Analyses of effects of variants with uncertain significance in the cancer related genes on the carcinogenesis in general population

• Project/Area Number: 17K07193
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor diagnostics
• Research Institution: Miyagi Prefectural Hospital Organization Miyagi Cancer Center (2018-2020); Tohoku University (2017)
• Principal Investigator: Yasuda Jun 地方独立行政法人宮城県立病院機構宮城県立がんセンター(研究所), 発がん制御研究部, 部長 (00281684)
• Co-Investigator(Kenkyū-buntansha): 齋藤 さかえ 東北大学, 東北メディカル・メガバンク機構, 講師 (20335491)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: がん素因遺伝子 / VUS / 前向きゲノムコホート / 家族性乳がん卵巣がん症候群 / 有害変異 / がん関連遺伝子 / 一般住民 / 全ゲノム解読 / ゲノム解析

Outline of Final Research Achievements

We investigated moderately morbid VUS of familial tumor-associated genes based on Tohoku University's Japanese whole genome reference panel data to see whether they indicate an accumulation of history of malignancy and family history of malignancy based on the questionnaire information. We examined BRCA1/2, the causative gene of hereditary breast and ovarian cancer syndromes, which is included in the Japanese standard genome panel 3.5KJPNv2, and established the conditions for moderately pathological mutations (CADD>25, Eigen>0.5, MAF<0.0005). Furthermore, we compared the results with those of 35,000 participants' past and family history data collected by the Tohoku Medical Megabank Project and found that the incidence of cancer in sisters of the cohort with these moderately pathological mutations was statistically significantly higher than that of their counterparts, which was reported in a European peer-reviewed journal.

Academic Significance and Societal Importance of the Research Achievements

家族性腫瘍関連遺伝子の中等度に病的なVUSの腫瘍発症への寄与が統計学的に検出可能であることを示したのは前向きゲノムコホートが研究上有用であることを示した。また、こうした腫瘍関連遺伝子の中等度の病的変異を持つ個人にとってがんの発症予防や早期の検診受診などで直接利益が生まれる可能性がある。今後こうした中等度の病的変異をリスク要因として組み込んだ精密医療の確立に大きく資する研究成果と考えられる。

Research Products

• [Journal Article] Study Profile of the Tohoku Medical Megabank Community-Based Cohort Study (2021)
  • Author(s): Hozawa A, Tanno K, Nakaya N, Nakamura T, Tsuchiya N, Hirata T, Narita A, Kogure M, Nochioka K, Sasaki R, Takanashi N, Otsuka K, Sakata K, Kuriyama S, Kikuya M, 13名略, Kobayashi T, 53名略, Yamamoto M.
  • Journal Title: Journal of Epidemiology Volume: 31 Issue: 1 Pages: 65-76
  • DOI: 10.2188/jea.JE20190271
  • NAID: 130007966030
  • ISSN: 0917-5040, 1349-9092
  • Year and Date: 2021-01-05
  • Peer Reviewed / Open Access
• [Journal Article] Robustness of a Cancer Profiling Test Using Formalin-fixed Paraffin Embedded Tumor Specimens (2021)
  • Author(s): ITO SHIN、SATO IKURO、MOCHIZUKI MAI、YAMAGUCHI KAZUNORI、TAMAI KEIICHI、MINATO TAKAMICHI、TANUMA NOBUHIRO、SHIMA HIROSHI、YASUDA JUN
  • Journal Title: Anticancer Research Volume: 41 Issue: 3 Pages: 1341-1348
  • DOI: 10.21873/anticanres.14891
  • Peer Reviewed / Open Access
• [Journal Article] A global phylogenetic analysis of Japanese tonsil-derived Epstein-Barr virus strains using viral whole-genome cloning and long-read sequencing (2021)
  • Author(s): Yajima Misako、Kakuta Risako、Saito Yutaro、Kitaya Shiori、Toyoda Atsushi、Ikuta Kazufumi、Yasuda Jun、Ohta Nobuo、Kanda Teru
  • Journal Title: Journal of General Virology Volume: 102 Issue: 3
  • DOI: 10.1099/jgv.0.001549
  • Peer Reviewed / Open Access
• [Journal Article] Construction and integration of three de novo Japanese human genome assemblies toward a population-specific reference (2021)
  • Author(s): Takayama Jun、Tadaka Shu、Yano Kenji、Katsuoka Fumiki、Gocho Chinatsu、Funayama Takamitsu、Makino Satoshi、Okamura Yasunobu、Kikuchi Atsuo、Sugimoto Sachiyo、Kawashima Junko、Otsuki Akihito、Sakurai-Yageta Mika、Yasuda Jun、Kure Shigeo、Kinoshita Kengo、Yamamoto Masayuki、Tamiya Gen
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 226-226
  • DOI: 10.1038/s41467-020-20146-8
  • Peer Reviewed / Open Access
• [Journal Article] Novel candidates of pathogenic variants of the BRCA1 and BRCA2 genes from a dataset of 3,552 Japanese whole genomes (3.5KJPNv2) (2021)
  • Author(s): Tokunaga Hideki、Iida Keita、Hozawa Atsushi、Ogishima Soichi、Watanabe Yoh、Shigeta Shogo、Shimada Muneaki、Yamaguchi-Kabata Yumi、Tadaka Shu、Katsuoka Fumiki、Ito Shin、Kumada Kazuki、Hamanaka Yohei、Fuse Nobuo、Kinoshita Kengo、Yamamoto Masayuki、Yaegashi Nobuo、Yasuda Jun
  • Journal Title: PLOS ONE Volume: 16 Issue: 1 Pages: e0236907-e0236907
  • DOI: 10.1371/journal.pone.0236907
  • Peer Reviewed / Open Access
• [Journal Article] Discovery of a chemical compound that suppresses expression of BEX2, a dormant cancer stem cell-related protein (2021)
  • Author(s): Saijoh S, Nakamura-Shima M, Shibuya-Takahashi R, Ito R, Sugawara A, Yamazaki T, Imai T, Asada Y, Matsuura K, Iwai W, Wakui Y, Abue M, Kawamura S, Katayose Y, Fujimori H, Mochizuki M, Yasuda J, Yamaguchi K, Sugamura K,Satoh K, Katori Y, Tamai K.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 537 Pages: 132-139
  • DOI: 10.1016/j.bbrc.2020.11.022
  • Peer Reviewed
• [Journal Article] BEX2 suppresses mitochondrial activity and is required for dormant cancer stem cell maintenance in intrahepatic cholangiocarcinoma (2020)
  • Author(s): Tamai Keiichi、Nakamura-Shima Mao、Shibuya-Takahashi Rie、Kanno Shin-Ichiro、Yasui Akira、Mochizuki Mai、Iwai Wataru、Wakui Yuta、Abue Makoto、Yamamoto Kuniharu、Miura Koh、Mizuma Masamichi、Unno Michiaki、Kawamura Sadafumi、Sato Ikuro、Yasuda Jun、Yamaguchi Kazunori、Sugamura Kazuo、Satoh Kennichi
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 21592-21592
  • DOI: 10.1038/s41598-020-78539-0
  • Peer Reviewed / Open Access
• [Journal Article] Aberrant (pro)renin receptor expression induces genomic instability in pancreatic ductal adenocarcinoma through upregulation of SMARCA5/SNF2H (2020)
  • Author(s): Shibayama,Y., Takahashi, K., Yamaguchi, H., Yasuda, J., Yamazaki, D., Rahman, A., Fujimori, T., Fujisawa, Y., Takai, S., Furukawa, T., Nakagawa, T., Ohsaki, H., Kobara, H., Wong, J.H., Masaki, T., Yuzawa, Y., Kiyomoto, H., Yachida, S., Fujimoto, A., Nishiyama, A.
  • Journal Title: Communications Biology Volume: 3 Issue: 1 Pages: 724-724
  • DOI: 10.1038/s42003-020-01434-x
  • NAID: 130008001357
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of HLA-G long-read genomic sequences in mother?offspring pairs with preeclampsia (2020)
  • Author(s): Nishizawa Ayako、Kumada Kazuki、Tateno Keiko、Wagata Maiko、Saito Sakae、Katsuoka Fumiki、Mizuno Satoshi、Ogishima Soichi、Yamamoto Masayuki、Yasuda Jun、Sugawara Junichi
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 20027-20027
  • DOI: 10.1038/s41598-020-77081-3
  • Peer Reviewed / Open Access
• [Journal Article] Identification of the Novel Variants in Patients With Chronic Thromboembolic Pulmonary Hypertension (2020)
  • Author(s): Yaoita N, Satoh K, Tatebe S, Yasuda S, Shimokawa H et al.
  • Journal Title: J Am Heart Assoc . Volume: 9 Issue: 21 Pages: 1-12
  • DOI: 10.1161/jaha.120.015902
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of a Monoclonal Antibody That Recognizes Cysteine-Rich Domain 1 of Human CD271 (2020)
  • Author(s): Morita Shinkichi、Mochizuki Mai、Shibuya-Takahashi Rie、Nakamura-Shima Mao、Yamazaki Tomoko、Imai Takayuki、Asada Yukinori、Matsuura Kazuto、Kawamura Sadafumi、Yamaguchi Kazunori、Yasuda Jun、Sugamura Kazuo、Katori Yukio、Satoh Kennichi、Tamai Keiichi
  • Journal Title: Monoclonal Antibodies in Immunodiagnosis and Immunotherapy Volume: 39 Issue: 1 Pages: 6-11
  • DOI: 10.1089/mab.2019.0040
  • Peer Reviewed
• [Journal Article] Novel activating KRAS mutation candidates in lung adenocarcinoma (2020)
  • Author(s): Abe Jiro、Tanuma Nobuhiro、Nomura Miyuki、Ito Shin、Kasugai Isao、Sato Ikuro、Tamai Keiichi、Mochizuki Mai、Yamaguchi Kazunori、Shima Hiroshi、Okada Yoshinori、Yasuda Jun
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 522 Issue: 3 Pages: 690-696
  • DOI: 10.1016/j.bbrc.2019.11.151
  • Peer Reviewed
• [Journal Article] CD109 promotes the tumorigenic ability and metastatic motility of pancreatic ductal adenocarcinoma cells (2020)
  • Author(s): Hatsuzawa Yuuri、Yamaguchi Kazunori、Takanashi Tomoka、Sato Ikuro、Tamai Keiichi、Mochizuki Mai、Iwai Wataru、Wakui Yuta、Abue Makoto、Yamamoto Kuniharu、Yasuda Jun、Mizuma Masamichi、Unno Michiaki、Sugamura Kazuo
  • Journal Title: Pancreatology Volume: 20 Issue: 3 Pages: 493-500
  • DOI: 10.1016/j.pan.2020.01.013
  • Peer Reviewed
• [Journal Article] Identification of genetic alterations in extramammary Paget disease using whole exome analysis (2019)
  • Author(s): Kiniwa Yukiko、Yasuda Jun、Saito Sakae、Saito Rumiko、Motoike Ikuko N.、Danjoh Inaho、Kinoshita Kengo、Fuse Nobuo、Yamamoto Masayuki、Okuyama Ryuhei
  • Journal Title: Journal of Dermatological Science Volume: 94 Issue: 1 Pages: 229-235
  • DOI: 10.1016/j.jdermsci.2019.03.006
  • Peer Reviewed / Open Access
• [Journal Article] Pathogenic mutations identified by a multimodality approach in 117 Japanese Fanconi anemia patients. (2019)
  • Author(s): Mori M, Hira A, Yoshida K, Muramatsu H, Okuno Y, Shiraishi Y, Anmae M, Yasuda J, Tadaka S, Kinoshita K, Osumi T, Noguchi Y, Adachi S, Kobayashi R, Kawabata H, Imai K, Morio T, Tamura K, Takaori-Kondo A, Yamamoto M, Miyano S, Kojima S, Ito E, Ogawa S, Matsuo K, Yabe H, Yabe M, Takata M.
  • Journal Title: Haematologica. Volume: - Issue: 10 Pages: 1962-1973
  • DOI: 10.3324/haematol.2018.207241
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Construction of JRG (Japanese reference genome) with single-molecule real-time sequencing (2019)
  • Author(s): Nagasaki Masao、（中略）、Yasuda Jun（２４人中２３番目）、Yamamoto Masayuki
  • Journal Title: Human Genome Variation Volume: 6 Issue: 1 Pages: 1-18
  • DOI: 10.1038/s41439-019-0057-7
  • Peer Reviewed / Open Access
• [Journal Article] Genome analyses for the Tohoku Medical Megabank Project towards establishment of personalized healthcare (2018)
  • Author(s): Yasuda Jun、Kinoshita Kengo、et al.,
  • Journal Title: The Journal of Biochemistry Volume: 165 Issue: 2 Pages: 139-158
  • DOI: 10.1093/jb/mvy096
  • NAID: 40021809939
  • Peer Reviewed / Open Access
• [Journal Article] Regional genetic differences among Japanese populations and performance of genotype imputation using whole-genome reference panel of the Tohoku Medical Megabank Project (2018)
  • Author(s): Yasuda Jun、et al.,
  • Journal Title: BMC Genomics Volume: 19 Issue: 1 Pages: 551-551
  • DOI: 10.1186/s12864-018-4942-0
  • Peer Reviewed / Open Access
• [Journal Article] Construction of full-length Japanese reference panel of class I HLA genes with single-molecule, real-time sequencing (2018)
  • Author(s): Mimori T, Fumiki K, Sakae S、Naoki N, 、Akira O, Minegishi N, Kinoshita K, Nagasaki M, Yamamoto M
  • Journal Title: Pharmacogenomics Volume: 63 Issue: 2 Pages: 213-230
  • DOI: 10.1038/s41397-017-0010-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Evaluation of reported pathogenic variants and their frequencies in a Japanese population based on a whole-genome reference panel of 2049 individuals article (2018)
  • Author(s): Y Yamaguchi-Kabata, J Yasuda, O Tanabe, Y Suzuki, H Kawame, N Fuse, M Nagasaki, Y Kawai, K Kojima, F Katsuoka, S Saito, I Danjoh, I Motoike, R Yamashita, S Koshiba, D Saigusa, G Tamiya, S Kure, N Yaegashi, Y Kawaguchi, F Nagami, S Kuriyama, J Sugawara, N Minegishi, A Hozawa, T Takai-Igarashi, K Kinoshita, M Yamamoto.
  • Journal Title: Journal of Human Genetics. Volume: 63 Issue: 2 Pages: 213
  • DOI: 10.1038/s10038-017-0347-1
  • URL: https://pure.teikyo.jp/en/publications/68f9baf0-ba55-4278-8354-a10148b91802
  • Peer Reviewed / Open Access
• [Journal Article] Identification of somatic genetic alterations in ovarian clear cell carcinoma with next generation sequencing (2017)
  • Author(s): Shibuya Yusuke、Tokunaga Hideki、Saito Sakae、Shimokawa Kazurou、Katsuoka Fumiki、Bin Li、Kojima Kaname、Nagasaki Masao、Yamamoto Masayuki、Yaegashi Nobuo、Yasuda Jun
  • Journal Title: Genes Chromosomes Cancer. Volume: 57 Issue: 2 Pages: 51-60
  • DOI: 10.1002/gcc.22507
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide identification of inter-individually variable DNA methylation sites improves the efficacy of epigenetic association studies (2017)
  • Author(s): Hachiya Tsuyoshi、Furukawa Ryohei、Shiwa Yuh、Ohmomo Hideki、Ono Kanako、Katsuoka Fumiki、Nagasaki Masao、Yasuda Jun、Fuse Nobuo、Kinoshita Kengo、Yamamoto Masayuki、Tanno Kozo、Satoh Mamoru、Endo Ryujin、Sasaki Makoto、Sakata Kiyomi、Kobayashi Seiichiro、Ogasawara Kuniaki、Hitomi Jiro、Sobue Kenji、Shimizu Atsushi
  • Journal Title: NPJ Genom Med. Volume: 2 Issue: 1 Pages: 0016-5
  • DOI: 10.1038/s41525-017-0016-5
  • Peer Reviewed / Open Access
• [Presentation] Mutation spectrum of MEF cells caused by overexpression of novel activating KRAS mutation candidates in lung adenocarcinoma (2020)
  • Author(s): Jiro Abe, Nobuhiro Tanuma, Miyuki Nomura, Shin Ito, Isao Kasugai, Ikuro Sato, Keiichi Tamai, Mai Mochizuki, Kazunori Yamaguchi, Hiroshi Shima, Yoshinori Okada, Jun Yasuda
  • Organizer: Annual Meeting of American Association of Cancer Research
  • Int'l Joint Research
• [Presentation] Variants of uncertain significance of the cancer predisposing genes in 3.5 thousand Japanese whole genome sequencing data (2019)
  • Author(s): Jun Yasuda
  • Organizer: AACR Annual Meeting 2019
  • Int'l Joint Research
• [Presentation] Identification of somatic genetic alterations in ovarian clear cell carcinomas with next generation seqeuencing (2017)
  • Author(s): Yusuke Shibuya, (five others), Jun Yasuda
  • Organizer: SRI 64th Annual Scientific Meeting
  • Int'l Joint Research
• [Presentation] Identification of somatic genetic alterations in ovarian clear cell carcinomas with next generation seqeuencing (2017)
  • Author(s): Yusuke Shibuya, (five others), Jun Yasuda
  • Organizer: 日本産婦人科学会