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

Cancer Cell. 2021 Jun 14;39(6):793-809.e8. doi: 10.1016/j.ccell.2021.05.008.

Authors

Yoichi Fujii¹, Yusuke Sato², Hiromichi Suzuki³, Nobuyuki Kakiuchi⁴, Tetsuichi Yoshizato³, Andrew T Lenis⁵, Shigekatsu Maekawa⁶, Akira Yokoyama³, Yasuhide Takeuchi⁴, Yoshikage Inoue⁴, Yotaro Ochi³, Yusuke Shiozawa³, Kosuke Aoki³, Kenichi Yoshida³, Keisuke Kataoka⁷, Masahiro M Nakagawa³, Yasuhito Nannya⁴, Hideki Makishima⁴, Jimpei Miyakawa⁶, Taketo Kawai⁶, Teppei Morikawa⁸, Yuichi Shiraishi⁹, Kenichi Chiba⁹, Hiroko Tanaka¹⁰, Genta Nagae¹¹, Masashi Sanada¹², Eiji Sugihara¹³, Taka-Aki Sato¹³, Tohru Nakagawa¹⁴, Masashi Fukayama⁸, Tetsuo Ushiku⁸, Hiroyuki Aburatani¹¹, Satoru Miyano¹⁵, Jonathan A Coleman⁵, Yukio Homma¹⁶, David B Solit¹⁷, Haruki Kume⁶, Seishi Ogawa¹⁸

Affiliations

¹ Department of Pathology and Tumor Biology, Kyoto University, Kyoto 606-8501, Japan; Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto 606-8501, Japan; Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
² Department of Pathology and Tumor Biology, Kyoto University, Kyoto 606-8501, Japan; Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
³ Department of Pathology and Tumor Biology, Kyoto University, Kyoto 606-8501, Japan.
⁴ Department of Pathology and Tumor Biology, Kyoto University, Kyoto 606-8501, Japan; Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto 606-8501, Japan.
⁵ Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
⁶ Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
⁷ Department of Pathology and Tumor Biology, Kyoto University, Kyoto 606-8501, Japan; Division of Molecular Oncology, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
⁸ Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
⁹ Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
¹⁰ Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
¹¹ Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo 153-8904, Japan.
¹² Department of Advanced Diagnosis, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya 460-0001, Japan.
¹³ Research and Development Center for Precision Medicine, University of Tsukuba, Tsukuba, Ibaraki 305-8550, Japan.
¹⁴ Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; Department of Urology, Teikyo University School of Medicine, Tokyo 173-8606, Japan.
¹⁵ Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
¹⁶ Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; Department of Urology, Japanese Red Cross Medical Center, Tokyo 150-8935, Japan.
¹⁷ Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁸ Department of Pathology and Tumor Biology, Kyoto University, Kyoto 606-8501, Japan; Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto 606-8501, Japan; Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institute, Stockholm 17177, Sweden. Electronic address: sogawa-tky@umin.ac.jp.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Biomarkers, Tumor / genetics
Biomarkers, Tumor / urine*
Carcinoma, Transitional Cell / diagnosis*
Carcinoma, Transitional Cell / genetics*
Carcinoma, Transitional Cell / mortality
DNA Methylation
Female
Gene Dosage
Gene Expression Regulation, Neoplastic
Humans
Male
Middle Aged
Mutation
Polymorphism, Single Nucleotide
Proto-Oncogene Proteins c-mdm2 / genetics
Receptor, Fibroblast Growth Factor, Type 3 / genetics
Tumor Suppressor Protein p53 / genetics
Ureteral Neoplasms / diagnosis*
Ureteral Neoplasms / genetics*
Ureteral Neoplasms / mortality
ras Proteins / genetics

Substances

Biomarkers, Tumor
TP53 protein, human
Tumor Suppressor Protein p53
MDM2 protein, human
Proto-Oncogene Proteins c-mdm2
FGFR3 protein, human
Receptor, Fibroblast Growth Factor, Type 3
ras Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding