Identification of molecular pathway aberrations in uterine serous carcinoma by genome-wide analyses.

• Project/Area Number: 23592450
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Obstetrics and gynecology
• Research Institution: Shimane University
• Principal Investigator: MIYAZAKI Kohji 島根大学, 医学部, 教授 (50145322)
• Co-Investigator(Kenkyū-buntansha): NAKAYAMA Kentaro 島根大学, 医学部, 講師 (70346401)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 子宮体癌 / ゲノムワイド / がん遺伝子 / がん抑制遺伝子 / 国際情報交換 / TypeII 体癌 / 遺伝子増幅 / 癌遺伝子 / 国際情報交流

Research Abstract

We analyzed the genomes of uterine serous carcinoma samples to better understand the molecular genetic characteristics of this cancer. Whole-exome sequencing was performed on 10 uterine serous carcinomas and the matched normal blood or tissue samples. We found frequent somatic mutations in TP53 (81.6%), PIK3CA (23.7%), FBXW7 (19.7%), and PPP2R1A (18.4%) among the 76 uterine serous carcinomas examined. All nine serous carcinomas that had an associated serous endometrial intraepithelial carcinoma had concordant PIK3CA, PPP2R1A, and TP53 mutation status between uterine serous carcinoma and the concurrent serous endometrial intraepithelial carcinoma component. DNA copy number analysis revealed frequent genomic amplification of the CCNE1 locus and deletion of the FBXW7 locus. Nearly half of these uterine serous carcinomas (48%) harbored PIK3CA mutation and/or PIK3CA amplification.

Research Products

• [Journal Article] ESR1 gene amplification in endometrial carcinomas : A clinicopathological analysis (2013)
  • Author(s): Rahman MT, Nakayama K, Rahman M, Ishikawa M, Katagiri H, Katagiri A, Ishibashi T, Sato E, Iida K, Nakayama N, Ishikawa N, Miyazaki K
  • Journal Title: Anticancer Res Volume: 33 Pages: 3775-3781
• [Journal Article] KRAS and MAPK1 gene amplification in type II ovarian carcinomas (2013)
  • Author(s): Rahman MT, Nakayama K, Rahman M, Katagiri H, Katagiri A, Ishibashi T, Ishikawa M, Sato E, Iida K, Nakayama N, Ishikawa N, Miyazaki K
  • Journal Title: Int J Mol Sci Volume: 14 Pages: 13748-13762
• [Journal Article] Fatty acid synthase is a potential therapeutic target in estrogen receptor-/progesterone receptor-positive endometrioid endometrial cancer (2013)
  • Author(s): Rahman MT, Nakayama K, Ishikawa M, Rahman M, Katagiri H, Katagiri A, Ishibashi T, Iida K, Miyazaki K
  • Journal Title: Oncology Volume: 84 Pages: 166-173
• [Journal Article] PPP2R1A mutation is a rare event in ovarian carcinoma across histological subtypes (2013)
  • Author(s): Rahman M, Nakayama K, Rahman MT, Nakayama N, Katagiri H, Katagiri A, Ishibashi T, Ishikawa M, Iida K, Otsuki Y, Nakayama S, Miyazaki K
  • Journal Title: Anticancer Res Volume: 33 Pages: 113-118
• [Journal Article] Is ATP7B a predictive marker in patients with ovarian carcinoma treated with platinum-taxane combination chemotherapy? (2013)
  • Author(s): Katagiri H, Nakayama K, Rahman MT, Rahman M, Katagiri A, Ishibashi T, Ishikawa M, Iida K, Nakayama S, Otsuki Y, Miyazaki K
  • Journal Title: Int J Gynecol Cancer Volume: 23 Pages: 60-64
• [Journal Article] Clinicopathological analysis of loss of AT-rich interactive domain 1A expression in endometrial cancer (2013)
  • Author(s): Rahman M, Nakayama K, Rahman MT, Katagiri H, Katagiri A, Ishibashi T, Ishikawa M, Iida K, Miyazaki K
  • Journal Title: Hum Pathol Volume: 44 Pages: 103-109
• [Journal Article] Development of a novel ovarian cancer molecular target therapy against cancer related transcriptional factor, NAC1. (2013)
  • Author(s): Nakayama K, Nakayama N, Miyazaki K
  • Journal Title: J Obstet Gynaecol Res. Volume: 39 Pages: 18-25
  • Peer Reviewed
• [Journal Article] KRAS and MAPK1 gene amplification in type II ovarian carcinomas. (2013)
  • Author(s): Rahman MT, Nakayama K, Rahman M, Katagiri H, Katagiri A, Ishibashi T, Ishikawa M, Sato E, Iida K, Nakayama N, Ishikawa N, Miyazaki K.
  • Journal Title: Int J Mol Sci. Volume: 14 Pages: 13748-13762
  • Peer Reviewed
• [Journal Article] Rahman MT, Nakayama K, Rahman M, Ishikawa M, Katagiri H, Katagiri A, Ishibashi T, Sato E, Iida K, Nakayama N, Ishikawa N, Miyazaki K.: ESR1 gene amplification in endometrial carcinomas: A clinicopathological analysis. (2013)
  • Author(s): Rahman MT, Nakayama K, Rahman M, Ishikawa M, Katagiri H, Katagiri A, Ishibashi T, Sato E, Iida K, Nakayama N, Ishikawa N, Miyazaki K
  • Journal Title: Anticancer Res. Volume: 33 Pages: 3775-3781
  • Peer Reviewed
• [Journal Article] Clinicopathological analysis of loss of AT-rich interactive domain 1A expression in endometrial cancer. (2013)
  • Author(s): Rahman M, Nakayama K, Rahman MT, Katagiri H, Katagiri A, Ishibashi T, Ishikawa M, Iida K, Miyazaki K.
  • Journal Title: Hum Pathol. Volume: 44 Pages: 103-109
  • Peer Reviewed
• [Journal Article] Fatty Acid Synthase is a Potential Therapeutic Target in ER/PR Positive Endometrioid Endometrial Cancer. (2013)
  • Author(s): Rahman MT, Nakayama K, Ishikawa M, Rahman M, Katagiri H, Katagiri A, Ishibashi T, Iida K, Miyazaki K.
  • Journal Title: Oncology Volume: 84 Issue: 3 Pages: 166-173
  • DOI: 10.1159/000342967
  • Peer Reviewed
• [Journal Article] Low expression of nucleus accumbens-associated protein 1 predicts poor prognosis for patients with pancreatic ductal adenocarcinoma (2012)
  • Author(s): Nishi T, Maruyama R, Urano T, Nakayama N, Kawabata Y, Yano S, Yoshida M, Nakayama K, Miyazaki K, Takenaga K, Tanaka T, Tajima Y
  • Journal Title: Pathol Int Volume: 62 Pages: 802-810
• [Journal Article] eM.: Identification of molecular pathway aberrations in uterine serous carcinoma by genome-wide analyses (2012)
  • Author(s): Kuhn E, Wu RC, Guan B, Wu G, Zhang J, Wang Y, Song L, Yuan X, Wei L, Roden RB, Kuo KT, Nakayama K, Clarke B, Shaw P, Olvera N, Kurman RJ, Levine DA, Wang TL, Shih I
  • Journal Title: J Natl Cancer Inst Volume: 104 Pages: 1503-1513
• [Journal Article] NAC1 is an actin-binding protein that is essential for effective cytokinesis in cancer cells (2012)
  • Author(s): Yap KL, Fraley SI, Thiaville MM, Jinawath N, Nakayama K, Wang J, Wang TL, Wirtz D, Shih IeM
  • Journal Title: Cancer Res Volume: 72 Pages: 4085-4096
• [Journal Article] Notch3 overexpression as potential therapeutic target in advanced stage chemoresistant ovarian cancer (2012)
  • Author(s): Rahman MT, Nakayama K, Rahman M, Katagiri H, Katagiri A, Ishibashi T, Ishikawa M, Iida K, Nakayama S, Otsuki S, Miyazaki K
  • Journal Title: Am J Clin Pathol Volume: 138 Pages: 535-544
• [Journal Article] NAC1, a BTB/POZ protein overexpressed in uterine sarcomas (2012)
  • Author(s): Rahman MT, Nakayama K, Ishikawa M, Rahman M, Katagiri H, Katagiri A, Ishibashi T, Iida K, Yamada T, Miyazaki K
  • Journal Title: Anticancer Res Volume: 32 Pages: 3841-3845
• [Journal Article] Gene amplification of ZNF217 located at chr20q13.2 is associated with lymph node metastasis in ovarian clear cell carcinoma (2012)
  • Author(s): Rahman MT, Nakayama K, Rahman M, Katagiri H, Katagiri A, Ishibashi T, Ishikawa M, Iida K, Nakayama N, Otsuki Y, Nakayama S, Miyazaki K
  • Journal Title: Anticancer Res Volume: 32 Pages: 3091-3095
• [Journal Article] Clinicopathologic and biological analysis of PIK3CA mutation in ovarian clear cell carcinoma (2012)
  • Author(s): Rahman M, Nakayama K, Rahman MT, Nakayama N, Ishikawa M, Katagiri A, Iida K, Nakayama S, Otsuki Y, Shih IeM, Miyazaki K
  • Journal Title: Hum Pathol Volume: 43 Pages: 2197-2206
• [Journal Article] Nuclear localization signal in a cancer-related transcriptional regulator protein NAC1 (2012)
  • Author(s): Okazaki K, Nakayama N, Nariai Y, Nakayama K, Miyazaki K, Maruyama R, Kato H, Kosugi S, Urano T, Sakashita G
  • Journal Title: Carcinogenesis Volume: 33 Pages: 1854-1862
• [Journal Article] Fatty acid synthase expression associated with NAC1 is a potential therapeutic target in ovarian clear cell carcinomas (2012)
  • Author(s): Rahman MT, Nakayama K, Rahman M, Katagiri H, Katagiri A, Ishibashi T, Ishikawa M, Iida K, Nakayama N, Otsuki Y, Nakayama S, Miyazaki K.:
  • Journal Title: Br J Cancer Volume: 107 Pages: 300-307
• [Journal Article] Frequent loss of tumor suppressor ARID1A protein expression in adenocarcinomas/adenosquamous carcinomas of the uterine cervix (2012)
  • Author(s): Katagiri A, Nakayama K, Rahman MT, Rahman M, Katagiri H, Ishikawa M, Ishibashi T, Iida K, Otsuki Y, Nakayama S, Miyazaki K
  • Journal Title: Int J Gynecol Cancer Volume: 22 Pages: 208-212
• [Journal Article] Prognostic and therapeutic impact of the chromosome 20q13.2 ZNF217 locus amplification in ovarian clear cell carcinoma (2012)
  • Author(s): Rahman MT, Nakayama K, Rahman M, Nakayama N, Ishikawa M, Katagiri A, Iida K, Nakayama S, Otsuki Y, Shih IeM, Miyazaki K
  • Journal Title: Cancer Volume: 118 Pages: 2846-2857
  • Peer Reviewed
• [Journal Article] Papadopoulos N, Shih IeM.: Low-grade serous carcinomas of the ovary contain very few point mutations (2012)
  • Author(s): Jones S, Wang TL, Kurman RJ, Nakayama K, Velculescu VE, Vogelstein B, Kinzler KW
  • Journal Title: J Pathol Volume: 226 Pages: 413-420
• [Journal Article] Loss of ARID1A expression is related to shorter progression-free survival and chemoresistance in ovarian clear cell carcinoma (2012)
  • Author(s): Katagiri A, Nakayama K, Rahman MT, Rahman M, Katagiri H, Nakayama N Ishikawa M, Ishibashi T, Iida K, Otsuki Y, Nakayama S, Miyazaki K
  • Journal Title: Mod Pathol Volume: 25 Pages: 282-288
• [Journal Article] Biological and clinical significance of NAC1 expression in cervical carcinomas : a comparative study between squamous cell carcinomas and adenocarcinomas/adenosquamous carcinomas (2012)
  • Author(s): Yeasmin S, Nakayama K, Rahman MT, Rahman M, Ishikawa M, Katagiri A, Iida K, Nakayama N, Otsuki Y, Kobayashi H, Nakayama S, Miyazaki K
  • Journal Title: Hum Pathol Volume: 43 Pages: 506-519
• [Journal Article] Genome-wide analyses of uterine serous carcinoma identify pathway aberrations involvingcyclinE-Fbxw7, PI3K and p53. (2012)
  • Author(s): Kuhn E, Wu RC, Wu G, Guan B, Zhang J, Wang Y, Song L,Yuan X, Wei Lei, Roden RBS, Kuo KT, Nakayama K, Clarke B,Shaw P, Olvera N, Levine DA, Kurman RJ, Wang TL, Shih IeM,
  • Journal Title: J Natl Cancer Inst. Volume: 19 Issue: 19 Pages: 1503-1513
  • DOI: 10.1093/jnci/djs345
  • Peer Reviewed
• [Journal Article] Endometrial Serous Carcinoma: its molecular characteristics and histology-specific treatment strategies. (2012)
  • Author(s): Nakayama K, Nakayama N, Ishikawa M, Miyazaki K
  • Journal Title: Cancers Volume: 4 Issue: 3 Pages: 499-807
  • DOI: 10.3390/cancers4030799
  • Peer Reviewed
• [Journal Article] NAC1, A BTB/POZ Protein Overexpressed in Uterine Sarcomas. (2012)
  • Author(s): Rahman MT, Nakayama K, Ishikawa M, Rahman M, Katagiri H, Katagiri A, Ishibashi T, Iida K, Yamada T, Miyazaki K.
  • Journal Title: Anticancer Res. Volume: 32 Pages: 3841-3845
  • Peer Reviewed
• [Journal Article] Biological and clinical significance of NAC1 expression in cervical carcinomas: a comparative study between squamous cell carcinomas and adenocarcinomas/adenosquamous carcinomas. (2012)
  • Author(s): Yeasmin S, Nakayama K, Rahman MT, Rahman M, Ishikawa M, Katagiri A, Iida K, Nakayama N, Otuski Y, Kobayashi H, Nakayama S, Miyazaki K.
  • Journal Title: Hum Pathol. Volume: 43 Pages: 506-519
  • Peer Reviewed
• [Journal Article] Loss of ARID1A expression is related to shorter progression-free survival and chemoresistance in ovarian clear cell carcinoma. (2012)
  • Author(s): Katagiri A, Nakayama K, Rahman MT, Rahman M, Katagiri H, Nakayama N, Ishikawa M, Ishibashi T, Iida K, Kobayashi H, Otsuki Y, Nakayama S, Miyazaki K
  • Journal Title: Mod Pathol. Volume: 25 Pages: 282-288
  • Peer Reviewed
• [Journal Article] Prognostic and therapeutic impact of amplification of the chr20q13.2 ZNF217 locus in ovarian (2012)
  • Author(s): Rahman MT, Nakayama K, Rahman M, Nakayama N, Ishikawa M, Katagiri A, Iida K, Nakayama S, Otsuki Y,
  • Journal Title: Cancer Volume: 118 Issue: 11 Pages: 2846-2857
  • DOI: 10.1002/cncr.26598
  • Peer Reviewed
• [Journal Article] Frequent loss of tumor suppressor ARID1A protein expression in adenocarcinomas/adenosquamous carcinomas of the uterine cervix. (2012)
  • Author(s): Katagiri A, Nakayama K, Rahman MT, Rahman M, Katagiri H, Ishikawa M, Ishibashi T, Iida K, Otsuki Y, Nakayama S, Miyazaki K.
  • Journal Title: Int J Gynecol Cancer. Volume: 22 Pages: 208-212
  • Peer Reviewed
• [Journal Article] EGFR gene amplification is related to adverse clinical outcomes in cervical squamous cell carcinoma, making the EGFR pathway a novel therapeutic target (2011)
  • Author(s): Iida K, Nakayama K, Rahman MT, Rahman M, Ishikawa M, Katagiri A, Yeasmin S, Otsuki Y, Kobayashi H, Nakayama S, Miyazaki K
  • Journal Title: Br J Cancer Volume: 105 Pages: 420-427
• [Journal Article] MKK4 acts as a potential tumor suppressor in ovarian cancer (2011)
  • Author(s): Yeasmin S, Nakayama K, Rahman MT, Rahman M, Ishikawa M, Katagiri A, Iida K, Nakayama N, Miyazaki K
  • Journal Title: Tumour Biol Volume: 32 Pages: 661-670
• [Journal Article] Amplification of the ch19p13.2 NACC1 locus in ovarian high-grade serous carcinoma (2011)
  • Author(s): Shih IeM, Nakayama K, Wu G, Nakayama N, Zhang J, Wang TL
  • Journal Title: Mod Pathol Volume: 24 Pages: 638-645
• [Journal Article] Loss of MKK4 expression in ovarian cancer : a potential role for the epithelial to mesenchymal transition (2011)
  • Author(s): Yeasmin S, Nakayama K, Rahman MT, Rahman M, Ishikawa M, Katagiri A, Iida K, Nakayama N, Miyazaki K
  • Journal Title: Int J Cancer Volume: 128 Pages: 94-104
• [Journal Article] EGFR gene amplification is related to adverse clinical outcomes in cervical squamous cell carcinoma, making the EGFR pathway a novel therapeutic target. (2011)
  • Author(s): Iida K, Nakayama K, Rahman MT, Rahman M, Ishikawa M, Katagiri A, Yeasmin S, Otsuki Y, Kobayashi H, Nakayama S, Miyazaki K.
  • Journal Title: Br J Cancer. Volume: 105 Pages: 420-427
  • Peer Reviewed
• [Presentation] 卵巣癌におけるNAC1 pathwayに基づいた創薬への展開、(婦人科がんにおけるトランスレーショナルリサーチ、シーズの探索から臨床応用まで) (2013)
  • Author(s): 中山健太郎、中山真美、石川雅子、片桐浩、片桐敦子、佐藤絵美、飯田幸司、Mohammed Tanjimur Rahman、Munmun Rahman、宮崎康二
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜、横浜市
  • Year and Date: 2013-10-03
• [Presentation] 新規癌関連転写因子NAC1を標的とした卵巣癌治療法の開発、(卵巣癌のMolecular Medicine) (2013)
  • Author(s): 中山健太郎、石川雅子、片桐浩、片桐敦子、石橋朋佳、佐藤絵美、Mohammed Tanjimur Rahman、Munmun Rahman、飯田幸司、中山真美、宮崎康二
  • Organizer: 第54回日本婦人科腫瘍学会
  • Place of Presentation: ホテルグランパシフィックLE DAIBA、東京
  • Year and Date: 2013-07-20
• [Presentation] 卵巣癌におけるNAC1/Gadd45/MKK4経路を介した腹膜播種機構の解明と阻害剤開発による臨床応用、(婦人科癌の浸潤・転移機構の解明と臨床応用) (2013)
  • Author(s): 中山健太郎
  • Organizer: 第65回日本産科婦人科学会学術講演会
  • Place of Presentation: ロイトン札幌(札幌市)
  • Year and Date: 2013-05-10
• [Presentation] 卵巣癌におけるNAC1/Gadd45/MKK4経路を介した腹膜播種機構の解明と阻害剤開発による臨床応用 (2013)
  • Author(s): 中山健太郎
  • Organizer: 第65回 日本産科婦人科学会学術講演会
  • Place of Presentation: 札幌 ロイトン札幌
• [Presentation] 新規癌関連転写因子NAC1を標的とした卵巣癌治療法の開発 (2013)
  • Author(s): 中山健太郎、石川雅子、片桐 浩、片桐敦子、石橋朋佳、佐藤絵美、Mohammed Tanjimur
  • Organizer: 第54回 日本婦人科腫瘍学会
  • Place of Presentation: 東京 ホテルグランパシフィック台場
• [Presentation] 卵巣癌におけるNAC1 pathwayに基づいた創薬への展開 (2013)
  • Author(s): 中山健太郎、中山真美、石川雅子、片桐 浩、片桐敦子、佐藤絵美、飯田幸司、Mohammed
  • Organizer: 第72回 日本癌学会学術総会
  • Place of Presentation: 横浜 パシフィコヨコハマ
• [Presentation] Clinical and molecular features of ovarian clear cell carcinoma, Ovarian Clear Cell Carcinoma: Update (2013)
  • Author(s): Nakayama K
  • Organizer: The 3rd ASGO (Asian Society of Gynecologic Oncology )
  • Place of Presentation: 京都 ウエスティン都ホテル
  • Invited
• [Presentation] 卵巣明細胞腺癌における新規遺伝子異常の発見 (2011)
  • Author(s): 中山健太郎、Siân Jones2、Ie-Ming Shih2、Tian-Li Wang2、Bert Vogelstein2、Kenneth W. Kinzler、Victor E. Velculescu、Nickolas Papadopoulos、宮崎康二
  • Organizer: 第21回日本サイトメトリー学会学術集会(招待講演)
  • Place of Presentation: 京都市国際交流会館(京都）
• [Presentation] 卵巣癌の分子生物学的特性を利用した新規治療法の開発 (2011)
  • Author(s): 中山健太郎
  • Organizer: 第63回日本産科婦人科学会学術講演会(招待講演)
  • Place of Presentation: 大阪国際会議場（大阪）
• [Presentation] 卵巣明細胞腺癌における新規遺伝子異常の発見～新規癌抑制遺伝子ARID1Aのmutation及び癌遺伝子ZNF217の遺伝子増幅～ (2011)
  • Author(s): 中山健太郎1、Siân Jones2、Ie-Ming Shih2、Tian-Li Wang2、Bert Vogelstein2、Kenneth W. Kinzler2、Victor E. Velculescu2、Nickolas Papadopoulos2、宮崎康二
  • Organizer: 第8回 婦人科がん会議(招待講演)
  • Place of Presentation: 全日空ホテルズラグナガーデン（沖縄）
• [Presentation] 静かなる殺人者（サイレントキラー）の驚異 ～難治性卵巣がんの解明に挑む～
  • Author(s): 中山健太郎
  • Organizer: 第４３回島根大学サイエンスカフェ(市民公開講座)
  • Place of Presentation: 松江テルサ（松江市）
  • Invited
• [Presentation] 過多月経と卵巣がんの最新治療
  • Author(s): 中山健太郎
  • Organizer: 日本助産師会、中国、四国地区研修会
  • Place of Presentation: ビッグハート出雲(出雲市）
  • Invited
• [Presentation] 卵巣癌における新規転写制御因子NAC1発現の臨床的、分子生物学的意義
  • Author(s): 石川雅子、中山健太郎、片桐浩、片桐敦子、石橋朋佳、Mohammed Tanjimur Rahman、Munmun Rahman、飯田幸司、折出亜希、金崎春彦、青木昭和、宮崎康二
  • Organizer: 日本産婦人科学会総会
  • Place of Presentation: 神戸ポートピアホテル（神戸市）
• [Presentation] 卵巣明細胞腺癌において新規癌抑制遺伝子ARID1Aの発現消失は早期再発、化学療法抵抗性に関連する
  • Author(s): 片桐敦子、中山健太郎、片桐浩、石川雅子、石橋朋佳、Mohammed Tanjimur Rahman、Munmun Rahman、飯田幸司、宮崎康二
  • Organizer: 日本婦人科腫瘍学会
  • Place of Presentation: 高輪プリンスホテル（東京）
• [Book] 今日の治療指針、私はこう治療している 原発性腹膜癌 (2013)
  • Author(s): 中山健太郎
  • Total Pages: 2
  • Publisher: 医学書院