Shusuke Akamatsu

Genome-wide association study identifies five new susceptibility loci for prostate cancer in the Japanese population

Prostate cancer is one of the most common malignancies in males throughout the world, and its incidence is increasing in Asian countries. We carried out a genome-wide association study and replication study using 4,584 Japanese men with prostate cancer and 8,801 control subjects. From the thirty-one associated SNPs reported in previous genome-wide association studies in European populations, we confirmed the association of nine SNPs at P < 1.0 × 10−7 and ten SNPs at P < 0.05 in the Japanese population. The remaining 12 SNPs showed no association (P > 0.05). In addition, we report here five new loci for prostate cancer susceptibility, at 5p15 (λ-corrected probability PGC = 3.9 × 10−18), GPRC6A/RFX6 (PGC = 1.6 × 10−12), 13q22 (PGC = 2.8 × 10−9), C2orf43 (PGC = 7.5 × 10−8) and FOXP4 (PGC = 7.6 × 10−8). These findings advance our understanding of the genetic basis of prostate carcinogenesis and also highlight the genetic heterogeneity of prostate cancer susceptibility among different ethnic populations.

Association of a novel long non-coding RNA in 8q24 with prostate cancer susceptibility

Recent genome‐wide association studies reported strong and reproducible associations of multiple genetic variants in a large “gene‐desert” region of chromosome 8q24 with susceptibility to prostate cancer (PC). However, the causative or functional variants of these 8q24 loci and their biological mechanisms associated with PC susceptibility remain unclear and should be investigated. Here, focusing on its most centromeric region (so‐called Region 2: Chr8: 128.14‐128.28 Mb) among the multiple PC loci on 8q24, we performed fine mapping and re‐sequencing of this critical region and identified SNPs (single nucleotide polymorphisms) between rs1456315 and rs7463708 (chr8: 128,173,119‐128,173,237 bp) to be most significantly associated with PC susceptibility (P = 2.00 × 10−24, OR = 1.74, 95% confidence interval = 1.56–1.93). Importantly, we show that this region was transcribed as a ∼13 kb intron‐less long non‐coding RNA (ncRNA), termed PRNCR1 (prostate cancer non‐coding RNA 1), and PRNCR1 expression was upregulated in some of the PC cells as well as precursor lesion prostatic intraepithelial neoplasia. Knockdown of PRNCR1 by siRNA attenuated the viability of PC cells and the transactivation activity of androgen receptor, which indicates that PRNCR1 could be involved in prostate carcinogenesis possibly through androgen receptor activity. These findings could provide a new insight in understanding the pathogenesis of genetic factors for PC susceptibility and prostate carcinogenesis. (Cancer Sci 2011; 102: 245–252)

Common variants at 11q12, 10q26 and 3p11.2 are associated with prostate cancer susceptibility in Japanese

We have previously reported multiple loci associated with prostate cancer susceptibility in a Japanese population using a genome-wide association study (GWAS). To identify additional prostate cancer susceptibility loci, we genotyped nine SNPs that were nominally associated with prostate cancer (P < 1 × 10−4) in our previous GWAS in three independent studies of prostate cancer in Japanese men (2,557 individuals with prostate cancer (cases) and 3,003 controls). In a meta-analysis of our previous GWAS and the replication studies, which included a total of 7,141 prostate cancer cases and 11,804 controls from a single ancestry group, three new loci reached genome-wide significance on chromosomes 11q12 (rs1938781; P = 1.10 × 10−10; FAM111A-FAM111B), 10q26 (rs2252004; P = 1.98 × 10−8) and 3p11.2 (rs2055109; P = 3.94 × 10−8). We also found suggestive evidence of association at a previously reported prostate cancer susceptibility locus at 2p11 (rs2028898; P = 1.08 × 10−7). The identification of three new susceptibility loci should provide additional insight into the pathogenesis of prostate cancer and emphasizes the importance of conducting GWAS in diverse populations.

Plasma low-molecular-weight proteome profiling identified neuropeptide-Y as a prostate cancer biomarker polypeptide.

In prostate cancer diagnosis, PSA test has greatly contributed to the early detection of prostate cancer; however, expanding overdiagnosis and unnecessary biopsies have emerged as serious issues. To explore plasma biomarkers complementing the specificity of PSA test, we developed a unique proteomic technology QUEST-MS (Quick Enrichment of Small Targets for Mass Spectrometry). The QUEST-MS method based on 96-well formatted sequential reversed-phase chromatography allowing efficient enrichment of <20 kDa proteins quickly and reproducibly. Plasma from 24 healthy controls, 19 benign prostate hypertrophy patients, and 73 prostate cancer patients were purified with QUEST-MS and analyzed by LC/MS/MS. Among 153 057 nonredundant peptides, 189 peptides showed prostate cancer specific detection pattern, which included a neurotransmitter polypeptide neuropeptide-Y (NPY). We further validated the screening results by targeted multiple reaction monitoring technology using independent sample set (n = 110). The ROC curve analysis revealed that logistic regression-based combination of NPY, and PSA showed 81.5% sensitivity and 82.2% specificity for prostate cancer diagnosis. Thus QUEST-MS technology allowed comprehensive and high-throughput profiling of plasma polypeptides and had potential to effectively uncover very low abundant tumor-derived small molecules, such as neurotransmitters, peptide hormones, or cytokines.

IRX4 at 5p15 Suppresses Prostate Cancer Growth through the Interaction with Vitamin D Receptor, Conferring Prostate Cancer Susceptibility

Recent genome-wide association studies (GWAS) identified a number of prostate cancer (PC) susceptibility loci, but most of their functional significances are not elucidated. Through our previous GWAS for PC in a Japanese population and subsequent resequencing and fine mapping, we here identified that IRX4 (Iroquois homeobox 4), coding Iroquois homeobox 4, is a causative gene of the PC susceptibility locus (rs12653946) at chromosome 5p15. IRX4 is expressed specifically in the prostate and heart, and quantitative expression analysis revealed a significant association between the genotype of rs12653946 and IRX4 expression in normal prostate tissues. Knockdown of IRX4 in PC cells enhanced their growth and IRX4 overexpression in PC cells suppressed their growth, indicating the functional association of IRX4 with PC and its tumor suppressive effect. Immunoprecipitation confirmed its protein-protein interaction to vitamin D receptor (VDR), and we found a significant interaction between IRX4 and VDR in their reciprocal transcriptional regulation. These findings indicate that the PC-susceptibility locus represented by rs12653946 at 5p15 is likely to regulate IRX4 expression in prostate which could suppress PC growth by interacting with the VDR pathway, conferring to PC susceptibility.

Prostate cancer genomics, biology, and risk assessment through genome-wide association studies.

Prostate cancer (PC) is the most common malignancy observed in men. It is evident that genetic factors play some important roles in PC etiology. Recently, genome‐wide association studies in diverse ethnic groups have identified more than 40 germline variants of various genes or chromosomal loci that are significantly associated with PC susceptibility, including multiple 8q24 loci, prostate‐specific genes, metabolic and hormone‐related genes, and many regions where no coding gene is annotated. However, there are only a few variants or genes for which biological significance or functions have been elucidated so far. The greatest challenge related to genome‐wide association studies loci in prostate genomics is to understand the functional consequences of these PC‐associated loci and their involvement in PC biology and carcinogenesis. There have been attempts to determine PC risk estimations by combining multiple PC‐associated variants for clinical tests, and these can identify a very minor population with high risk of PC. However, they cannot distinguish risk of aggressive PC from that of non‐aggressive PC. Further identification of PC‐susceptibility loci in larger genome‐wide association studies cohorts and biological insights gained from such functional analyses have the potential to translate into clinical benefits, including the development of reliable biomarkers, risk estimation, and effective strategies for screening and prevention of PC. (Cancer Sci 2012; 103: 607–613)

Primary large cell neuroendocrine carcinoma of the urinary bladder

Large cell neuroendocrine carcinoma (LCNEC) of the urinary bladder is rare. It is a type of neuroendocrine carcinoma morphologically distinct from small cell carcinoma. We report here a case of primary LCNEC of the urinary bladder. We observed a very large invasive tumor, which was not able to be detected three months previously by cystoscopy or computed tomography. The tumor cells morphologically and immunohistochemically resembled that of pulmonary LCNEC. With prompt cystoprostatectomy and chemotherapy, the patient is free of disease 16 months after diagnosis. Although LCNEC is usually very aggressive, it may be controlled by early diagnosis and treatment.

Reproducibility, performance, and clinical utility of a genetic risk prediction model for prostate cancer in Japanese.

Prostate specific antigen (PSA) is widely used as a diagnostic biomarker for prostate cancer (PC). However, due to its low predictive performance, many patients without PC suffer from the harms of unnecessary prostate needle biopsies. The present study aims to evaluate the reproducibility and performance of a genetic risk prediction model in Japanese and estimate its utility as a diagnostic biomarker in a clinical scenario. We created a logistic regression model incorporating 16 SNPs that were significantly associated with PC in a genome-wide association study of Japanese population using 689 cases and 749 male controls. The model was validated by two independent sets of Japanese samples comprising 3,294 cases and 6,281 male controls. The areas under curve (AUC) of the model were 0.679, 0.655, and 0.661 for the samples used to create the model and those used for validation. The AUCs were not significantly altered in samples with PSA 1–10 ng/ml. 24.2% and 9.7% of the patients had odds ratio <0.5 (low risk) or >2 (high risk) in the model. Assuming the overall positive rate of prostate needle biopsies to be 20%, the positive biopsy rates were 10.7% and 42.4% for the low and high genetic risk groups respectively. Our genetic risk prediction model for PC was highly reproducible, and its predictive performance was not influenced by PSA. The model could have a potential to affect clinical decision when it is applied to patients with gray-zone PSA, which should be confirmed in future clinical studies.

Exploring the optimal sequence of abiraterone and enzalutamide in patients with chemotherapy-naïve castration-resistant prostate cancer: The Kyoto-Baltimore collaboration

To evaluate and compare the efficacy of sequential treatment with abiraterone followed by enzalutamide or vice versa for castration‐resistant prostate cancer.

Prognostic and predictive biomarkers in prostate cancer: Latest evidence and clinical implications

Advances in our understanding of the mechanisms driving castration-resistant prostate cancer have promoted the development of several new drugs including androgen receptor-directed therapy and chemotherapy. Concomitant docetaxel treatment at the beginning of hormonal therapy for metastatic prostate cancer has resulted in longer overall survival than with hormonal therapy alone. Elucidating an appropriate treatment sequence using these therapies is important for maximizing clinical benefit in castration-sensitive and castration-resistant prostate cancer patients. The development of advanced high-throughput ‘omics’ technology has enabled the use of novel markers to guide prognosis and treatment of this disease. In this review, we outline the genomic landscape of prostate cancer and the molecular mechanisms of castration-resistant progression, and how these affect the development of new drugs, and their clinical implications for selecting treatment sequence. We also discuss many of the potential tissue-based or liquid biomarkers that may soon enter clinical use, with the hope that several of these prognostic or predictive markers will guide precision medicine for prostate cancer patients in the near future.