Molecular classification and diagnostics of upper urinary tract urothelial carcinoma

Yoichi Fujii; Yusuke Sato; Hiromichi Suzuki; Nobuyuki Kakiuchi; Tetsuichi Yoshizato; Andrew T. Lenis; Shigekatsu Maekawa; Akira Yokoyama; Yasuhide Takeuchi; Yoshikage Inoue; Yotaro Ochi; Yusuke Shiozawa; Kosuke Aoki; Kenichi Yoshida; Keisuke Kataoka; Masahiro M. Nakagawa; Yasuhito Nannya; Hideki Makishima; Jimpei Miyakawa; Taketo Kawai; Teppei Morikawa; Yuichi Shiraishi; Kenichi Chiba; Hiroko Tanaka; Genta Nagae; Masashi Sanada; Eiji Sugihara; Taka Aki Sato; Tohru Nakagawa; Masashi Fukayama; Tetsuo Ushiku; Hiroyuki Aburatani; Satoru Miyano; Jonathan A. Coleman; Yukio Homma; David B. Solit; Haruki Kume; Seishi Ogawa

doi:10.1016/j.ccell.2021.05.008

Molecular classification and diagnostics of upper urinary tract urothelial carcinoma

Yoichi Fujii, Yusuke Sato, Hiromichi Suzuki, Nobuyuki Kakiuchi, Tetsuichi Yoshizato, Andrew T. Lenis, Shigekatsu Maekawa, Akira Yokoyama, Yasuhide Takeuchi, Yoshikage Inoue, Yotaro Ochi, Yusuke Shiozawa, Kosuke Aoki, Kenichi Yoshida, Keisuke Kataoka, Masahiro M. Nakagawa, Yasuhito Nannya, Hideki Makishima, Jimpei Miyakawa, Taketo KawaiTeppei Morikawa, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Genta Nagae, Masashi Sanada, Eiji Sugihara, Taka Aki Sato, Tohru Nakagawa, Masashi Fukayama, Tetsuo Ushiku, Hiroyuki Aburatani, Satoru Miyano, Jonathan A. Coleman, Yukio Homma, David B. Solit, Haruki Kume, Seishi Ogawa

Research output: Contribution to journal › Article › peer-review

53 Citations (Scopus)

Abstract

Upper urinary tract urothelial carcinoma (UTUC) is one of the common urothelial cancers. Its molecular pathogenesis, however, is poorly understood, with no useful biomarkers available for accurate diagnosis and molecular classification. Through an integrated genetic study involving 199 UTUC samples, we delineate the landscape of genetic alterations in UTUC enabling genetic/molecular classification. According to the mutational status of TP53, MDM2, RAS, and FGFR3, UTUC is classified into five subtypes having discrete profiles of gene expression, tumor location/histology, and clinical outcome, which is largely recapitulated in an independent UTUC cohort. Sequencing of urine sediment-derived DNA has a high diagnostic value for UTUC with 82.2% sensitivity and 100% specificity. These results provide a solid basis for better diagnosis and management of UTUC.

Original language	English
Pages (from-to)	793-809.e8
Journal	Cancer Cell
Volume	39
Issue number	6
DOIs	https://doi.org/10.1016/j.ccell.2021.05.008
Publication status	Published - 2021 Jun 14
Externally published	Yes

Keywords

FGFR3
RAS
TP53
hypermutation
integrated molecular study
molecular classification
molecular diagnostic
transcriptome
upper urinary tract urothelial carcinoma
urothelial carcinoma

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.ccell.2021.05.008

Cite this

Fujii, Y., Sato, Y., Suzuki, H., Kakiuchi, N., Yoshizato, T., Lenis, A. T., Maekawa, S., Yokoyama, A., Takeuchi, Y., Inoue, Y., Ochi, Y., Shiozawa, Y., Aoki, K., Yoshida, K., Kataoka, K., Nakagawa, M. M., Nannya, Y., Makishima, H., Miyakawa, J., ... Ogawa, S. (2021). Molecular classification and diagnostics of upper urinary tract urothelial carcinoma. Cancer Cell, 39(6), 793-809.e8. https://doi.org/10.1016/j.ccell.2021.05.008

Fujii, Y, Sato, Y, Suzuki, H, Kakiuchi, N, Yoshizato, T, Lenis, AT, Maekawa, S, Yokoyama, A, Takeuchi, Y, Inoue, Y, Ochi, Y, Shiozawa, Y, Aoki, K, Yoshida, K, Kataoka, K, Nakagawa, MM, Nannya, Y, Makishima, H, Miyakawa, J, Kawai, T, Morikawa, T, Shiraishi, Y, Chiba, K, Tanaka, H, Nagae, G, Sanada, M, Sugihara, E, Sato, TA, Nakagawa, T, Fukayama, M, Ushiku, T, Aburatani, H, Miyano, S, Coleman, JA, Homma, Y, Solit, DB, Kume, H & Ogawa, S 2021, 'Molecular classification and diagnostics of upper urinary tract urothelial carcinoma', Cancer Cell, vol. 39, no. 6, pp. 793-809.e8. https://doi.org/10.1016/j.ccell.2021.05.008

@article{9e220643ecc24defa8f4d3a2a3c3258b,

title = "Molecular classification and diagnostics of upper urinary tract urothelial carcinoma",

abstract = "Upper urinary tract urothelial carcinoma (UTUC) is one of the common urothelial cancers. Its molecular pathogenesis, however, is poorly understood, with no useful biomarkers available for accurate diagnosis and molecular classification. Through an integrated genetic study involving 199 UTUC samples, we delineate the landscape of genetic alterations in UTUC enabling genetic/molecular classification. According to the mutational status of TP53, MDM2, RAS, and FGFR3, UTUC is classified into five subtypes having discrete profiles of gene expression, tumor location/histology, and clinical outcome, which is largely recapitulated in an independent UTUC cohort. Sequencing of urine sediment-derived DNA has a high diagnostic value for UTUC with 82.2% sensitivity and 100% specificity. These results provide a solid basis for better diagnosis and management of UTUC.",

keywords = "FGFR3, RAS, TP53, hypermutation, integrated molecular study, molecular classification, molecular diagnostic, transcriptome, upper urinary tract urothelial carcinoma, urothelial carcinoma",

author = "Yoichi Fujii and Yusuke Sato and Hiromichi Suzuki and Nobuyuki Kakiuchi and Tetsuichi Yoshizato and Lenis, {Andrew T.} and Shigekatsu Maekawa and Akira Yokoyama and Yasuhide Takeuchi and Yoshikage Inoue and Yotaro Ochi and Yusuke Shiozawa and Kosuke Aoki and Kenichi Yoshida and Keisuke Kataoka and Nakagawa, {Masahiro M.} and Yasuhito Nannya and Hideki Makishima and Jimpei Miyakawa and Taketo Kawai and Teppei Morikawa and Yuichi Shiraishi and Kenichi Chiba and Hiroko Tanaka and Genta Nagae and Masashi Sanada and Eiji Sugihara and Sato, {Taka Aki} and Tohru Nakagawa and Masashi Fukayama and Tetsuo Ushiku and Hiroyuki Aburatani and Satoru Miyano and Coleman, {Jonathan A.} and Yukio Homma and Solit, {David B.} and Haruki Kume and Seishi Ogawa",

note = "Funding Information: This work was supported by the Japan Agency for Medical Research and Development (AMED); the Project for Development of Innovative Research on Cancer Therapeutics (JP15cm0106056 and JP19cm0106501 to S.O.) and the Core Research for Evolutional Science and Technology (CREST) (JP21gm1110011 to S.O.); the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) as ”Priority Issue on Post-K computer” (hp150265, hp160219, hp170227, hp180198, and hp190158 to S.O.) and “Program for Promoting Researches on the Supercomputer Fugaku” (hp200138 and hp210167 to S.O. and S. Miyano) (this research used computational resources of the K computer/ the supercomputer Fugaku provided by the RIKEN Advanced Institute for Computational Science through the HPCI System Research project); the Japan Society for the Promotion of Science (JSPS); Scientific Research on Innovative Areas (JP15H05909 to S.O. and S. Miyano; JP15H05912 to S. Miyano), KAKENHI (JP19H05656 to S.O.; JP15J12625 and JP19K18576 to Y. Sato), and “Stem Cell Aging and Disease” (14430052 to M.S.); Takeda Science Foundation (S.O. H.M. T.Y. Y. Sato); Uehara Memorial Foundation (H.S.); the Japanese Urological Association (Young Researcher Promotion Grant) ( Y. Sato); SGH Foundation (Y. Sato); and onsulted with and recieved honoraria from Pfizer, Loxo/Lilly Oncology, Vividion Therapeutics, Scorpion Therapeutics and BridgeBio. and theYasuda Medical Foundation (Y. Sato). S.O. is a recipient of JSPS Core-to-Core Program, A. Advanced Research Networks. The schematic illustration in the graphic abstract was created with BioRender.com. We thank Maki Nakamura and Takeshi Shirahari for technical assistance. We also thank Kenichi Hashimoto, Shoichi Nagamoto, Masaomi Ikeda, Toshikazu Okaneya, Yukimasa Matsuzawa, Kanade Hagiwara, Tomoyuki Kaneko, Hiroaki Nishimatsu, Yoshikazu Hirano, and all staff at the Department of Urology, The University of Tokyo Hospital, for collecting samples. Wethnk iLAC for sequencing support. Y.F. Y. Sato, H.S. T.N. Y.H. H.K. and S.O. designed the study. Y. Sato, T.K. T.N. Y.H. and H.K. provided specimens. J.M. T.M. M.F. and T.U. performed histological analysis. Y.F. N.K. A.Y. Y.I. Y.T. and S. Maekawa performed sample preparation. A.T.L. J.A.C. and D.B.S. provided MSKCC data. K.Y. M.S. E.S. and T.S. performed sequencing. Y.F. H.S. N.K. T.Y. Y.T. Y.O. Y. Shiozawa, K.K. M.M.N. Y.N. Y. Shiraishi, G.N. K.C. H.T. H.A. and S. Miyano performed bioinformatics analysis. Y.F. H.M. and S.O. prepared the manuscript. D.B.S. has consulted with and received honoraria from Pfizer, Loxo/Lilly Oncology, Vividion Therapeutics, Scorpion Therapeutics and BridgeBio. Funding Information: This work was supported by the Japan Agency for Medical Research and Development (AMED); the Project for Development of Innovative Research on Cancer Therapeutics ( JP15cm0106056 and JP19cm0106501 to S.O.) and the Core Research for Evolutional Science and Technology (CREST) ( JP21gm1110011 to S.O.); the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) as ”Priority Issue on Post-K computer” ( hp150265 , hp160219 , hp170227 , hp180198 , and hp190158 to S.O.) and “ Program for Promoting Researches on the Supercomputer Fugaku ” ( hp200138 and hp210167 to S.O. and S. Miyano) (this research used computational resources of the K computer/ the supercomputer Fugaku provided by the RIKEN Advanced Institute for Computational Science through the HPCI System Research project); the Japan Society for the Promotion of Science (JSPS); Scientific Research on Innovative Areas ( JP15H05909 to S.O. and S. Miyano; JP15H05912 to S. Miyano), KAKENHI ( JP19H05656 to S.O.; JP15J12625 and JP19K18576 to Y. Sato), and “Stem Cell Aging and Disease” ( 14430052 to M.S.); Takeda Science Foundation (S.O., H.M., T.Y., Y. Sato); Uehara Memorial Foundation (H.S.); the Japanese Urological Association (Young Researcher Promotion Grant) ( Y. Sato); SGH Foundation (Y. Sato); and onsulted with and recieved honoraria from Pfizer, Loxo/Lilly Oncology, Vividion Therapeutics, Scorpion Therapeutics and BridgeBio. and the Yasuda Medical Foundation (Y. Sato). S.O. is a recipient of JSPS Core-to-Core Program, A. Advanced Research Networks. The schematic illustration in the graphic abstract was created with BioRender.com . We thank Maki Nakamura and Takeshi Shirahari for technical assistance. We also thank Kenichi Hashimoto, Shoichi Nagamoto, Masaomi Ikeda, Toshikazu Okaneya, Yukimasa Matsuzawa, Kanade Hagiwara, Tomoyuki Kaneko, Hiroaki Nishimatsu, Yoshikazu Hirano, and all staff at the Department of Urology, The University of Tokyo Hospital, for collecting samples. Wethnk iLAC for sequencing support. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2021",

month = jun,

day = "14",

doi = "10.1016/j.ccell.2021.05.008",

language = "English",

volume = "39",

pages = "793--809.e8",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "6",

}

TY - JOUR

T1 - Molecular classification and diagnostics of upper urinary tract urothelial carcinoma

AU - Fujii, Yoichi

AU - Sato, Yusuke

AU - Suzuki, Hiromichi

AU - Kakiuchi, Nobuyuki

AU - Yoshizato, Tetsuichi

AU - Lenis, Andrew T.

AU - Maekawa, Shigekatsu

AU - Yokoyama, Akira

AU - Takeuchi, Yasuhide

AU - Inoue, Yoshikage

AU - Ochi, Yotaro

AU - Shiozawa, Yusuke

AU - Aoki, Kosuke

AU - Yoshida, Kenichi

AU - Kataoka, Keisuke

AU - Nakagawa, Masahiro M.

AU - Nannya, Yasuhito

AU - Makishima, Hideki

AU - Miyakawa, Jimpei

AU - Kawai, Taketo

AU - Morikawa, Teppei

AU - Shiraishi, Yuichi

AU - Chiba, Kenichi

AU - Tanaka, Hiroko

AU - Nagae, Genta

AU - Sanada, Masashi

AU - Sugihara, Eiji

AU - Sato, Taka Aki

AU - Nakagawa, Tohru

AU - Fukayama, Masashi

AU - Ushiku, Tetsuo

AU - Aburatani, Hiroyuki

AU - Miyano, Satoru

AU - Coleman, Jonathan A.

AU - Homma, Yukio

AU - Solit, David B.

AU - Kume, Haruki

AU - Ogawa, Seishi

N1 - Funding Information: This work was supported by the Japan Agency for Medical Research and Development (AMED); the Project for Development of Innovative Research on Cancer Therapeutics (JP15cm0106056 and JP19cm0106501 to S.O.) and the Core Research for Evolutional Science and Technology (CREST) (JP21gm1110011 to S.O.); the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) as ”Priority Issue on Post-K computer” (hp150265, hp160219, hp170227, hp180198, and hp190158 to S.O.) and “Program for Promoting Researches on the Supercomputer Fugaku” (hp200138 and hp210167 to S.O. and S. Miyano) (this research used computational resources of the K computer/ the supercomputer Fugaku provided by the RIKEN Advanced Institute for Computational Science through the HPCI System Research project); the Japan Society for the Promotion of Science (JSPS); Scientific Research on Innovative Areas (JP15H05909 to S.O. and S. Miyano; JP15H05912 to S. Miyano), KAKENHI (JP19H05656 to S.O.; JP15J12625 and JP19K18576 to Y. Sato), and “Stem Cell Aging and Disease” (14430052 to M.S.); Takeda Science Foundation (S.O. H.M. T.Y. Y. Sato); Uehara Memorial Foundation (H.S.); the Japanese Urological Association (Young Researcher Promotion Grant) ( Y. Sato); SGH Foundation (Y. Sato); and onsulted with and recieved honoraria from Pfizer, Loxo/Lilly Oncology, Vividion Therapeutics, Scorpion Therapeutics and BridgeBio. and theYasuda Medical Foundation (Y. Sato). S.O. is a recipient of JSPS Core-to-Core Program, A. Advanced Research Networks. The schematic illustration in the graphic abstract was created with BioRender.com. We thank Maki Nakamura and Takeshi Shirahari for technical assistance. We also thank Kenichi Hashimoto, Shoichi Nagamoto, Masaomi Ikeda, Toshikazu Okaneya, Yukimasa Matsuzawa, Kanade Hagiwara, Tomoyuki Kaneko, Hiroaki Nishimatsu, Yoshikazu Hirano, and all staff at the Department of Urology, The University of Tokyo Hospital, for collecting samples. Wethnk iLAC for sequencing support. Y.F. Y. Sato, H.S. T.N. Y.H. H.K. and S.O. designed the study. Y. Sato, T.K. T.N. Y.H. and H.K. provided specimens. J.M. T.M. M.F. and T.U. performed histological analysis. Y.F. N.K. A.Y. Y.I. Y.T. and S. Maekawa performed sample preparation. A.T.L. J.A.C. and D.B.S. provided MSKCC data. K.Y. M.S. E.S. and T.S. performed sequencing. Y.F. H.S. N.K. T.Y. Y.T. Y.O. Y. Shiozawa, K.K. M.M.N. Y.N. Y. Shiraishi, G.N. K.C. H.T. H.A. and S. Miyano performed bioinformatics analysis. Y.F. H.M. and S.O. prepared the manuscript. D.B.S. has consulted with and received honoraria from Pfizer, Loxo/Lilly Oncology, Vividion Therapeutics, Scorpion Therapeutics and BridgeBio. Funding Information: This work was supported by the Japan Agency for Medical Research and Development (AMED); the Project for Development of Innovative Research on Cancer Therapeutics ( JP15cm0106056 and JP19cm0106501 to S.O.) and the Core Research for Evolutional Science and Technology (CREST) ( JP21gm1110011 to S.O.); the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) as ”Priority Issue on Post-K computer” ( hp150265 , hp160219 , hp170227 , hp180198 , and hp190158 to S.O.) and “ Program for Promoting Researches on the Supercomputer Fugaku ” ( hp200138 and hp210167 to S.O. and S. Miyano) (this research used computational resources of the K computer/ the supercomputer Fugaku provided by the RIKEN Advanced Institute for Computational Science through the HPCI System Research project); the Japan Society for the Promotion of Science (JSPS); Scientific Research on Innovative Areas ( JP15H05909 to S.O. and S. Miyano; JP15H05912 to S. Miyano), KAKENHI ( JP19H05656 to S.O.; JP15J12625 and JP19K18576 to Y. Sato), and “Stem Cell Aging and Disease” ( 14430052 to M.S.); Takeda Science Foundation (S.O., H.M., T.Y., Y. Sato); Uehara Memorial Foundation (H.S.); the Japanese Urological Association (Young Researcher Promotion Grant) ( Y. Sato); SGH Foundation (Y. Sato); and onsulted with and recieved honoraria from Pfizer, Loxo/Lilly Oncology, Vividion Therapeutics, Scorpion Therapeutics and BridgeBio. and the Yasuda Medical Foundation (Y. Sato). S.O. is a recipient of JSPS Core-to-Core Program, A. Advanced Research Networks. The schematic illustration in the graphic abstract was created with BioRender.com . We thank Maki Nakamura and Takeshi Shirahari for technical assistance. We also thank Kenichi Hashimoto, Shoichi Nagamoto, Masaomi Ikeda, Toshikazu Okaneya, Yukimasa Matsuzawa, Kanade Hagiwara, Tomoyuki Kaneko, Hiroaki Nishimatsu, Yoshikazu Hirano, and all staff at the Department of Urology, The University of Tokyo Hospital, for collecting samples. Wethnk iLAC for sequencing support. Publisher Copyright: © 2021 Elsevier Inc.

PY - 2021/6/14

Y1 - 2021/6/14

N2 - Upper urinary tract urothelial carcinoma (UTUC) is one of the common urothelial cancers. Its molecular pathogenesis, however, is poorly understood, with no useful biomarkers available for accurate diagnosis and molecular classification. Through an integrated genetic study involving 199 UTUC samples, we delineate the landscape of genetic alterations in UTUC enabling genetic/molecular classification. According to the mutational status of TP53, MDM2, RAS, and FGFR3, UTUC is classified into five subtypes having discrete profiles of gene expression, tumor location/histology, and clinical outcome, which is largely recapitulated in an independent UTUC cohort. Sequencing of urine sediment-derived DNA has a high diagnostic value for UTUC with 82.2% sensitivity and 100% specificity. These results provide a solid basis for better diagnosis and management of UTUC.

AB - Upper urinary tract urothelial carcinoma (UTUC) is one of the common urothelial cancers. Its molecular pathogenesis, however, is poorly understood, with no useful biomarkers available for accurate diagnosis and molecular classification. Through an integrated genetic study involving 199 UTUC samples, we delineate the landscape of genetic alterations in UTUC enabling genetic/molecular classification. According to the mutational status of TP53, MDM2, RAS, and FGFR3, UTUC is classified into five subtypes having discrete profiles of gene expression, tumor location/histology, and clinical outcome, which is largely recapitulated in an independent UTUC cohort. Sequencing of urine sediment-derived DNA has a high diagnostic value for UTUC with 82.2% sensitivity and 100% specificity. These results provide a solid basis for better diagnosis and management of UTUC.

KW - FGFR3

KW - RAS

KW - TP53

KW - hypermutation

KW - integrated molecular study

KW - molecular classification

KW - molecular diagnostic

KW - transcriptome

KW - upper urinary tract urothelial carcinoma

KW - urothelial carcinoma

UR - http://www.scopus.com/inward/record.url?scp=85107591334&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85107591334&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2021.05.008

DO - 10.1016/j.ccell.2021.05.008

M3 - Article

C2 - 34129823

AN - SCOPUS:85107591334

SN - 1535-6108

VL - 39

SP - 793-809.e8

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

Molecular classification and diagnostics of upper urinary tract urothelial carcinoma

Abstract

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ASJC Scopus subject areas

UN SDGs

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