腫瘍ゲノム研究部 Department of Cancer Genome Research
メンバー
部長(PI) | 中岡 博史 | Hirofumi Nakaoka | Researchmap メールアドレス h-nakaoka |
研究員 | |||
研究助手 | 西川 桂子 | Keiko Nishikawa | メールアドレス k-nishikawa |
共同研究員 |
※メールアドレスには@po.kyoundo.jpをつけて下さい
研究内容
卵巣子宮内膜症と正常子宮内膜における遺伝子変異解明
子宮内膜症は子宮内膜に似た組織が子宮以外の組織に生着・増殖し、月経周期に応じて出血や疼痛をきたす疾患で、生殖年齢にある女性の約10%が罹患すると言われています。月経困難症、骨盤痛や不妊症との関連も指摘されており、少子化や女性の社会進出の障害として、社会的損失が大きい疾患です。子宮内膜症が最も多く発症する部位は骨盤腹膜や卵巣です。また、疫学研究により子宮内膜症が特定の組織型の卵巣がん(明細胞腺がん、類内膜がん)の発症リスクになることが報告されています。しかし、卵巣がんの発症母地(前がん病変)とされる卵巣子宮内膜症におけるゲノム変異については明らかにされていませんでした。 そこで、私たちは卵巣子宮内膜症および正常子宮内膜におけるゲノム解析を行い、良性腫瘍である子宮内膜症のみならず正常子宮内膜においても、多数のがん関連遺伝子に変異が存在することを明らかにしました。特に子宮内膜症と関連する卵巣がんで高頻度に認められるKRAS、PIK3CA、FBXW7、PPP2R1A、PIK3R1、ARID1Aの変異が多く認められました。発がんドライバーであるがん関連遺伝子変異が認められたにもかかわらず、これら上皮細胞において病理学的な形態異常は認められませんでした。また、子宮内膜症上皮において、がん関連遺伝子変異、特に卵巣がんで変異頻度の高いKRASおよびPIK3CAに変異を保有する上皮細胞がクローン性に増殖していることが分かりました。 さらに、正常子宮内膜上皮細胞が管状構造(図1)を呈して発達していることに着目し、単一腺管レベルという最小機能単位で体細胞変異プロファイリングを行いました。その結果、正常な子宮内膜から採取した腺管において、KRAS やPIK3CAを含むがん関連遺伝子に体細胞変異が多数検出されました。興味深いことに、各腺管で保有する変異はクローナルな状態に達していましたが、腺管ごとに異なる体細胞変異を保有していました。つまり、子宮内膜組織は、個々に異なる体細胞変異を有する腺管が集合して構成される組織であるため、ゲノムがモザイク状態を呈することが分かりました。これらの結果は、モザイク状ゲノムを呈する子宮内膜が月経血逆流を介して卵巣に生着・増殖する過程で、KRASなどのがん関連遺伝子変異を有する上皮細胞が生存に有利となり、クローナルに増殖することで、子宮内膜症発症に至ることを示唆しています。我々の解析結果は卵巣子宮内膜症発症における月経逆流説をゲノムレベルで支持するものとなりました(図1)。 ヒト正常子宮内膜に存在するがん関連遺伝子変異の機能的影響は未解明です。私たちの研究によって、がん関連遺伝子に体細胞変異を有する細胞クローンが子宮内膜組織において正の選択を受けていることが分かりました。しかし、そのような細胞クローンが存在していても、ほとんどの女性が婦人科がんを発症するには至りません。がん関連遺伝子変異を有する細胞クローンはがん化の危険性という負の側面だけではなく、子宮内膜のように月経周期に応じて再生を繰り返す組織において、増殖能の高い腺管が組織維持に役立っている可能性も考えられます。がん関連遺伝子変異を保有する正常子宮内膜の詳細なゲノム解析を通じて、がん化を抑え、生体を維持する分子機構を解明するための研究に取り組んでいます。 また、子宮内膜だけではなく、肺、胃、食道、皮膚といった他の組織においても、正常細胞における体細胞変異とがん化に関する研究を進めています。様々な正常組織におけるがん関連遺伝子変異の探索・機能的特性を評価することで、組織を越えて共通する分子機構、さらには、組織特有の分子機構を見出すことを目的としています。
研究業績(過去5年間)
- Nakayama A*, Nakatochi M*, Kawamura Y*, Yamamoto K*, Nakaoka H*, Shimizu S, Higashino T, Koyama T, Hishida A, Kuriki K, Watanabe M, Shimizu T, Ooyama K, Ooyama H, Nagase M, Hidaka Y, Matsui D, Tamura T, Nishiyama T, Shimanoe C, Katsuura-Kamano S, Takashima N, Shirai Y, Kawaguchi M, Takao M, Sugiyama R, Takada Y, Nakamura T, Nakashima H, Tsunoda M, Danjoh I, Hozawa A, Hosomichi K, Toyoda Y, Kubota Y, Takada T, Suzuki H, Stiburkova B, Major TJ, Merriman TR, Kuriyama N, Mikami H, Takezaki T, Matsuo K, Suzuki S, Hosoya T, Kamatani Y, Kubo M, Ichida K, Wakai K, Inoue I, Okada Y, Shinomiya N, Matsuo H on behalf of Japan Gout Genomics Consortium (Japan Gout). Subtype-specific gout susceptibility loci and enrichment of selection pressure on ABCG2 and ALDH2 identified by subtype genome-wide meta-analyses of clinically-defined gout patients. Ann Rheum Dis. in press. *Co-first author.
- Tamura R, Yoshihara K, Nakaoka H, Yachida N, Yamaguchi M, Suda K, Ishiguro T, Nishino K, Ichikawa H, Honma K, Kikuchi A, Ueda Y, Takei Y, Fujiwara H, Motoyama T, Okuda S, Wakai T, Inoue I, Enomoto T. XCL1 expression correlates with CD8 positive T cells infiltration and PD-L1 expression in squamous cell carcinoma arising from mature cystic teratoma of the ovary. Oncogene. in press.
- Hata C, Nakaoka H, Xiang Y, Wang D, Yang A, Liu D, Liu F, Zou Q, Wei L, Zheng K, Inoue I, You H. Germline mutations of multiple breast cancer-related genes are differentially associated with triple-negative breast cancers and prognostic factors. J Hum Genet. in press.
- Higashino T*, Morimoto K*, Nakaoka H*, Toyoda Y*, Kawamura Y*, Shimizu S*, Nakamura T, Hosomichi K, Nakayama A, Ooyama K, Ooyama H, Shimizu T, Ueno M, Ito T, Tamura T, Naito M, Nakashima H, Kawaguchi M, Takao M, Kawai Y, Osada N, Ichida K, Yamamoto K, Suzuki H, Shinomiya N, Inoue I, Takada T, Matsuo H. Dysfunctional missense variant of OAT10/SLC22A13 decreases gout risk and serum uric acid levels. Ann Rheum Dis. 2020; 79(1):164-166. *Co-first author.
- Zhang S, Kohira Y, Orita H, Ishimine M, Kobayashi T, Chua SMB, Nakaoka H, Inoue I, Hino O, Yokomizo T, Fukunaga T, Lee-Okada HC. Sensitization of gastric cancer cells to irinotecan by p53 activation. BPB Rep. 2019; 2: 130-133.
- Sugino K, Tamura R, Nakaoka H, Yachida N, Yamaguchi M, Mori Y, Yamawaki K, Suda K, Ishiguro T, Adachi S, Isobe M, Yamaguchi M, Kashima K, Motoyama T, Inoue I, Yoshihara K, Enomoto T. Germline and somatic mutations of homologous recombination-associated genes in Japanese ovarian cancer patients. Sci Rep. 2019; 9(1):17808.
- Suda K, Nakaoka H, Yoshihara K, Ishiguro T, Adachi S, Kase H, Motoyama T, Inoue I, Enomoto T. Different mutation profiles between epithelium and stroma in endometriosis and normal endometrium. Hum Reprod. 2019; 34(10):1899-1905.
- Hata C, Nakaoka H, Xiang Y, Wang D, Yang A, Liu D, Liu F, Zou Q, Zheng K, Inoue I, You H. Exploration of intermediate-sized indels by next-generation multigene panel testing in Han Chinese patients with breast cancer. Hum Genome Var. 2019; 6:51.
- Kawamura Y*, Nakaoka H*, Nakayama A*, Okada Y*, Yamamoto K*, Higashino T, Sakiyama M, Shimizu T, Ooyama H, Ooyama K, Nagase M, Hidaka Y, Shirahama Y, Hosomichi K, Nishida Y, Shimoshikiryo I, Hishida A, Katsuura-Kamano S, Shimizu S, Kawaguchi M, Uemura H, Ibusuki R, Hara M, Naito M, Takao M, Nakajima M, Iwasawa S, Nakashima H, Ohnaka K, Nakamura T, Stiburkova B, Merriman TR, Nakatochi M, Ichihara S, Yokota M, Takada T, Saitoh T, Kamatani Y, Takahashi A, Arisawa K, Takezaki T, Tanaka K, Wakai K, Kubo M, Hosoya T, Ichida K, Inoue I, Shinomiya N, Matsuo H. Genome-wide association study revealed novel loci which aggravate asymptomatic hyperuricaemia into gout. Ann Rheum Dis. 2019; 78(10):1430-1437. *Co-first author.
- Suda K, Nakaoka H, Hata C, Yahata N, Isobe M, Kameyama H, Wakai T, Motoyama T, Inoue I, Yoshihara K, Enomoto T. Concurrent isolated retroperitoneal HGSC and STIC defined by somatic mutation analysis: a case report. Diagn Pathol. 2019; 14(1):17.
- Hirata J, Hosomichi K, Sakaue S, Kanai M, Nakaoka H, Ishigaki K, Suzuki K, Akiyama M, Kishikawa T, Ogawa K, Masuda T, Yamamoto K, Hirata M, Matsuda K, Momozawa Y, Inoue I, Kubo M, Kamatani Y, Okada Y. Genetic and phenotypic landscape of the major histocompatibility complex region in the Japanese population. Nat Genet. 2019; 51(3):470-480.
- Romero V, Nakaoka H, Hosomichi K, Inoue I. High order formation and evolution of hornerin in primates. Genome Biol Evol. 2018; 10(12):3167-3175.
- Takahashi K, Hayano T, Sugimoto R, Kashiwagi H, Shinoda M, Nishijima Y, Suzuki T, Suzuki S, Ohnuki Y, Kondo A, Shiina T, Nakaoka H, Inoue I, Izumi SI. Exome and copy number variation analyses of Mayer-Rokitansky-Küster-Hauser syndrome. Hum Genome Var. 2018; 5:27.
- Tamura R, Nakaoka H, Yoshihara K, Mori Y, Yachida N, Nishikawa N, Motoyama T, Okuda S, Inoue I, Enomoto T. Novel MXD4-NUTM1 fusion transcript identified in primary ovarian undifferentiated small round cell sarcoma. Genes Chromosomes Cancer. 2018; 57(11): 557-563.
- Suda K*, Nakaoka H*, Yoshihara K, Ishiguro T, Tamura R, Mori Y, Yamawaki K, Adachi S, Takahashi T, Kase H, Tanaka K, Yamamoto T, Motoyama T, Inoue I, Enomoto T. Clonal expansion and diversification of cancer-associated mutations in endometriosis and normal endometrium. Cell Rep. 2018; 24(7):1777-1789. *Co-first author.
- Yang YX, Wei L, Zhang YJ, Hayano T, Piñeiro Pereda MDP, Nakaoka H, Li Q, Barragán Mallofret I, Lu YZ, Tamagnone L, Inoue I, Li X, Luo JY, Zheng K, You H. Long non-coding RNA p10247, high expressed in breast cancer (lncRNA-BCHE), is correlated with metastasis. Clin Exp Metastasis. 2018; 35(3):109-121.
- Sakiyama M, Matsuo H, Nakaoka H, Kawamura Y, Kawaguchi M, Higashino T, Nakayama A, Akashi A, Ueyama J, Kondo T, Wakai K, Sakurai Y, Yamamoto K, Ooyama H, Shinomiya N. Common variant of BCAS3 is associated with gout risk in Japanese population : the first replication study after gout GWAS in Han Chinese. BMC Med Genet. 2018; 19(1): 96.
- Ishimine M, Lee HC, Nakaoka H, Orita H, Kobayashi T, Mizuguchi K, Endo M, Inoue I, Sato K, Yokomizo T. The relationship between TP53 gene status and carboxylesterase 2 expression in human colorectal cancer. Dis Markers. 2018; 2018: 5280736.
- Tamura R, Yoshihara K, Saito T, Ishimura R, Martínez-Ledesma JE, Xin H, Ishiguro T, Mori Y, Yamawaki K, Suda K, Sato S, Itamochi H, Motoyama T, Aoki Y, Okuda S, Casingal CR, Nakaoka H, Inoue I, Verhaak RGW, Komatsu M, Enomoto T. Novel therapeutic strategy for cervical cancer harboring FGFR3-TACC3 fusions. Oncogenesis. 2018; 7(1): 4.
- Higashino T*, Takada T*, Nakaoka H*, Toyoda Y, Stiburkova B, Miyata H, Ikebuchi Y, Nakashima H, Shimizu S, Kawaguchi M, Sakiyama M, Nakayama A, Akashi A, Tanahashi Y, Kawamura Y, Nakamura T, Wakai K, Okada R, Yamamoto K, Hosomichi K, Hosoya T, Ichida K, Ooyama H, Suzuki H, Inoue I, Merriman TR, Shinomiya N, Matsuo H. Multiple common and rare variants of ABCG2 cause gout. RMD Open. 2017; 3(2): e000464. *Co-first author.
- Ito J, Sugimoto R, Nakaoka H, Yamada S, Kimura T, Hayano T, Inoue I. Systematic identification and characterization of regulatory elements derived from human endogenous retroviruses. PLOS Genet. 2017; 13(7): e1006883.
- Matsumoto Y, Goto T, Nishino J, Nakaoka H, Tanave A, Takano-Shimizu T, Mott RF, Koide T. Selective breeding and selection mapping using a novel wild-derived heterogeneous stock of mice revealed two closely-linked loci for tameness. Sci Rep. 2017; 7(1): 4607.
- Nakayama A*, Nakaoka H*, Yamamoto K*, Sakiyama M*, Shaukat A*, Toyoda Y*, Okada Y, Kamatani Y, Nakamura T, Takada T, Inoue K, Yasujima T, Yuasa H, Shirahama Y, Nakashima H, Shimizu S, Higashino T, Kawamura Y, Ogata H, Kawaguchi M, Ohkawa Y, Danjoh I, Tokumasu A, Ito T, Kondo T, Wakai K, Stiburkova B, Pavelka K, Stamp LK, Dalbeth N, Eurogout Consortium, Sakurai Y, Suzuki H, Hosoyamada M, Fujimori S, Yokoo T, Hosoya T, Inoue I, Takahashi A, Kubo M, Ooyama H, Shimizu T, Ichida K, Shinomiya N, Merriman TR, Matsuo H. GWAS of clinically-defined gout and subtypes identifies multiple susceptibility loci including transporter genes. Ann Rheum Dis. 2017; 76(5): 869-877. *Co-first authors.
- Ahmadloo S*, Nakaoka H*,†, Hayano T, Hosomichi K, You H, Utsuno E, Sangai T, Nishimura M, Matsushita K, Hata A, Nomura F, Inoue I. Rapid and cost-effective high-throughput sequencing for identification of germline mutations of BRCA1 and BRCA2. J Hum Genet. 2017; 62(5): 561-567. *Co-first author. †Corresponding author.
- Yamaguchi T, Hosomichi K, Yano K, Kim YI, Nakaoka H, Kimura R, Otsuka H, Nonaka N, Haga S, Takahashi M, Shirota T, Kikkawa Y, Yamada A, Kamijo R, Park SB, Nakamura M, Maki K, Inoue I. Comprehensive genetic exploration of selective tooth agenesis of mandibular incisors by exome sequencing. Hum Genome Var. 2017; 4: 17005.
- Mori T, Hosomichi K, Chiga M, Mandai S, Nakaoka H, Sohara E, Okado T, Rai T, Sasaki S, Inoue I, Uchida S. Comprehensive genetic testing approach for major inherited kidney diseases, using next-generation sequencing with a custom panel. Clin Exp Nephrol. 2017; 21(1): 63-75.
- Romero V, Hosomichi K, Nakaoka H, Shibata H, Inoue I. Structure and evolution of the filaggrin gene repeated region in primates. BMC Evol Biol. 2017; 17(1): 10.
- Hayano T, Matsui H, Nakaoka H, Ohtake N, Hosomichi K, Suzuki K, Inoue I. Germline variants of prostate cancer in Japanese families. PLOS ONE. 2016; 11(10): e0164233.
- van ‘t Hof FN, Ruigrok YM, Lee CH, Ripke S, Anderson G, de Andrade M, Baas AF, Blankensteijn JD, Böttinger EP, Bown MJ, Broderick J, Bijlenga P, Carrell DS, Crawford DC, Crosslin DR, Ebeling C, Eriksson JG, Fornage M, Foroud T, von Und Zu Fraunberg M, Friedrich CM, Gaál EI, Gottesman O, Guo DC, Harrison SC, Hernesniemi J, Hofman A, Inoue I, Jääskeläinen JE, Jones GT, Kiemeney LA, Kivisaari R, Ko N, Koskinen S, Kubo M, Kullo IJ, Kuivaniemi H, Kurki MI, Laakso A, Lai D, Leal SM, Lehto H, LeMaire SA, Low SK, Malinowski J, McCarty CA, Milewicz DM, Mosley TH, Nakamura Y, Nakaoka H, Niemelä M, Pacheco J, Peissig PL, Pera J, Rasmussen-Torvik L, Ritchie MD, Rivadeneira F, van Rij AM, Santos-Cortez RL, Saratzis A, Slowik A, Takahashi A, Tromp G, Uitterlinden AG, Verma SS, Vermeulen SH, Wang GT; Aneurysm Consortium; Vascular Research Consortium of New Zealand, Han B, Rinkel GJ, de Bakker PI. Shared genetic risk factors of intracranial, abdominal, and thoracic aneurysms. J Am Heart Assoc. 2016; 5(7): e002603.
- Sakiyama M, Matsuo H, Nakaoka H, Yamamoto K, Nakayama A, Nakamura T, Kawai S, Okada R, Ooyama H, Shimizu T, Shinomiya N. Identification of rs671, a common variant of ALDH2, as a gout susceptibility locus. Sci Rep. 2016; 6:25360.
- Nakaoka H, Gurumurthy A, Hayano T, Ahmadloo A, Omer WH, Yoshihara K, Yamamoto A, Kurose K, Enomoto T, Akira S, Hosomichi K, Inoue I. Allelic imbalance in regulation of ANRIL through chromatin interaction at 9p21 endometriosis risk locus. PLOS Genet. 2016; 12(4): e1005893.
- Matsuo H*, Yamamoto K*, Nakaoka H*, Nakayama A*, Sakiyama M*, Chiba T, Takahashi A, Nakamura T, Nakashima H, Takada Y, Danjoh I, Shimizu S, Abe J, Kawamura Y, Terashige S, Ogata H, Tatsukawa S, Guang Y, Okada R, Morita E, Naito M, Tokumasu A, Onoue H, Iwaya K, Ito T, Takada T, Inoue K, Kato Y, Nakamura Y, Sakurai Y, Suzuki H, Kanai Y, Hosoya T, Hamajima N, Inoue I, Kubo M, Ichida K, Ooyama H, Shimizu T, Shinomiya N. Genome-wide association study of clinically defined gout identifies multiple risk loci and its association with clinical subtypes. Ann Rheum Dis. 2016; 75(4): 652-659. *Co-first author.
- Rabbani B, Nakaoka H, Akhondzadeh S, Tekin M, Mahdieh N. Next Generation Sequencing: Implications in personalized medicine and pharmacogenomics. Mol Biosyst. 2016; 12(6): 1818-1830.
- Hayano T, Yamada S, Hosomichi K, Nakaoka H, Yoshihara K, Adachi S, Kashima K, Tanaka K, Enomoto T, Inoue I. Identification of novel exonic mobile element insertions in epithelial ovarian cancers. Hum Genome Var. 2015; 2: 15030.
- Miura H, Inoko H, Tanaka M, Nakaoka H, Kimura M, Gurumurthy CB, Sato M, Ohtsuka M. Assessment of artificial miRNA architectures for higher knockdown efficiencies without the undesired effects in mice. PLOS ONE. 2015; 10(8): e0135919.
- Mitsunaga S, Hosomichi K, Okudaira Y, Nakaoka H, Suzuki Y, Kuwana M, Sato S, Kaneko Y, Homma Y, Oka A, Shiina T, Inoko H, Inoue I. Aggregation of rare/low frequency variants of the mitochondria respiratory chain-related proteins in rheumatoid arthritis patients. J Hum Genet. 2015; 60(8): 449-454.
- Nakaoka H,† Inoue I. Distribution of HLA haplotypes across Japanese Archipelago: similarity, difference and admixture. J Hum Genet. 2015; 60(11): 683-690. † Corresponding author.
- Hayano T, Yokota Y, Hosomichi K, Nakaoka H, Yoshihara K, Adachi S, Kashima K, Tsuda H, Moriya T, Tanaka K, Enomoto T, Inoue I. Molecular characterization of an intact p53 pathway subtype in high-grade serous ovarian cancer. PLOS ONE. 2014; 9(12): e114491.
- Yonezawa T, Kurata R, Tajima A, Cui X, Maruta H, Nakaoka H, Nakajima K, Inoko H. Comparative proteomics and network analysis identify PKC epsilon underlying long-chain fatty acid signaling. J Proteomics Bioinform. 2014; 7(11): 340-346.
- Nakaoka H, Tajima A, Yoneyama T, Hosomichi K, Kasuya H, Mizutani T, Inoue I. Gene expression profiling reveals distinct molecular signatures associated with the rupture of intracranial aneurysm. Stroke. 2014; 45(8): 2239-2245.
- Nakayama A, Matsuo H, Nakaoka H, Nakamura T, Nakashima H, Takada Y, Oikawa Y, Takada T, Sakiyama M, Shimizu S, Kawamura Y, Chiba T, Abe J, Wakai K, Kawai S, Okada R, Tamura T, Shichijo Y, Akashi A, Suzuki H, Hosoya T, Sakurai Y, Ichida K, Shinomiya N. Common dysfunctional variants of ABCG2 have stronger impact on hyperuricemia progression than typical environmental risk factors. Sci Rep. 2014; 4, 5227.
- Yamaguchi T*, Nakaoka H*, Yamamoto K, Fujikawa T, Kim YI, Yano K, Haga S, Katayama K, Shibusawa T, Park SB, Maki K, Kimura R, Inoue I. Genome-wide association study of degenerative bony changes of the temporomandibular joint. Oral Dis. 2014; 20(4): 409-415. *Co-first author.
- Matsuo H, Nakayama A, Sakiyama M, Chiba T, Shimizu S, Kawamura Y, Nakashima H, Nakamura T, Takada Y, Oikawa Y, Takada T, Nakaoka H, Abe J, Inoue H, Wakai K, Kawai S, Guang Y, Nakagawa H, Ito T, Niwa K, Yamamoto K, Sakurai Y, Suzuki H, Hosoya T, Ichida K, Shimizu T, Shinomiya N. ABCG2 dysfunction causes hyperuricemia due to both renal urate underexcretion and renal urate overload. Sci Rep. 2014; 4, 3755.