rs12621278 (2q31, P = .04) and rs6465657 (7q21, P = .02), respectively. CONCLUSION Certain alleles associated with CaP susceptibility might be associated with an increased or a decreased risk of other malignancies in CaP probands and their first-degree relatives. Additional studies are warranted to examine the underlying mechanisms of these SNPs in CaP and other malignancies.

Radical prostatectomy outcomes during prostate-specific antigen era in Ireland compared to a matched American population

Objectives: To examine temporal trends in clinico-pathological outcomes following radical prostatectomy (RP) in Ireland over time, and perform matched comparison of between Ireland and the USA based upon initiation of prostate-specific antigen (PSA) screening. Methods: Between 2000–2010, 651 RPs were carried out at a single institution in Ireland. Clinic-pathologic tumor features were compared to 1302 men treated in the USA from the same time interval (matching on year of diagnosis, 1:2 ratio). As historical comparison, we included a separate group of 150 USA men who underwent RP during the early PSA era (1990–1992). Results: We observed a downward migration in biopsy tumor burden (p=0.002), RP tumor volume (p<0.001) and pathologic stage (p=0.001) in Irish men. In comparison to USA men (same interval), Irish patients had higher percentage Gleason 7–10 prostate cancer (p=0.003), higher median tumor volume (20% versus 8%, p<0.0001), and marginally higher stage disease (pT3 20% versus 16.7%, p=0.06). In comparison to USA men from the early PSA era (1990–1992) Irish men are younger (p<0.001), have more high-grade disease on both biopsy (p=0.001) and RP (p<0.001) specimens. Although there is no significant difference between tumor volumes between both eras, Irish men are more likely to have organ-confined disease (p=0.02). Conclusions: During the past decade of increasing PSA utilization in Ireland, we found evidence of pathological stage migration. In comparison to a USA population, Irish men have worse pathological characteristics, however, in comparison to the early USA PSA era, Irish men are more likely to have organ-confined disease.

2032 POSSIBLE PITFALLS IN USING PROSTATE SPECIFIC ANTIGEN VELOCITY FOR DETECTION OF PROSTATE CANCER

INTRODUCTION AND OBJECTIVES: Prostate Specific Antigen (PSA) is a well-documented marker for prostate cancer (CaP). PSA velocity (PSAV) is a derivative that has been used to increase PSA performance characteristics for CaP detection. Elevated PSAV may be an early sign of underlying CaP, but has somewhat limited sensitivity and specificity. Explanations for false-positive PSAV include missed CaP on biopsy; prostatitis; or assay standardization bias. Reasons for false-negative PSAV include very low volume CaP or high grade CaP (severely de-differentiated cells produce less PSA); prior, resolved prostatitis; or assay standardization bias. METHODS: We assessed patients who underwent prostate biopsy after prior screening with 3 PSA blood tests. PSAV was calculated using linear regression. Elevated PSAV was defined as change in PSA 0.35 ng/mL/yr. After stratifying based on PSAV, we specifically examined: 1) patients with an elevated PSAV but no CaP on biopsy and 2) patients with low PSAV but CaP on biopsy. RESULTS: Between 2003 and 2010, 1358 patients underwent prostate biopsy after previous screening with 3 PSA tests. 106 had PSAV 0.35 ng/mL/yr and negative biopsy. Of these, 62 (58%) had CaP on biopsy at a later date, suggesting negative biopsy at the time of elevated PSAV may have been due to missed early, low volume CaP. 10 (9.4%) biopsies revealed prostatic intraepithelial neoplasia (PIN), also suggesting a possibly missed small CaP. 12 biopsies (11.3%) had signs of prostatitis. In the remaining 22 (20.7%), cause for elevated PSAV was not readily apparent; transient inflammation, prostatic trauma, or assay standardization bias may have played a role. 480 patients with PSAV 0.35 had CaP on biopsy. Of these, 22 (4.6%) had a Gleason 8–10 tumor. 464 were treated with radical prostatectomy. Surgical pathology for 266 (55.4%) revealed total CaP volume 5% of submitted tissue. Of the remaining patients, 30% had possibly slow growing Gleason 6 tumors involving 6–20% of submitted tissue, and 54% had Gleason 7 tumors. In some cases, assay standardization bias or prior resolved prostatitis may have caused the spuriously low PSAV. CONCLUSIONS: Nearly 80% of patients with false-positive PSAV had an easily explained confounder-missed CaP or prostatitis. Nearly 60% of patients with false-positive PSAV were eventually found to have CaP, underscoring the need to closely follow a patient’s PSA despite initial negative biopsy. False-negative tests can often be explained by low volume or high Gleason grade disease, prior resolved prostatitis, or possible PSA assay standardization bias.