Identification of novel therapeutic target of melanoma with focus on gain-of-function mutation of SH3 domain of KIT

2016 Fiscal Year Annual Research Report

• Project/Area Number: 15K15414
• Research Institution: Fujita Health University
• Principal Investigator: 杉浦 一充 藤田保健衛生大学, 医学部, 教授 (70335032)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Keywords: 悪性黒色腫 / KIT / 色素異常症

Outline of Annual Research Achievements

私たちは稀な遺伝性の全身性色素斑の病因遺伝子同定の研究で、臨床的に色素産生は来すが悪性腫瘍化は来さない、全く新しいタイプのKIT 変異（SH3 ドメインを創出する変異）を発見した。本研究の目的は2つある。目的１は、KIT 変異による悪性黒色腫の新規治療標的分子を同定すること。標的分子が同定されれば、KIT 変異による悪性黒色腫の新規治療法の開発へ繋がっていく。目的2 は、発見したKIT 変異が本当にSH3 ドメインを創出する変異か否かについて結合するタンパク質の同定とともに解明すること。悪性腫瘍化変異（c-kit p.Lys642Glu とc-kit p.Asp820Tyr）、非悪性腫瘍化変異(c-kit p.Ala829Pro)、
c-kit 野生型を恒常的に発現する無色素性メラノーマ由来細胞株を実験1、2、3 で使用した。１．プロテオーム解析でc-kit p.Ala829Pro が細胞内領域にSH3 ドメインを創出する変異であることを特異的に結合するタンパク質の同定とともに解明した。2．c-kit 恒常発現株それぞれの増殖能をBrdU ELISAで比較検討した。3．悪性腫瘍化変異と非悪性腫瘍化変異と野生型の恒常発現株の抽出液のタンパク質発現をプロテオーム解析で比較検討し、悪性腫瘍化変異恒常発現株に特異的に発現するタンパク質群を抽出した。4．50 例の悪性黒色腫のパラファイン切片からDNA を抽出し、KIT 変異を解析した。5．KIT 変異による悪性黒色腫組織において、実験3 のプロテオーム解析で抽出したタンパク質群について免疫組織化学を実施した。

Research Products

• [Journal Article] Impetigo Herpetiformis Complicated with Intrauterine Growth Restriction Treated Successfully with Granulocyte and Monocyte Apheresis. (2017)
  • Author(s): Saito-Sasaki N, Izu K, Sawada Y, Hino R, Nakano R, Shimajiri S, Nishimura I, Nakamura H, Sugiura K, Nakamura M.
  • Journal Title: Acta Derm Venereol Volume: 97 Pages: 410-411.
  • DOI: 10.2340/00015555-2527.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Striate palmoplantar keratoderma showing transgrediens in a patient harboring heterozygous nonsense mutations in both DSG1 and SERPINB7. (2017)
  • Author(s): Fukaura R, Takeichi T, Okuno Y, Kojima D, Kono M, Sugiura K, Suga Y, Akiyama M.
  • Journal Title: Acta Derm Venereol Volume: 97 Pages: 399-401.
  • DOI: 10.2340/00015555-2553.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Punctate Palmoplantar Keratoderma Type 1 with a Novel AAGAB Frameshift Mutation: intrafamilial phenotype variation due to aging. (2017)
  • Author(s): Kono M, Fukai K, Shimizu N, Nagao J, Takeichi T, Tsuruta D, Sugiura K, Akiyama M.
  • Journal Title: J Eur Acad Dermatol Venereol Volume: 31 Pages: e175-e176.
  • DOI: 10.1111/jdv.13906.
  • Int'l Joint Research
• [Journal Article] Ripple-pattern lichen amyloidosis in a case of ichthyosis vulgaris with a novel FLG mutation. (2017)
  • Author(s): Kono M, Nishida K, Takeichi T, Sugiura K, Akiyama M.
  • Journal Title: J Eur Acad Dermatol Venereol Volume: 31 Pages: e130-e132.
  • DOI: 10.1111/jdv.13877.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A case of epidermolytic ichthyosis showing a very mild phenotype due to a novel tail extension mutation in KRT10. (2017)
  • Author(s): Kono M, Fukai K, Omura R, Sugawara K, Tsuruta D, K Sugiura K, Akiyama M.
  • Journal Title: J Eur Acad Dermatol Venereol Volume: 31 Pages: e68-e69.
  • DOI: 10.1111/jdv.13729.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pityriasis rubra pilaris type V as an auto inflammatory disease by CARD14 mutations. (2017)
  • Author(s): Takeichi T, Sugiura K, Nomura T, Sakamoto T, Ogawa Y, Oiso N, Futei Y, Fujisaki A, Koizumi A, Aoyama Y, Nakajima K, Hatano Y, Hayashi K, Akemi Ishida-Yamamoto A, Fujiwara S, Sano S, Iwatsuki K, Kawada A, Suga Y, Shimizu H, McGrath JA, Akiyama M.
  • Journal Title: JAMA Dermatol Volume: 153 Pages: 66-70.
  • DOI: 10.1001/jamadermatol.2016.3601.
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] A newly revealed IL36RN mutation in sibling cases complements our IL36RN mutation statistics for generalized pustular psoriasis. (2017)
  • Author(s): Takeichi T, Togawa Y, Taniguchi R, Okuno Y, Kono M, Matsue H, Sugiura K, Akiyama M.
  • Journal Title: J Dermatol Sci Volume: 85 Pages: 58-60.
  • DOI: 10.1016/j.jdermsci.2016.10.009.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Novel and recurrent ATP2A2 mutations in Japanese patients with Darier’s disease. (2016)
  • Author(s): Noda K, Takeichi T, Okuno Y, Takama H, Miura S, Kagami S, Hino H, Nakamura Y, Fujio Y, Konohana I, Otani A, Mukai H, Sugiura K, Akiyama M.
  • Journal Title: Nagoya J Med Sci Volume: 78 Pages: 485-492.
  • DOI: 10.18999/nagjms.78.4.485.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Darier’s disease complicated with schizophrenia caused by a novel ATP2A2 mutation. (2016)
  • Author(s): Takeichi T, Sugiura K, Nakamura Y, Konohana I, Akiyama M.
  • Journal Title: .Acta Derm Venereol Volume: 96 Pages: 993-994.
  • DOI: 10.2340/00015555-2422.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Epididymitis with epididymal cysts indicating IgA vasculitis in an adult. (2016)
  • Author(s): Nanbu A, Sugiura K, Sassa N, Akiyama M.
  • Journal Title: Acta Derm Venereol Volume: 96 Pages: 985-986.
  • DOI: 10.2340/00015555-2382.
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Hyperpigmentation over the metacarpophalangeal joints and the malleoli in a case of hyaline fibromatosis syndrome with ANTXR2 mutations. (2016)
  • Author(s): Sugiura K, Ohno A, Kono M, Kitoh H, Itomi K, Akiyama M.
  • Journal Title: J Eur Acad Dermatol Venereol Volume: 30 Pages: e44-e46.
  • DOI: 10.1111/jdv.13290.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A 45-year-old woman with Ehlers-Danlos syndrome caused by dermatan 4-O-sulfotransferase-1 deficiency: implications of dermatan sulfate depletion on early aging. (2016)
  • Author(s): Kono M, Hasegawa-Murakami Y, Sugiura K, Ono M, Toriyama K, Miyake N, Hatamochi A, Kamei Y, Kosho T, Akiyama M.
  • Journal Title: Acta Derm Venereol Volume: 96 Pages: 830-831.
  • DOI: 10.2340/00015555-2390.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Erythrokeratoderma variabilis caused by p.Gly45Glu in connexin 31: the importance of the first extracellular loop glycine residue for gap junction function. (2016)
  • Author(s): Takeichi T, Sugiura K, Hsu CK, Nomura T, Takama H, Simpson MA, Shimizu H, McGrath JA, Akiyama M.
  • Journal Title: Acta Derm Venereol Volume: 96 Pages: 577-579.
  • DOI: 10.2340/00015555-2307.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lipodystrophia centrifugalis abdominalis infantilis accompanied by idiopathic encephalopathy. (2016)
  • Author(s): Kaibuchi-Noda K, Sugiura K, Akiyama M.
  • Journal Title: J Eur Acad Dermatol Venereol Volume: 30 Pages: 862-864.
  • DOI: 10.1111/jdv.13031.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Dyschromatosis symmetrica hereditaria and Aicardi-Goutières syndrome 6 are phenotypic variants caused by ADAR1 mutations. (2016)
  • Author(s): Kono M, Matsumoto F, Suzuki Y, Suganuma M, Saitsu H, Ito Y, Fujiwara S, Matsumoto K, Moriwaki S, Matsumoto N, Tomita Y, Sugiura K, Akiyama M.
  • Journal Title: J Invest Dermatol Volume: 136 Pages: 875-878.
  • DOI: 10.1016/j.jid.2015.12.034.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Cutaneous Manifestations in Dermatomyositis: Key Clinical and Serological Features-a Comprehensive Review (2016)
  • Author(s): Muro Y, Sugiura K, Akiyama M.
  • Journal Title: Clin Rev Allergy Immunol Volume: 51 Pages: 293-302.
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Genetic background of generalized pustular psoriasis (2016)
  • Author(s): Kazumitsu Sugiura
  • Organizer: 日本研究皮膚科学会第41回年次学術大会・総会
  • Place of Presentation: 仙台市(仙台国際センター）
  • Year and Date: 2016-12-09 – 2016-12-09
  • Invited
• [Presentation] IL36RN 遺伝子と膿疱性乾癬 (2016)
  • Author(s): 杉浦 一充
  • Organizer: 第46回日本皮膚アレルギー・接触皮膚炎学会総会学術大会
  • Place of Presentation: 東京都新宿区(京王プラザホテル)
  • Year and Date: 2016-11-06 – 2016-11-06
  • Invited
• [Presentation] IL-36と乾癬 (2016)
  • Author(s): 杉浦 一充
  • Organizer: 第80回日本皮膚科学会東部支部学術大会
  • Place of Presentation: 浜松市(浜松アクトシティ)
  • Year and Date: 2016-10-29 – 2016-10-29
  • Invited
• [Presentation] 膿疱症とDITRA(deficiency of interleukin-36 receptor antagonist) (2016)
  • Author(s): 杉浦 一充
  • Organizer: 第32回日本臨床皮膚科医会 東海北陸ブロック総会
  • Place of Presentation: 名古屋市(キャッスルプラザ)
  • Year and Date: 2016-10-16 – 2016-10-16
  • Invited
• [Presentation] Genetic background of pustular psoriasis (2016)
  • Author(s): Kazumitsu Sugiura
  • Organizer: 12th Meeting of the German-Japanese Society of Dermatology
  • Place of Presentation: 東京都文京区(東京医科歯科大学)
  • Year and Date: 2016-10-15 – 2016-10-15
  • Int'l Joint Research / Invited
• [Presentation] 皮膚科の自己炎症性疾患；DITRAとCAMPS (2016)
  • Author(s): 杉浦 一充
  • Organizer: 日本皮膚科学会愛媛地方会第64回学術大会
  • Place of Presentation: 松山市(いよてつ会館)
  • Year and Date: 2016-10-01 – 2016-10-01
  • Invited
• [Presentation] 自己炎症性疾患としての膿疱性乾癬 (2016)
  • Author(s): 杉浦 一充
  • Organizer: 第31回日本乾癬学会学術大会
  • Place of Presentation: 宇都宮市(ホテル東日本宇都宮)
  • Year and Date: 2016-09-02 – 2016-09-02
  • Invited
• [Presentation] IL-36R阻害剤 (2016)
  • Author(s): 杉浦 一充
  • Organizer: 第31回日本乾癬学会学術大会
  • Place of Presentation: 宇都宮市(ホテル東日本宇都宮)
  • Year and Date: 2016-09-02 – 2016-09-02
  • Invited
• [Presentation] Genetic background of pustular psoriasis (2016)
  • Author(s): Kazumitsu Sugiura
  • Organizer: Asia-Pacific Combined Dermatology Research Conference
  • Place of Presentation: Noosa, Australia(Sofitel Pacific Resort Noosa Hotel)
  • Year and Date: 2016-08-27 – 2016-08-27
  • Int'l Joint Research / Invited
• [Presentation] インターロイキン36受容体拮抗因子欠損と加齢が身体に及ぼす影響の検討 (2016)
  • Author(s): 杉浦 一充
  • Organizer: 第12回加齢皮膚医学研究会
  • Place of Presentation: 神戸市（兵庫県医師会館）
  • Year and Date: 2016-07-09 – 2016-07-09
  • Invited
• [Presentation] 意外な遺伝性皮膚疾患 (2016)
  • Author(s): 杉浦一充
  • Organizer: 第276回日本皮膚科学会東海地方会
  • Place of Presentation: 名古屋市（大正製薬(株)中日本支店）
  • Year and Date: 2016-06-26 – 2016-06-26
  • Invited
• [Presentation] 汎発性膿疱性乾癬における膿疱形成のメカニズム (2016)
  • Author(s): 杉浦 一充
  • Organizer: 第115回日本皮膚科学会総会
  • Place of Presentation: 京都市（京都国際会館）
  • Year and Date: 2016-06-03 – 2016-06-03
  • Invited
• [Presentation] 遺伝性の乾癬：DITRAとCAMPS (2016)
  • Author(s): 杉浦 一充
  • Organizer: 第60回日本リウマチ学会総会・学術集会
  • Place of Presentation: 横浜市（パシフィコ横浜）
  • Year and Date: 2016-04-21 – 2016-04-21
  • Invited
• [Presentation] Genetic background of generalized pustular psoriasis (2016)
  • Author(s): Kazumitsu Sugiura
  • Organizer: International congress of human genetics
  • Place of Presentation: 京都市(京都国際会館）
  • Year and Date: 2016-04-06 – 2016-04-06
  • Int'l Joint Research / Invited