Development of glycan-related cfDNA markers to predict therapeutic efficacy in castration-resistant prostate cancer

• Project/Area Number: 20K18107
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56030:Urology-related
• Research Institution: Hirosaki University
• Principal Investigator: Hamano Itsuto 弘前大学, 医学研究科, 客員研究員 (40868064)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2022: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
• Keywords: 前立腺癌 / 糖鎖解析 / バイオマーカー / 去勢抵抗性 / cell-free DNA / 去勢抵抗性前立腺癌 / 糖転移酵素 / アンドロゲン受容体

Outline of Research at the Start

去勢抵抗性前立腺癌（CRPC）は予後不良であり、かつその病勢を測るバイオマーカーが確立されていない。本研究では、CRPCにおけるCell free DNA（cfDNA）を抽出し、去勢抵抗性獲得に関与しているアンドロゲン受容体遺伝子増幅（AR-amp）やグルココルチコイド受容体増幅（GR-amp）に加えGCNT2、β４GALNT4、C2GNT1といった糖転移酵素の発現、更にはPTENやTP53変異を定量的に解析することで、CRPCの去勢抵抗性獲得に関わる複雑な分子機構を解明し、新規バイオマーカーを開発することを目的とする。

Outline of Final Research Achievements

Castration-resistant prostate cancer (CRPC) is associated with a poor prognosis, and there is a need to develop biomarkers. In this study, we analyzed biomarkers involved in the acquisition of castration resistance from cfDNA, and found that total cfDNA and androgen receptor amplification were significantly increased in the CRPC group compared with non-CRPC. MYCN, AURKA, and NCOR2, which are considered to be associated with the acquisition of castration resistance, were not significantly altered. However, expression of glycosyltransferase β4GALNT4 was significantly decreased in the CRPC group, indicating a poor prognosis. The expression level of glycosyltransferases may be a prognostic factor for CRPC.

Academic Significance and Societal Importance of the Research Achievements

去勢抵抗性前立腺癌（CRPC）は予後不良であるため、その病勢を測るバイオマーカー開発が求められている。本研究では、cfDNAから去勢抵抗性獲得に関与しているバイオマーカーを解析した。本研究では、CRPCと非CRPCを比較し、CRPC群でcfDNA総量、アンドロゲン受容体増幅が有意に増加、糖転移酵素β4GALNT4の発現が有意に低下しており、予後不良であった。本研究から糖転移酵素の発現量はCRPCの予後因子である可能性が示唆されたことより、研究成果の学術的意義や社会的意義は大きいと思われる。

Research Products

• [Journal Article] Combination of Muscle Quantity and Quality Is Useful to Assess the Necessity of Surveillance after a 5-Year Cancer-Free Period in Patients Who Undergo Radical Cystectomy: A Multi-Institutional Retrospective Study. (2023)
  • Author(s): Fujita N, Momota M, Horiguchi H, Hamano I, Mikami J, Hatakeyama S, Ito H, Yoneyama T, Hashimoto Y, Nishimura S, Yoshikawa K, Ohyama C.
  • Journal Title: Cancers (Basel) Volume: 15(5) Issue: 5 Pages: 1489-1489
  • DOI: 10.3390/cancers15051489
  • Peer Reviewed / Open Access
• [Journal Article] Relationship of frailty with treatment modality selection in patients with muscle-invasive bladder cancer (FRART-BC study) (2021)
  • Author(s): Iwamura Hiromichi、Hatakeyama Shingo、Momota Masaki、Kojima Yuta、Narita Takuma、Okamoto Teppei、Fujita Naoki、Hamano Itsuto、Togashi Kyou、Hamaya Tomoko、Yoneyama Tohru、Yamamoto Hayato、Yoneyama Takahiro、Hashimoto Yasuhiro、Ohyama Chikara
  • Journal Title: Translational Andrology and Urology Volume: 10 Issue: 3 Pages: 1143-1151
  • DOI: 10.21037/tau-20-1351
  • Peer Reviewed / Open Access
• [Journal Article] Prognostic significance of total plasma cell-free DNA level and androgen receptor amplification in castration-resistant prostate cancer (2021)
  • Author(s): Kubota Yuka、Hatakeyama Shingo、Yoneyama Tohru、Yoneyama Mihoko Sutoh、Hamano Itsuto、Konishi Sakae、Okamoto Teppei、Yamamoto Hayato、Yoneyama Takahiro、Hashimoto Yasuhiro、Ohyama Chikara
  • Journal Title: World Journal of Urology Volume: 39 Issue: 9 Pages: 3265-3271
  • DOI: 10.1007/s00345-021-03649-x
  • Peer Reviewed
• [Journal Article] Oncologic and patient-reported outcomes after robot-assisted radical prostatectomy in men aged >75 years (2021)
  • Author(s): Togashi Kyo、Hatakeyama Shingo、Okamoto Teppei、Kojima Yuta、Iwamura Hiromichi、Fujita Naoki、Narita Takuma、Hamano Itsuto、Hamaya Tomoko、Yoneyama Tohru、Yamamoto Hayato、Yoneyama Takahiro、Hashimoto Yasuhiro、Ohyama Chikara
  • Journal Title: Urologic Oncology: Seminars and Original Investigations Volume: - Issue: 10 Pages: 729.e17-729.e25
  • DOI: 10.1016/j.urolonc.2020.12.001
  • Peer Reviewed
• [Journal Article] Editorial Comment (2021)
  • Author(s): Hatakeyama Shingo、Hamano Itsuto、Ohyama Chikara
  • Journal Title: Journal of Urology Volume: 205 Issue: 1 Pages: 107-107
  • DOI: 10.1097/ju.0000000000001325.01
  • Peer Reviewed
• [Journal Article] The effect of frailty on the quality of life and lower urinary symptoms following robot-assisted radical prostatectomy: A longitudinal analysis (FRARP-QL Study) (2021)
  • Author(s): Togashi Kyo、Hatakeyama Shingo、Kojima Yuta、Momota Masaki、Narita Takuma、Iwamura Hiromichi、Hamano Itsuto、Hamaya Tomoko、Fujita Naoki、Okamoto Teppei、Yoneyama Tohru、Yamamoto Hayato、Yoneyama Takahiro、Hashimoto Yasuhiro、Ohyama Chikara
  • Journal Title: Urologic Oncology: Seminars and Original Investigations Volume: 39 Issue: 3 Pages: 192.e7-192.e14
  • DOI: 10.1016/j.urolonc.2020.08.010
  • Peer Reviewed
• [Journal Article] Effect of frailty and comorbidity on surgical contraindication in patients with localized prostate cancer (FRART-PC Study) (2021)
  • Author(s): Kodama Hirotake、Hatakeyama Shingo、Momota Masaki、Togashi Kyo、Hamaya Tomoko、Hamano Itsuto、Fujita Naoki、Kojima Yuta、Okamoto Teppei、Yoneyama Tohru、Yamamoto Hayato、Yoshikawa Kazuaki、Yoneyama Takahiro、Hashimoto Yasuhiro、Ohyama Chikara
  • Journal Title: Urologic Oncology: Seminars and Original Investigations Volume: 39 Issue: 3 Pages: 191.e1-191.e8
  • DOI: 10.1016/j.urolonc.2020.06.019
  • Peer Reviewed / Open Access
• [Journal Article] Overactive Bladder and Sleep Disturbance Have a Significant Effect on Indoor Falls: Results From the Community Health Survey in Japan． (2021)
  • Author(s): Konishi S, Hatakeyama S, Imai A, Kumagai M, Okita K, Togashi K, Hamaya T, Hamano I, Okamoto T, Iwamura H, Yamamoto H, Yoneyama T, Hashimoto Y, Ohyama C
  • Journal Title: Low Urin Tract Symptoms. Volume: 13(1) Issue: 1 Pages: 56-63
  • DOI: 10.1111/luts.12326
  • Peer Reviewed / Open Access
• [Journal Article] Utility of plasma cell‐free DNA in metastatic castration‐resistant prostate cancer (2020)
  • Author(s): Hamano Itsuto、Hatakeyama Shingo、Hamaya Tomoko、Togashi Kyo、Okamoto Teppei、Yamamoto Hayato、Yoneyama Tohru、Yoneyama Takahiro、Hashimoto Yasuhiro、Ohyama Chikara
  • Journal Title: IJU Case Reports Volume: 3 Issue: 4 Pages: 141-144
  • DOI: 10.1002/iju5.12172
  • Peer Reviewed
• [Journal Article] A Longitudinal Study of Bidirectional Relationships between Sleep Disorder and Frequency of Nocturia: Results from the Iwaki Health Promotion Project (2020)
  • Author(s): Konishi Sakae、Hatakeyama Shingo、Imai Atsushi、Kumagai Mika、Okamoto Teppei、Okita Kazutaka、Hamano Itsuto、Narita Takuma、Kojima Yuta、Iwamura Hiromichi、Yamamoto Hayato、Yoneyama Tohru、Yoneyama Takahiro、Hashimoto Yasuhiro、Ohyama Chikara
  • Journal Title: Urologia Internationalis Volume: - Issue: 3-4 Pages: 1-8
  • DOI: 10.1159/000509976
  • Peer Reviewed
• [Journal Article] Association between the baseline frailty and quality of life in patients with prostate cancer (FRAQ-PC study) (2020)
  • Author(s): Hamaya Tomoko、Hatakeyama Shingo、Momota Masaki、Narita Takuma、Iwamura Hiromichi、Kojima Yuta、Hamano Itsuto、Fujita Naoki、Okamoto Teppei、Togashi Kyo、Yoneyama Tohru、Yamamoto Hayato、Yoneyama Takahiro、Hashimoto Yasuhiro、Ohyama Chikara
  • Journal Title: International Journal of Clinical Oncology Volume: 26 Issue: 1 Pages: 199-206
  • DOI: 10.1007/s10147-020-01798-4
  • Peer Reviewed
• [Journal Article] Geriatric 8 screening of frailty in patients with prostate cancer (2020)
  • Author(s): Momota Masaki、Hatakeyama Shingo、Soma Osamu、Tanaka Toshikazu、Hamano Itsuto、Fujita Naoki、Okamoto Teppei、Yoneyama Tohru、Yamamoto Hayato、Imai Atsushi、Yoshikawa Kazuaki、Yoneyama Takahiro、Hashimoto Yasuhiro、Ohyama Chikara
  • Journal Title: International Journal of Urology Volume: 27 Issue: 8 Pages: 642-648
  • DOI: 10.1111/iju.14256
  • Peer Reviewed / Open Access
• [Journal Article] The Impact of Microalbuminuria on Overactive Bladders: Results From a Community-Based Four-Year Longitudinal Study in Japan (2020)
  • Author(s): Okamoto T, Hatakeyama S, Ando M, Songee J, Imai A, Hamano I, Fujita N, Okamoto A, Yamamoto H, Yoneyama T, Yoneyama T, Hashimoto Y, Ohyama C
  • Journal Title: Int J Urol. Volume: 39(5) Issue: 5 Pages: 1567-1575
  • DOI: 10.1002/nau.24405
  • Peer Reviewed / Open Access
• [Journal Article] Frailty is significantly associated with the type of urinary diversion in patients with muscle-invasive bladder cancer. (2020)
  • Author(s): Okita K, Hatakeyama S, Momota M, Soma O, Hamano I, Tanaka T, Iwamura H, Fujita N, Okamoto T, Yamamoto H, Yoneyama T, Hashimoto Y, Yoshikawa K, Kawaguchi T, Ohyama C
  • Journal Title: Int J Urol. Volume: 27(8) Issue: 8 Pages: 649-654
  • DOI: 10.1111/iju.14263
  • Peer Reviewed / Open Access
• [Journal Article] Living Kidney Transplantation From Marginal Donors Presents Feasible Donor Renal Function Despite Inferior Recipient Renal Function (2020)
  • Author(s): Hamano Itsuto、Hatakeyama Shingo、Fujita Takeshi、Murakami Reiichi、Hamaya Tomoko、Togashi Kyo、Suzuki Yuichiro、Yamamoto Hayato、Yoneyama Tohru、Yoneyama Takahiro、Hashimoto Yasuhiro、Narumi Shunji、Tomita Hirofumi、Ohyama Chikara
  • Journal Title: Transplantation Proceedings Volume: 52 Issue: 6 Pages: 1723-1728
  • DOI: 10.1016/j.transproceed.2020.01.157
  • Peer Reviewed
• [Journal Article] Outcome of ABO Blood Type Incompatible Living-Related Donor Kidney Transplantation Under a Contemporary Immunosuppression Strategy in Japan (2020)
  • Author(s): Hamano Itsuto、Hatakeyama Shingo、Fujita Takeshi、Murakami Reiichi、Hamaya Tomoko、Togashi Kyo、Suzuki Yuichiro、Yamamoto Hayato、Yoneyama Tohru、Yoneyama Takahiro、Hashimoto Yasuhiro、Narumi Shunji、Tomita Hirofumi、Ohyama Chikara
  • Journal Title: Transplantation Proceedings Volume: 52 Issue: 6 Pages: 1700-1704
  • DOI: 10.1016/j.transproceed.2020.01.152
  • Peer Reviewed
• [Journal Article] Survey on attitudes toward brain-dead and living donor transplantation in medical students: a cross-sectional study in Japan. (2020)
  • Author(s): Hamano I, Hatakeyama S, Yamamoto H, Fujita T, Murakami R, Shimada M, Imai A, Yoneyama T, Yoneyama T, Hashimoto Y, Saitoh H, Suzuki T, Tomita H, Ohyama C
  • Journal Title: Clin Exp Nephrol. Volume: - Issue: 7 Pages: 638-645
  • DOI: 10.1007/s10157-020-01878-9
  • Peer Reviewed