Rong Na

Genome-wide association study in Chinese men identifies two new prostate cancer risk loci at 9q31.2 and 19q13.4

Prostate cancer risk–associated variants have been reported in populations of European descent, African-Americans and Japanese using genome-wide association studies (GWAS). To systematically investigate prostate cancer risk–associated variants in Chinese men, we performed the first GWAS in Han Chinese. In addition to confirming several associations reported in other ancestry groups, this study identified two new risk-associated loci for prostate cancer on chromosomes 9q31.2 (rs817826, P = 5.45 × 10−14) and 19q13.4 (rs103294, P = 5.34 × 10−16) in 4,484 prostate cancer cases and 8,934 controls. The rs103294 marker at 19q13.4 is in strong linkage equilibrium with a 6.7-kb germline deletion that removes the first six of seven exons in LILRA3, a gene regulating inflammatory response, and was significantly associated with the mRNA expression of LILRA3 in T cells (P < 1 × 10−4). These findings may advance the understanding of genetic susceptibility to prostate cancer.

A novel Germline mutation in HOXB13 is associated with prostate cancer risk in Chinese men

A rare mutation G84E in HOXB13 was recently identified to be associated with prostate cancer (PCa) in Caucasians. The goal of this study is to test association between HOXB13 genetic variants and PCa risk in Chinese men.

Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death

BACKGROUND Germline mutations in BRCA1/2 and ATM have been associated with prostate cancer (PCa) risk. OBJECTIVE To directly assess whether germline mutations in these three genes distinguish lethal from indolent PCa and whether they confer any effect on age at death. DESIGN, SETTING, AND PARTICIPANTS A retrospective case-case study of 313 patients who died of PCa and 486 patients with low-risk localized PCa of European, African, and Chinese descent. Germline DNA of each of the 799 patients was sequenced for these three genes. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Mutation carrier rates and their effect on lethal PCa were analyzed using the Fishers exact test and Cox regression analysis, respectively. RESULTS AND LIMITATIONS The combined BRCA1/2 and ATM mutation carrier rate was significantly higher in lethal PCa patients (6.07%) than localized PCa patients (1.44%), p=0.0007. The rate also differed significantly among lethal PCa patients as a function of age at death (10.00%, 9.08%, 8.33%, 4.94%, and 2.97% in patients who died ≤ 60 yr, 61-65 yr, 66-70 yr, 71-75 yr, and over 75 yr, respectively, p=0.046) and time to death after diagnosis (12.26%, 4.76%, and 0.98% in patients who died ≤ 5 yr, 6-10 yr, and>10 yr after a PCa diagnosis, respectively, p=0.0006). Survival analysis in the entire cohort revealed mutation carriers remained an independent predictor of lethal PCa after adjusting for race and age, prostate-specific antigen, and Gleason score at the time of diagnosis (hazard ratio=2.13, 95% confidence interval: 1.24-3.66, p=0.004). A limitation of this study is that other DNA repair genes were not analyzed. CONCLUSIONS Mutation status of BRCA1/2 and ATM distinguishes risk for lethal and indolent PCa and is associated with earlier age at death and shorter survival time. PATIENT SUMMARY Prostate cancer patients with inherited mutations in BRCA1/2 and ATM are more likely to die of prostate cancer and do so at an earlier age.

Combination of Rapamycin, CI-1040, and 17-AAG Inhibits Metastatic Capacity of Prostate Cancer via Slug Inhibition

Though prostate cancer (PCa) has slow progression, the hormone refractory (HRCP) and metastatic entities are substantially lethal and lack effective treatments. Transcription factor Slug is critical in regulating metastases of various tumors including PCa. Here we studied targeted therapy against Slug using combination of 3 drugs targeting 3 pathways respectively converging via Slug and further regulating PCa metastasis. Using in vitro assays we confirmed that Slug up-regulation incurred inhibition of E-cadherin that was anti-metastatic, and inhibited Bim-regulated cell apoptosis in PCa. Upstream PTEN/Akt, mTOR, Erk, and AR/Hsp90 pathways were responsible for Slug up-regulation and each of these could be targeted by rapamycin, CI-1040, and 17-AAG respectively. In 4 PCa cell lines with different traits in terms of PTEN loss and androgen sensitivity we tested the efficacy of mono- and combined therapy with the drugs. We found that metastatic capacity of the cells was maximally inhibited only when all 3 drugs were combined, due to the crosstalk between the pathways. 17-AAG decreases Slug expression via blockade of HSP90-dependent AR stability. Combination of rapamycin and CI-1040 diminishes invasiveness more potently in PCa cells that are androgen insensitive and with PTEN loss. Slug inhibited Bim-mediated apoptosis that could be rescued by mTOR/Erk/HSP90 inhibitors. Using mouse models for circulating PCa DNA quantification, we found that combination of mTOR/Erk/HSP90 inhibitors reduced circulating PCa cells in vivo significantly more potently than combination of 2 or monotherapy. Conclusively, combination of mTOR/Erk/Hsp90 inhibits metastatic capacity of prostate cancer via Slug inhibition.

Performance of serum prostate-specific antigen isoform [-2]proPSA (p2PSA) and the prostate health index (PHI) in a Chinese hospital-based biopsy population

The use of serum [‐2]proPSA (p2PSA) and its derivative, the prostate health index (PHI), in detecting prostate cancer (PCa) have been consistently shown to have better performance than total prostate‐specific antigen (tPSA) in discriminating biopsy outcomes in western countries. However, little is known about their performance in Chinese men. Our objective is to test the performance of p2PSA and PHI and their added value to tPSA in discriminating biopsy outcomes in Chinese men.

Prediction of prostate cancer from prostate biopsy in Chinese men using a genetic score derived from 24 prostate cancer risk-associated SNPs.

Twenty‐four prostate cancer (PCa) risk‐associated single nucleotide polymorphisms (SNPs) in Chinese men have been cataloged. We evaluated whether these SNPs can independently predict outcomes of prostate biopsy, and improve the predictive performance of existing clinical variables.

Genetic Score Is an Objective and Better Measurement of Inherited Risk of Prostate Cancer than Family History

Positive family history of prostate cancer (PCa) has been consistently associated with increased PCa risk [1]. It is widely used in clinical practice and is a strong indication, together with elevated prostate-specific antigen (PSA) levels, for prostate biopsy. An advantage of family history is that the information can be obtained without a laboratory test. However, rather than providing a direct measurement of the patient’s inherited risk, family history captures PCa information of the patient’s relatives. Consequently, family history is influenced by family size, age and survival status of male relatives, recall ability, family communication, and prevalence of the disease in populations. Several scenarios highlight these limitations: (1) Brothers are estimated to have exactly the same inherited risk for PCa based on family history, but in fact they share only 50% of their genetic makeup on average; (2) family history may change from negative to positive; and (3) in populations with low prevalence of PCa, such as among Asians, positive family history is rare and thus is not informative. Genetic score is another recently proposed measurement of inherited risk for PCa. It is calculated based on genotypes of multiple PCa risk-associated genetic markers, weighted by their relative risk (RR) to PCa. A genetic score of 1.0 indicates an average risk in the general population. Genetic score is now feasible because approximately 40 PCa risk-associated single nucleotide polymorphisms (SNPs) have been identified from rigorously designed genomewide association studies [2]. Risk alleles of these SNPs are common in the white population, and although they confer modest risk to PCa individually, they have a stronger cumulative effect on PCa [3,4]. Importantly, all published studies to date demonstrate that genetic score based on combinations of these SNPs is informative in measuring individual risk and can serve as an independent predictor of PCa [5,6]. Genetic score requires a laboratory test; however, this is a trivial task with high-throughput and low-cost genotyping technology. For example, a panel of 33 PCa risk-associated SNPs can be assayed in 1 d from a blood or saliva sample at a cost similar to a PSA test [6]. The goal of this study was to compare, head-to-head, these two measurements of inherited risk for PCa in several study populations with different study designs (clinical trials, observational prospective cohort, and case-control) and diverse geographic regions (North America, Western Europe, Eastern Europe, and Sweden). In all study populations, family history of PCa in first- and second-degree relatives was obtained by questionnaire, and genetic score was calculated from 33 PCa risk-associated SNPs, as detailed elsewhere [6]. We found that the proportion of men with a positive family history of PCa differed considerably among study populations, whereas mean genetic score was similar (Fig. 1a). For example, among three geographic regions from the single clinical trial, Reduction by Dutasteride of Prostate Cancer Events (REDUCE), the proportion of positive family history was significantly different: 4.2%, 10.9%, and 22.8% in Eastern Europe, Western Europe, and North America, respectively (p < 0.001). These large differences were found even though the same protocol was used to obtain family history information. Furthermore, even for the two study populations from the same country (Sweden), the percentage of men with a positive family history differed substantially: 25.8% in a prospective cohort of patients that underwent prostate biopsy (Stockholm-1) and 15.5% in a case-control study (Cancer of the Prostate in Sweden [CAPS]) (p < 0.001). In contrast, the mean genetic score was similar among different geographic regions within the REDUCE study (0.95–0.97, p = 0.88) and between the two different studies in Sweden (1.06–1.10, p = 0.02). Considering that genetic susceptibility to PCa is likely to be similar among these white populations, the volatile estimates of inherited risk obtained from family history expose the weakness of this measurement. In contrast, genetic score is a more reliable measurement of inherited PCa risk. Fig. 1 (a) The distribution of family history and genetic score in five study populations: (left panel) the proportion of men with one family member or more affected with prostate cancer (PCa); (right panel) the mean genetic score. A chi-square test was used ... The effects of family history and genetic score on PCa risk are presented in Figure 1b. The RR of family history for PCa differed considerably among geographic regions within the REDUCE trial: 1.20, 1.53, and 1.91 in North America, Eastern Europe, and Western Europe, respectively. Similarly, the RR of family history for PCa differed significantly between the two studies in Sweden: RR was 1.60 in the prospective Stockholm-1 study and 2.24 in the case-control CAPS study. The differences in RR estimates among these five study populations were statistically significant (p = 0.01). In contrast, the RR estimates of genetic score for PCa were similar among these five study populations, from 1.69 to 2.04 (p = 0.16). These results suggest that genetic score has better precision for measuring the effect of inherited risk on PCa risk than family history. The performance of family history and/or genetic score in discriminating PCa status in five study populations is shown in Table 1. The area under the receiver operating characteristic curve (AUC) of genetic score for predicting positive PCa biopsy was significantly higher (0.58–0.62) than family history (0.51–0.55) in each study population (p < 0.05). Furthermore, in each of the five study populations, the AUC of combined genetic score and family history was considerably higher than that of family history alone but was similar to that of genetic score alone. These results demonstrate that genetic score has a better predictive performance for biopsy outcome (PCa) than family history, and family history alone is not sufficient to capture inherited risk for PCa. Table 1 Performance of predicting prostate cancer outcome using family history and genetic score in five study populations It is possible that volatile estimates of positive family history and its effect on PCa risk observed in this study may be due to heterogeneous ascertainment of family history among different studies; this highlights the limitation of family history measurement. Collection of family history in real-world clinical settings is likely even more heterogeneous. It is expected that additional PCa risk-associated SNPs may be identified in the future, and these SNPs can be incorporated into genetic score to further improve its predictive performance for PCa. However, due to the polygenic inheritance of PCa and the likelihood that common PCa risk-associated SNPs with the strongest effect have already been identified, the potential for improvement over the current set of SNPs is expected to be small [7]. In contrast, rare and high-penetrance PCa risk-associated mutations may significantly improve the predictive performance of PCa in small subsets of men, as demonstrated for the newly identified G84E mutation of the homeobox B13 (HOXB13) gene [8]. In conclusion, if family history is accepted and used by urologists and primary care physicians to assess an individual’s risk for PCa, we believe that genetic score should be added to family history to improve assessment of inherited risk for PCa.

Evaluation of reported prostate cancer risk‐associated SNPs from genome‐wide association studies of various racial populations in Chinese men

Several genome‐wide association studies (GWAS) of prostate cancer (PCa) have identified many single nucleotide polymorphisms (SNPs) that are significantly associated with PCa risk in various racial groups. The objective of this study is to evaluate which of these SNPs are associated with PCa risk in Chinese men and estimate their strength of association.

Plateau effect of prostate cancer risk-associated SNPs in discriminating prostate biopsy outcomes.

Additional prostate cancer (PCa) risk‐associated single nucleotide polymorphisms (SNPs) continue to be identified. It is unclear whether addition of newly identified SNPs improves the discriminative performance of biopsy outcomes over previously established SNPs.

Large-scale association analysis in Asians identifies new susceptibility loci for prostate cancer

Genome-wide association studies (GWAS) have identified ∼100 genetic loci associated with prostate cancer risk. Less than a dozen of these loci were initially identified from GWAS in two Asian populations, likely because of smaller sample sizes of these individual GWAS in Asians. Here, we conduct a large-scale meta-analysis of two GWAS from the Japanese population (1,583 cases and 3,386 controls) and the Chinese population (1,417 cases and 1,008 controls), followed by replication in three independent sample sets. We identify two independent susceptibility loci for prostate cancer at 11p15.4 (rs12791447, P=3.59 × 10−8; PPFIBP2) and 14q23.2 (rs58262369, P=6.05 × 10−10; ESR2). The mRNA levels of PPFIBP2 and ESR2 are differentially expressed in prostate tumours and paired normal tissues. Our study adds two new loci to the limited number of prostate cancer risk-associated variants in Asians and provides important insight into potential biological mechanisms of prostate cancer.