Epigenomic regulation during development of testicular germ cell tumor

• Project/Area Number: 19K07444
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Keio University
• Principal Investigator: Arai Eri 慶應義塾大学, 医学部(信濃町), 准教授 (40446547)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 精巣腫瘍 / 精巣胚細胞腫瘍 / セミノーマ / 胎児性癌 / DNAメチル化 / エピジェネティクス / エピゲノム / 分化調節 / 発生分化 / 予後予測 / 病理学

Outline of Research at the Start

ホルマリン固定パラフィン包埋 (FFPE)標本のマイクロダイセクションと網羅的DNAメチル化プロファイリングに基づいて、精巣胚細胞腫瘍の組織亜型分化に伴って変化し各分化段階に寄与するDNAメチル化変化を理解する。Stage IセミノーマをDNAメチル化プロファイルの観点から層別化し、術後補助療法の選択に繋がる再発リスク診断指標を確立する。精巣胚細胞腫瘍の分化調節機構を明らかにし、人為的に介入することで増殖能の低い組織亜型に分化させる分化誘導療法の可能性を探索する。

Outline of Final Research Achievements

Testicular germ cell tumors (TCGTs) are malignant tumors which show intratumoral differentiation mimicking normal development. Each histologic subtype of TGCT had a unique DNA methylation profile, and their DNA methylation profiles were followed a differentiation process. Seminomas were clearly divided into two groups: Sem2, whose DNA methylation profile resembled embryonal carcinoma, and Sem1, whose did not. DNA hypermethylation occurred significantly in regions critical for the maintenance of chromosomal stability in Sem2 compared to Sem1. Genes that show different DNA methylation changes in the two groups of seminomas and that may result in different expression may be useful in diagnosing tumor grade and predicting prognosis of seminoma.

Academic Significance and Societal Importance of the Research Achievements

精巣胚細胞腫瘍は希少がんかつAYA世代に発生するがんである。形態学を基盤とした着想と技術に基づき、精巣胚細胞腫瘍がエピジェネティックに正常発生分化を模倣すること、形態学的に見分けのつかないセミノーマが悪性度の異なる2群に分けられることを明らかにした。これにより、最も頻度の高い精巣胚細胞腫瘍であるセミノーマの悪性度診断や予後予測、精巣胚細胞腫瘍の分化誘導療法の可能性を提示した。

Research Products

• [Journal Article] 肝発がんのエピゲノム・エピジェネティクス (2022)
  • Author(s): 新井恵吏、藏本純子
  • Journal Title: 病理と臨床 Volume: 40 Pages: 123-129
  • Peer Reviewed
• [Journal Article] Non-viral Induction of Transgene-free iPSCs from Somatic Fibroblasts of Multiple Mammalian Species. (2021)
  • Author(s): Yoshimatsu S, Nakajima M, Iguchi A, Sanosaka T, Sato T, Nakamura M, Nakajima R, Arai E, Ishikawa M, Imaizumi K, Watanabe H, Okahara J, Noce T, Takeda Y, Sasaki E, Behr R, Edamura K, Shiozawa S, Okano H.
  • Journal Title: Stem Cell Reports Volume: 16 Issue: 4 Pages: 754-770
  • DOI: 10.1016/j.stemcr.2021.03.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinicopathological impacts of DNA methylation alterations on pancreatic ductal adenocarcinoma: prediction of early recurrence based on genome-wide DNA methylation profiling. (2021)
  • Author(s): Endo Y, Fujimoto M, Ito N, Takahashi Y, Kitago M, Gotoh M, Hiraoka N, Yoshida T, Kitagawa Y, Kanai Y, Arai E.
  • Journal Title: J Cancer Res Clin Oncol Volume: 147 Issue: 5 Pages: 1341-1354
  • DOI: 10.1007/s00432-021-03541-6
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of clinical formalin-fixed paraffin-embedded tissue quality for targeted-bisulfite sequencing. (2021)
  • Author(s): Ohmomo H, Komaki S, Ono K, Sutoh Y, Hachiya T, Arai E, Fujimoto H, Yoshida T, Kanai Y, Sasaki M, Shimizu A.
  • Journal Title: Pathol Int Volume: 71 Issue: 2 Pages: 135-140
  • DOI: 10.1111/pin.13054
  • Peer Reviewed / Open Access
• [Journal Article] DNA hypermethylation of the ZNF132 gene participates in the clinicopathological aggressiveness of 'pan-negative'-type lung adenocarcinomas. (2021)
  • Author(s): Hamada K, Tian Y, Fujimoto M, Takahashi Y, Kohno T, Tsuta K, Watanabe SI, Yoshida T, Asamura H, Kanai Y, Arai E.
  • Journal Title: Carcinogenesis Volume: 42 Issue: 2 Pages: 169-179
  • DOI: 10.1093/carcin/bgaa115
  • Peer Reviewed / Open Access
• [Journal Article] 精巣 (2021)
  • Author(s): 新井恵吏
  • Journal Title: 病理と臨床第39巻臨時増刊号 治療方針を変える病理所見 Volume: 39 Pages: 249-258
  • Peer Reviewed
• [Journal Article] Methylation pattern of urinary DNA as a marker of kidney function decline in diabetes. (2020)
  • Author(s): Marumo T, Hoshino J, Kawarazaki W, Nishimoto M, Ayuzawa N, Hirohama D, Yamanouchi M, Ubara Y, Okaneya T, Fujii T, Yuki K, Atsumi Y, Sato A, Arai E, Kanai Y, Shimosawa T, Fujita T.
  • Journal Title: BMJ Open Diabetes Res Care Volume: 8 Issue: 1 Pages: e001501-e001501
  • DOI: 10.1136/bmjdrc-2020-001501
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cooperative participation of epigenomic and genomic alterations in the clinicopathological diversity of gastric adenocarcinomas: significance of cell adhesion and epithelial-mesenchymal transition-related signaling pathways. (2020)
  • Author(s): Yang M, Arai E, Takahashi Y, Totsuka H, Chiku S, Taniguchi H, Katai H, Sakamoto H, Yoshida T, Kanai Y.
  • Journal Title: Carcinogenesis Volume: 41 Issue: 11 Pages: 1473-1484
  • DOI: 10.1093/carcin/bgaa079
  • Peer Reviewed / Open Access
• [Journal Article] Aberrant DNA methylation results in altered gene expression in non-alcoholic steatohepatitis-related hepatocellular carcinomas. (2020)
  • Author(s): Tian Y, Arai E, Makiuchi S, Tsuda N, Kuramoto J, Ohara K, Takahashi Y, Ito N, Ojima H, Hiraoka N, Gotoh M, Yoshida T, Kanai Y.
  • Journal Title: J Cancer Res Clin Oncol Volume: 146 Issue: 10 Pages: 2461-2477
  • DOI: 10.1007/s00432-020-03298-4
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of diagnostic criteria for upper urinary tract urothelial carcinoma based on genome-wide DNA methylation analysis. (2020)
  • Author(s): Fujimoto M, Arai E, Tsumura K, Yotani T, Yamada Y, Takahashi Y, Maeshima AM, Fujimoto H, Yoshida T, Kanai Y.
  • Journal Title: Epigenetics Volume: 15 Issue: 12 Pages: 1289-1301
  • DOI: 10.1080/15592294.2020.1767374
  • Peer Reviewed / Open Access
• [Journal Article] Simple prediction model for homologous recombination deficiency in breast cancers in adolescents and young adults. (2020)
  • Author(s): Watanabe T, Honda T, Totsuka H, Yoshida M, Tanioka M, Shiraishi K, Shimada Y, Arai E, Ushiama M, Tamura K, Yoshida T, Kanai Y, Kohno T.
  • Journal Title: Breast Cancer Res Treat Volume: 182 Issue: 2 Pages: 491-502
  • DOI: 10.1007/s10549-020-05716-0
  • Peer Reviewed
• [Journal Article] Genome-wide DNA methylation profile of early-onset endometrial cancer: Its correlation with genetic aberrations and comparison with late-onset endometrial cancer. (2019)
  • Author(s): Makabe T, Arai E, Hirano T, Ito N, Fukamachi Y, Takahashi Y, Hirasawa A, Yamagami W, Susumu N, Aoki D, Kanai Y.
  • Journal Title: Carcinogenesis Volume: 印刷中 Issue: 5 Pages: 1-13
  • DOI: 10.1093/carcin/bgz046
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of permutation for cancer risk estimation in the urothelium based on genome-wide DNA methylation analysis. (2019)
  • Author(s): Tsumura K, Arai E, Tian Y, Shibuya A, Nishihara H, Yotani T, Yamada Y, Takahashi Y, Maeshima AM, Fujimoto H, Nakagawa T, Kume H, Homma Y, Yoshida T, Kanai Y.
  • Journal Title: Carcinogenesis Volume: 40 Issue: 11 Pages: 1308-1319
  • DOI: 10.1093/carcin/bgz112
  • Peer Reviewed
• [Journal Article] Establishment of Patient-Derived Organoids and Drug Screening for Biliary Tract Carcinoma. (2019)
  • Author(s): Saito Y, Muramatsu T, Kanai Y, Ojima H, Sukeda A, Hiraoka N, Arai E, Sugiyama Y, Matsuzaki J, Uchida R, Yoshikawa N, Furukawa R, Saito H.
  • Journal Title: Cell Rep Volume: 27 Issue: 4 Pages: 1265-1276
  • DOI: 10.1016/j.celrep.2019.03.088
  • Peer Reviewed / Open Access
• [Journal Article] 精巣胚細胞腫瘍 (2019)
  • Author(s): 新井恵吏, 金井弥栄.
  • Journal Title: 病理と臨床臨時増刊号「肉眼病理 症例から探る鑑別のヒント」 Volume: 37 Pages: 294-296
• [Journal Article] 精巣悪性リンパ腫 (2019)
  • Author(s): 新井恵吏, 金井弥栄.
  • Journal Title: 病理と臨床臨時増刊号「肉眼病理 症例から探る鑑別のヒント」 Volume: 37 Pages: 297-298
• [Journal Article] 精巣胚細胞腫瘍の転移 (2019)
  • Author(s): 新井恵吏, 金井弥栄.
  • Journal Title: 病理と臨床臨時増刊号「肉眼病理 症例から探る鑑別のヒント」 Volume: 37 Pages: 299-301
• [Journal Article] 乳頭状腎細胞癌 (2019)
  • Author(s): 新井恵吏, 金井弥栄.
  • Journal Title: 病理と臨床臨時増刊号「肉眼病理 症例から探る鑑別のヒント」 Volume: 37 Pages: 253-255
• [Presentation] Quantification of DNA methylation for carcinogenic risk estimation in patients with non-alcoholic steatohepatitis (2022)
  • Author(s): Kuramoto J, Arai E, Fujimoto M, Tian Y, Yamada Y, Yotani T, Makiuchi S, Tsuda N, Ojima H, Fukai M, Seki Y, Kasama K, Funahashi N, Udagawa H, Nammo T, Yasuda K, Taketomi A, Kanto T, Kanai Y
  • Organizer: American Association of Cancer Research Annual Meeting 2022
  • Int'l Joint Research
• [Presentation] Cancer-specific glycosylation regulated by epigenomic alteration in renal cell carcinoma (2022)
  • Author(s): Kitazume Y, Arai E, Matsuda A, Kakuda S, Ohara K, Maeshima AM, Yoshida T, Kuno A, Kanai Y
  • Organizer: American Association of Cancer Research Annual Meeting 2022
  • Int'l Joint Research
• [Presentation] Correlations between genome-wide DNA methylation profiles and genomic driver aberrations during multistage lung adenocarcinogenesis (2021)
  • Author(s): Hamada K, Tian Y, Fujimoto M, Takahashi Y, Kohno T, Tsuta K, Watanabe S, Yoshida T, Asamura H, Kanai Y, Arai E
  • Organizer: American Association of Cancer Research Annual Meeting 2021
  • Int'l Joint Research
• [Presentation] うつ病症例の血液検体におけるDNAメチル化異常 (2021)
  • Author(s): 長尾幸子、新井恵吏、田迎、藤本真央、亀山真一、高橋順子、服部功太郎、功刀浩、金井弥栄
  • Organizer: 第110回日本病理学会総会
• [Presentation] エピゲノムを基盤とした分子病理診断による患者の層別化と個別化医療 (2021)
  • Author(s): 新井恵吏
  • Organizer: 第110回日本病理学会総会
  • Invited
• [Presentation] Alteration of protein glycosylation in renal carcinogenesis (2021)
  • Author(s): Kitazume Y, Arai E, Matsuda A, Kakuda S, Ohara K, Maeshima AM, Yoshida T, Kuno A, Kanai Y
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] Personalized medicine development based on pathology (2021)
  • Author(s): Arai E
  • Organizer: 第80回日本癌学会学術総会
  • Invited
• [Presentation] Establishment of diagnostic criteria for upper urinary tract urothelial carcinoma based on genome-wide DNA methylation analysis. (2020)
  • Author(s): Fujimoto M, Arai E, Tsumura K, Yotani T, Yamada Y, Takahashi Y, Maeshima MA, Fujimoto H, Yoshida T, Kanai Y.
  • Organizer: American Association of Cancer Reserach Annual Meeting 2020
  • Int'l Joint Research
• [Presentation] Epigenomic alterations during developmental stages of non-inflammatory hepatocellular carcinoma of unknown etiology. (2020)
  • Author(s): Makichi S, Arai E, Kuramoto J, Tian Y, Tsuda N, Ojima H, Takahashi Y, Hiraoka N, Yoshida T, Kanai Y.
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Epigenetic profiling of endometrial atypical hyperplasia, a precancerous condition of endometrial cancer. (2020)
  • Author(s): Hirano T, Arai E, Makabe T, Hirasawa A, Yamagami W, Susumu N, Tanaka M, Aoki D, Kanai Y.
  • Organizer: 第72回日本産婦人科学会学術講演会
• [Presentation] 尿路上皮がんにおける糖鎖発現異常ならびに糖転移酵素のDNAメチル化異常 (2020)
  • Author(s): 藤本真央，新井恵吏，松田厚志，前島亜希子，藤元博行，久野敦，吉田輝彦，金井弥栄
  • Organizer: 第109回日本病理学会総会
• [Presentation] Genome-wide DNA methylation analysis in nonalcoholic steatohepatitis-related hepatocellular carcinomas. (2019)
  • Author(s): Tian Y, Arai E, Kuramoto J, Makiuchi S, Tsuda N, Ojima H, Fukamachi Y, Takahashi Y, Hiraoka N, Yoshida T, Kanai Y.
  • Organizer: 11th AACR-JCA Joint Conference on Breakthroughs in Cancer Research
  • Int'l Joint Research
• [Presentation] Intratumor DNA methylation heterogeneity reflects differentiation plasticity and malignant progression of human glioblastoma: Amethylome analysis using microdissected specimens. (2019)
  • Author(s): Ohara K, Arai E, Sasaki H, Nakatsukasa M, Yoshida K, Kanai Y.
  • Organizer: 11th AACR-JCA Joint Conference on Breakthroughs in Cancer Research
  • Int'l Joint Research
• [Presentation] Integrated analysis of genetic and epigenetic alterations in gastric carcinomas. (2019)
  • Author(s): Yang M, Arai E, Sakamoto H, Totsuka H, Taniguchi H, Katai H, Yoshida T, Kanai Y.
  • Organizer: American Association of Cancer Reserach Annual Meeting 2019
  • Int'l Joint Research
• [Presentation] 組織学的に特記すべき所見を示さない肝に発生する病因不明の肝細胞がんのエピゲノム異常． (2019)
  • Author(s): 牧内里美，新井恵吏，藏本純子，田迎，津田昇，尾島英知，深町幸宏，高橋順子，平岡伸介，吉田輝彦，金井弥栄．
  • Organizer: 第108回日本病理学会総会
• [Presentation] 非アルコール性脂肪性肝炎由来肝細胞がんに置けるエピゲノム異常． (2019)
  • Author(s): 津田昇，新井恵吏，藏本純子，田迎，牧内里美，尾島英知，高橋順子，平岡伸介，吉田輝彦，金井弥栄．
  • Organizer: 第108回日本病理学会総会
• [Presentation] ゲノム網羅的DNAメチル化プロフファイリングに基づく膵がん早期再発マーカーの開発． (2019)
  • Author(s): 遠藤泰，新井恵吏，平岡伸介，北郷実，北川雄光，吉田輝彦，金井弥栄．
  • Organizer: 第108回日本病理学会総会
• [Presentation] ゲノム網羅的DNAメチル化解析に基づく上部尿路上皮がん診断指標開発． (2019)
  • Author(s): 藤本真央，新井恵吏，津村功志，前島亜希子，藤元博行，吉田輝彦，金井弥栄．
  • Organizer: 第108回日本病理学会総会
• [Presentation] 若年性子宮体がん症例における妊孕性温存治療適応診断マーカーの開発． (2019)
  • Author(s): 平野卓朗，新井恵吏，真壁健，平沢晃，山上亘，進伸幸，青木大輔，金井弥栄．
  • Organizer: 第108回日本病理学会総会
• [Presentation] 腎発がん過程における蛋白の糖鎖修飾変化． (2019)
  • Author(s): 北爪賀子，新井恵吏，松田厚志，角田修一，伊藤菜々子，尾原健太郎，前島亜希子，久野敦，吉田輝彦，金井弥栄．
  • Organizer: 第108回日本病理学会総会
• [Presentation] ゲノム網羅的DNAメチル化解析に基づく尿路上皮がん筋層浸潤予測診断基準の開発． (2019)
  • Author(s): 草苅優，新井恵吏，津村功志，田迎，藤本真央，前島亜希子，藤元博之，吉田輝彦，金井弥栄．
  • Organizer: 第108回日本病理学会総会
• [Presentation] 尿路上皮がんマイクロダイセクション検体におけるゲノム網羅的DNAメチル化解析． (2019)
  • Author(s): 上田優加子，新井恵吏，津村功志，藤本真央，尾原健太郎，前島亜希子，藤元博之，吉田輝彦，金井弥栄．
  • Organizer: 第108回日本病理学会総会
• [Presentation] 腎発がん過程におけるタンパク質の糖鎖修飾変化． (2019)
  • Author(s): 北爪賀子，新井恵吏，松田厚志，角田修一，尾原健太郎，前島亜希子，久野敦，吉田輝彦，金井弥栄．
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] 非アルコール性脂肪性肝炎関連肝発がん過程におけるゲノム網羅的DNAメチル化解析． (2019)
  • Author(s): 田迎，新井恵吏，牧内里美，津田昇，藏本純子，尾島英知，高橋順子，平岡伸介，吉田輝彦，金井弥栄．
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] AYA世代乳がんにおける相同組換え欠損の予測モデルの構築． (2019)
  • Author(s): 渡辺智子，本多隆行，新井恵吏，金井弥栄，白石 航也，河野 隆志．
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] DNAメチル化プロファイルに基づく上部尿路がん診断基準の確立． (2019)
  • Author(s): 藤本真央，新井恵吏，津村功志，前島亜希子，藤元博行，吉田輝彦，金井弥栄．
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] 非炎症性病因不明肝細胞がんの発生過程におけるエピゲノム異常． (2019)
  • Author(s): 牧内里美，新井恵吏，田迎，津田昇，藏本純子，尾島英知，高橋順子，平岡伸介，吉田輝彦，金井弥栄．
  • Organizer: 第78回日本癌学会学術総会
• [Patent(Industrial Property Rights)] 腎がんを診断する又は検出するための方法及びキット (2021)
  • Inventor(s): 久野 敦・梶 裕之・金井 弥栄・新井 恵吏・北爪 賀子他
  • Industrial Property Rights Holder: 久野 敦・梶 裕之・金井 弥栄・新井 恵吏・北爪 賀子他
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2021-171950
  • Filing Date: 2021