title: Tumor evolution and progression in multifocal and paired non-invasive/invasive urothelial carcinoma.
abstract: Although multifocal tumors and non-invasive/invasive components are commonly encountered in surgical pathology, their genetic relationship is often poorly characterized. We used next-generation sequencing (NGS) to characterize somatic alterations in a patient with five spatially distinct, high-grade papillary urothelial carcinomas (UCs), with one tumor harboring an underlying invasive component. NGS of 409 cancer-related genes was performed on DNA isolated from formalin-fixed paraffin-embedded (FFPE) blocks representing each papillary tumor (n = 5), the invasive component of one tumor, and matched normal tissue. We identified nine unique non-synonymous somatic mutations across the six UC samples, including five present in each carcinoma sample, consistent with clonal origin and limited intertumoral heterogeneity. Copy number and loss of heterogeneity (LOH) profiles were similar in all six carcinomas; however, the invasive carcinoma component uniquely showed focal CDKN2A loss and chromosome 9 LOH and did not harbor gains of chromosomes 5p or X that were present in the other tumor samples. Phylogenetic analysis supported the invasive component arising from a shared progenitor prior to the outgrowth of cells in the non-invasive tumors. Results were extended to three additional cases of upper tract UC with paired non-invasive/invasive components, which identified driving alterations exclusive to both non-invasive and invasive components. Lastly, we performed targeted RNA sequencing (RNAseq) using a custom bladder cancer panel, which confirmed gene expression signature differences between paired non-invasive/invasive components. The results and approaches presented here may be useful in understanding the clonal relationships in multifocal cancers or paired non-invasive/invasive components from routine FFPE specimens.
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Joshua I
authors.initials: JI
authors.lastname: Warrick
authors.affiliation: Department of Computational Medicine & Bioinformatics, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Hovelson
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Anmol
authors.initials: A
authors.lastname: Amin
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Chia-Jen
authors.initials: CJ
authors.lastname: Liu
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Andi K
authors.initials: AK
authors.lastname: Cani
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: McDaniel
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Venkata
authors.initials: V
authors.lastname: Yadati
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI.|Department of Pathology, Oregon Health & Sciences University, Portland, OR.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Quist
authors.affiliation: Department of Urology, University of Michigan Medical School, Ann Arbor, MI.|Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Alon Z
authors.initials: AZ
authors.lastname: Weizer
authors.affiliation: Department of Otolaryngology, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: J Chad
authors.initials: JC
authors.lastname: Brenner
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI.|Department of Urology, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Felix Y
authors.initials: FY
authors.lastname: Feng
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Rohit
authors.initials: R
authors.lastname: Mehra
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI.|Department of Pathology, Oregon Health & Sciences University, Portland, OR.
authors.forename: Catherine S
authors.initials: CS
authors.lastname: Grasso
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI.|Department of Urology, University of Michigan Medical School, Ann Arbor, MI.|Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D063646:Carcinogenesis / Q000235:genetics / Q000473:pathology*; D002295:Carcinoma, Transitional Cell / Q000235:genetics / Q000473:pathology*; D018450:Disease Progression; D018628:Gene Dosage / Q000235:genetics; D019942:Genes, p16; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D008297:Male; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology*; D009857:Oncogenes / Q000235:genetics; D010802:Phylogeny; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000473:pathology*; D019459:Urothelium / Q000473:pathology*