title: HRAS mutations are frequent in inverted urothelial neoplasms.
abstract: Inverted urothelial papilloma (IUP) is an uncommon neoplasm of the urinary bladder with distinct morphologic features. Studies regarding the role of human papillomavirus (HPV) in the etiology of IUP have provided conflicting evidence of HPV infection. In addition, little is known regarding the molecular alterations present in IUP or other urothelial neoplasms, which might demonstrate inverted growth pattern like low-grade or high-grade urothelial carcinoma (UCA). Here, we evaluated for the presence of common driving somatic mutations and HPV within a cohort of IUPs, (n = 7) noninvasive low-grade papillary UCAs with inverted growth pattern (n = 5), and noninvasive high-grade papillary UCAs with inverted growth pattern (n = 8). HPV was not detected in any case of IUP or inverted UCA by either in situ hybridization or by polymerase chain reaction. Next-generation sequencing identified recurrent mutations in HRAS (Q61R) in 3 of 5 IUPs, described for the first time in this neoplasm. Additional mutations of Ras pathway members were detected including HRAS, KRAS, and BRAF. The presence of Ras pathway member mutations at a relatively high rate suggests this pathway may contribute to pathogenesis of inverted urothelial neoplasms. In addition, we did not find any evidence supporting a role for HPV in the etiology of IUP.
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: McDaniel
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Cho
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Saravana M
authors.initials: SM
authors.lastname: Dhanasekaran
authors.affiliation: Department of Urology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Montgomery
authors.affiliation: Department of Urology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Palapattu
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Javed
authors.initials: J
authors.lastname: Siddiqui
authors.affiliation: Department of Urology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Todd
authors.initials: T
authors.lastname: Morgan
authors.affiliation: Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Ajjai
authors.initials: A
authors.lastname: Alva
authors.affiliation: Department of Urology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Alon
authors.initials: A
authors.lastname: Weizer
authors.affiliation: Department of Urology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Cheryl T
authors.initials: CT
authors.lastname: Lee
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
authors.affiliation: Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Quist
authors.affiliation: Oregon Health and Science University, Portland, OR 97239, USA.
authors.forename: Catherine S
authors.initials: CS
authors.lastname: Grasso
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: mrohit@umich.edu.
authors.forename: Rohit
authors.initials: R
authors.lastname: Mehra
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D014408:Biomarkers, Tumor / Q000235:genetics*; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D005260:Female; D018628:Gene Dosage; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D009154:Mutation; D018308:Papilloma, Inverted / Q000235:genetics* / Q000473:pathology; D027383:Papillomaviridae / Q000235:genetics / Q000302:isolation & purification; D030361:Papillomavirus Infections / Q000821:virology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D017422:Sequence Analysis, DNA; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: HRAS; Human papilloma virus; Inverted urothelial papillomas; Next-generation sequencing
references.citation: Mod Pathol. 2012 Nov;25(11):1534-42
references.pmid: 22766788
references.citation: Am J Surg Pathol. 2007 Jun;31(6):938-46
references.pmid: 17527084
references.citation: Crit Rev Oncol Hematol. 2014 Jan;89(1):73-111
references.pmid: 24029603
references.citation: Cancer. 2006 Dec 1;107(11):2622-7
references.pmid: 17078053
references.citation: Cancer Biomark. 2011-2012;10(6):259-66
references.pmid: 22820081
references.citation: J Natl Cancer Inst. 1995 Oct 18;87(20):1524-9
references.pmid: 7563186
references.citation: Nature. 2014 Mar 20;507(7492):315-22
references.pmid: 24476821
references.citation: Br J Cancer. 2012 Jan 3;106(1):222-6
references.pmid: 22116302
references.citation: J Clin Pathol. 1997 Dec;50(12):1018-21
references.pmid: 9516885
references.citation: Histopathology. 2013 Mar;62(4):595-601
references.pmid: 23379729
references.citation: Am J Surg Pathol. 2007 Dec;31(12):1861-7
references.pmid: 18043040
references.citation: BJU Int. 2011 Apr;107 Suppl 3:24-6
references.pmid: 21492372
references.citation: Am J Pathol. 1999 Jul;155(1):105-13
references.pmid: 10393843
references.citation: Hum Pathol. 2003 Mar;34(3):222-7
references.pmid: 12673555
references.citation: Am J Pathol. 2010 Aug;177(2):884-95
references.pmid: 20581058
references.citation: Urology. 2006 Aug;68(2):333-6
references.pmid: 16904447
references.citation: Mod Pathol. 2006 Oct;19(10):1289-94
references.pmid: 16862073
references.citation: Hum Mol Genet. 1995 Sep;4(9):1569-77
references.pmid: 8541841
references.citation: Am J Surg Pathol. 2013 Aug;37(8):1223-8
references.pmid: 23681080
references.citation: Eur Urol. 2011 Feb;59(2):225-30
references.pmid: 21122976
references.citation: Nat Genet. 2013 Dec;45(12):1459-63
references.pmid: 24121792
references.citation: J Urol. 1963 Aug;90:175-9
references.pmid: 14044188
references.citation: Cancer Lett. 2010 Jun 28;292(2):171-5
references.pmid: 20036459
references.citation: J Med Genet. 2012 Jul;49(7):433-6
references.pmid: 22717648
references.citation: Eur Urol. 2013 Jan;63(1):16-35
references.pmid: 23083804
references.citation: J Med Virol. 2011 Feb;83(2):277-85
references.pmid: 21181923
references.citation: Med Oncol. 2011 Sep;28(3):919-23
references.pmid: 20428971
references.citation: Mod Pathol. 2009 May;22(5):627-32
references.pmid: 19287463
references.citation: Nat Genet. 2013 Dec;45(12):1464-9
references.pmid: 24121791
references.citation: Urol Oncol. 2013 Nov;31(8):1584-90
references.pmid: 22520573
references.citation: Pathology. 2009;41(3):245-7
references.pmid: 19291536
references.citation: BJU Int. 2001 Aug;88(3):198-201
references.pmid: 11488729
references.citation: Mod Pathol. 2012 Nov;25(11):1526-33
references.pmid: 22684221
references.citation: Cancer. 2000 Feb 1;88(3):632-6
references.pmid: 10649258