Tyler J Moss1, Yuan Qi1, Liu Xi2, Bo Peng1, Tae-Beom Kim1, Nader E Ezzedine3, Maribel E Mosqueda3, Charles C Guo4, Bogdan A Czerniak4, Michael Ittmann5, David A Wheeler6, Seth P Lerner7, Surena F Matin8. 1. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. 3. Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 4. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. 5. Department of Pathology, Baylor College of Medicine, Houston, TX, USA. 6. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. 7. Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA. Electronic address: slerner@bcm.edu. 8. Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: surmatin@mdanderson.org.
Abstract
BACKGROUND: Upper urinary tract urothelial cancer (UTUC) may have unique etiologic and genomic factors compared to bladder cancer. OBJECTIVE: To characterize the genomic landscape of UTUC and provide insights into its biology using comprehensive integrated genomic analyses. DESIGN, SETTING, AND PARTICIPANTS: We collected 31 untreated snap-frozen UTUC samples from two institutions and carried out whole-exome sequencing (WES) of DNA, RNA sequencing (RNAseq), and protein analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Adjusting for batch effects, consensus mutation calls from independent pipelines identified DNA mutations, gene expression clusters using unsupervised consensus hierarchical clustering (UCHC), and protein expression levels that were correlated with relevant clinical variables, The Cancer Genome Atlas, and other published data. RESULTS AND LIMITATIONS: WES identified mutations in FGFR3 (74.1%; 92% low-grade, 60% high-grade), KMT2D (44.4%), PIK3CA (25.9%), and TP53 (22.2%). APOBEC and CpG were the most common mutational signatures. UCHC of RNAseq data segregated samples into four molecular subtypes with the following characteristics. Cluster 1: no PIK3CA mutations, nonsmokers, high-grade <pT2 tumors, high recurrences. Cluster 2: 100% FGFR3 mutations, low-grade tumors, tobacco use, noninvasive disease, no bladder recurrences. Cluster 3: 100% FGFR3 mutations, 71% PIK3CA, no TP53 mutations, five bladder recurrences, tobacco use, tumors all <pT2. Cluster 4: KMT2D (62.5%), FGFR3 (50%), TP53 (50%) mutations, no PIK3CA mutations, high-grade pT2+ disease, tobacco use, carcinoma in situ, shorter survival. We identified a novel SH3KBP1-CNTNAP5 fusion. CONCLUSIONS: Mutations in UTUC occur at differing frequencies from bladder cancer, with four unique molecular and clinical subtypes. A novel SH3KBP1 fusion regulates RTK signaling. Further studies are needed to validate the described subtypes, explore their responses to therapy, and better define the novel fusion mutation. PATIENT SUMMARY: We conducted a comprehensive study of the genetics of upper urinary tract urothelial cancer by evaluating DNA, RNA and protein expression in 31 tumors. We identified four molecular subtypes with distinct behaviors. Future studies will determine if these subtypes appear to have different responses to treatments.
BACKGROUND:Upper urinary tract urothelial cancer (UTUC) may have unique etiologic and genomic factors compared to bladder cancer. OBJECTIVE: To characterize the genomic landscape of UTUC and provide insights into its biology using comprehensive integrated genomic analyses. DESIGN, SETTING, AND PARTICIPANTS: We collected 31 untreated snap-frozen UTUC samples from two institutions and carried out whole-exome sequencing (WES) of DNA, RNA sequencing (RNAseq), and protein analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Adjusting for batch effects, consensus mutation calls from independent pipelines identified DNA mutations, gene expression clusters using unsupervised consensus hierarchical clustering (UCHC), and protein expression levels that were correlated with relevant clinical variables, The Cancer Genome Atlas, and other published data. RESULTS AND LIMITATIONS: WES identified mutations in FGFR3 (74.1%; 92% low-grade, 60% high-grade), KMT2D (44.4%), PIK3CA (25.9%), and TP53 (22.2%). APOBEC and CpG were the most common mutational signatures. UCHC of RNAseq data segregated samples into four molecular subtypes with the following characteristics. Cluster 1: no PIK3CA mutations, nonsmokers, high-grade <pT2 tumors, high recurrences. Cluster 2: 100% FGFR3 mutations, low-grade tumors, tobacco use, noninvasive disease, no bladder recurrences. Cluster 3: 100% FGFR3 mutations, 71% PIK3CA, no TP53 mutations, five bladder recurrences, tobacco use, tumors all <pT2. Cluster 4: KMT2D (62.5%), FGFR3 (50%), TP53 (50%) mutations, no PIK3CA mutations, high-grade pT2+ disease, tobacco use, carcinoma in situ, shorter survival. We identified a novel SH3KBP1-CNTNAP5 fusion. CONCLUSIONS: Mutations in UTUC occur at differing frequencies from bladder cancer, with four unique molecular and clinical subtypes. A novel SH3KBP1 fusion regulates RTK signaling. Further studies are needed to validate the described subtypes, explore their responses to therapy, and better define the novel fusion mutation. PATIENT SUMMARY: We conducted a comprehensive study of the genetics of upper urinary tract urothelial cancer by evaluating DNA, RNA and protein expression in 31 tumors. We identified four molecular subtypes with distinct behaviors. Future studies will determine if these subtypes appear to have different responses to treatments.
Authors: Mounsif Azizi; Salim K Cheriyan; Charles C Peyton; Beat Foerster; Shahrokh F Shariat; Philippe E Spiess Journal: Curr Treat Options Oncol Date: 2019-04-01
Authors: Jonathan W Wischhusen; Chinedu Ukaegbu; Tara G Dhingra; Hajime Uno; Fay Kastrinos; Sapna Syngal; Matthew B Yurgelun Journal: Cancer Epidemiol Biomarkers Prev Date: 2019-10-15 Impact factor: 4.254
Authors: Vitaly Margulis; Maneka Puligandla; Edouard J Trabulsi; Elizabeth R Plimack; Elizabeth R Kessler; Surena F Matin; Guilherme Godoy; Ajjai Alva; Noah M Hahn; Michael A Carducci; Jean Hoffman-Censits Journal: J Urol Date: 2019-11-08 Impact factor: 7.450
Authors: Hanan Goldberg; Douglas C Cheung; Thenappan Chandrasekar; Zachary Klaassen; Christopher J D Wallis; Girish S Kulkarni; Rashid Sayyid; Andrew Evans; Mehdi Masoomian; Bharati Bapat; Theodorus van der Kwast; Robert J Hamilton; Alexandre Zlotta; Neil Fleshner Journal: Can Urol Assoc J Date: 2019-01-21 Impact factor: 1.862
Authors: Neeraj Agarwal; Sumanta K Pal; Andrew W Hahn; Roberto H Nussenzveig; Gregory R Pond; Sumati V Gupta; Jue Wang; Mehmet A Bilen; Gurudatta Naik; Pooja Ghatalia; Christopher J Hoimes; Dharmesh Gopalakrishnan; Pedro C Barata; Alexandra Drakaki; Bishoy M Faltas; Lesli A Kiedrowski; Richard B Lanman; Rebecca J Nagy; Nicholas J Vogelzang; Kenneth M Boucher; Ulka N Vaishampayan; Guru Sonpavde; Petros Grivas Journal: Cancer Date: 2018-03-08 Impact factor: 6.860
Authors: Brian R Winters; Navonil De Sarkar; Sonali Arora; Hamid Bolouri; Sujata Jana; Funda Vakar-Lopez; Heather H Cheng; Michael T Schweizer; Evan Y Yu; Petros Grivas; John K Lee; Lori Kollath; Sarah K Holt; Lisa McFerrin; Gavin Ha; Peter S Nelson; Robert B Montgomery; Jonathan L Wright; Hung-Ming Lam; Andrew C Hsieh Journal: JCI Insight Date: 2019-05-30
Authors: Ahmet M Aydin; Nirmish Singla; Vandana Panwar; Solomon L Woldu; Yuval Freifeld; Christopher G Wood; Jose A Karam; Alon Z Weizer; Jay D Raman; Mesut Remzi; Nathalie Rioux-Leclercq; Andrea Haitel; Marco Roscigno; Christian Bolenz; Karim Bensalah; Mary E Westerman; Arthur I Sagalowsky; Shahrokh F Shariat; Yair Lotan; Aditya Bagrodia; Payal Kapur; Vitaly Margulis; Laura-Maria Krabbe Journal: World J Urol Date: 2019-02-13 Impact factor: 4.226
Authors: François Audenet; Sumit Isharwal; Eugene K Cha; Mark T A Donoghue; Esther N Drill; Irina Ostrovnaya; Eugene J Pietzak; John P Sfakianos; Aditya Bagrodia; Paari Murugan; Guido Dalbagni; Timothy F Donahue; Jonathan E Rosenberg; Dean F Bajorin; Maria E Arcila; Jaclyn F Hechtman; Michael F Berger; Barry S Taylor; Hikmat Al-Ahmadie; Gopa Iyer; Bernard H Bochner; Jonathan A Coleman; David B Solit Journal: Clin Cancer Res Date: 2018-10-23 Impact factor: 12.531