title: Genomic Profiling of Penile Squamous Cell Carcinoma Reveals New Opportunities for Targeted Therapy.
abstract: Penile squamous cell carcinoma (PeSCCA) is a rare malignancy for which there are limited treatment options due to a poor understanding of the molecular alterations underlying disease development and progression. Therefore, we performed comprehensive, targeted next-generation sequencing to identify relevant somatic genomic alterations in a retrospective cohort of 60 fixed tumor samples from 43 PeSCCA cases (including 14 matched primary/metastasis pairs). We identified a median of two relevant somatic mutations and one high-level copy-number alteration per sample (range, 0-5 and 0-6, respectively). Expression of HPV and p16 was detectable in 12% and 28% of patients, respectively. Furthermore, advanced clinical stage, lack of p16 expression, and MYC and CCND1 amplifications were significantly associated with shorter time to progression or PeSCCA-specific survival. Notably, four cases harbored EGFR amplifications and one demonstrated CDK4 amplification, genes for which approved and investigational targeted therapies are available. Importantly, although paired primary tumors and lymph node metastases were largely homogeneous for relevant somatic mutations, we identified heterogeneous EGFR amplification in primary tumor/lymph node metastases in 4 of 14 cases, despite uniform EGFR protein overexpression. Likewise, activating HRAS mutations occurred in 8 of 43 cases. Taken together, we provide the first comprehensive molecular PeSCCA analysis, which offers new insight into potential precision medicine approaches for this disease, including strategies targeting EGFR.
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: McDaniel
authors.affiliation: Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Hovelson
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Andi K
authors.initials: AK
authors.lastname: Cani
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Chia-Jen
authors.initials: CJ
authors.lastname: Liu
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhai
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Yajia
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Urology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Alon Z
authors.initials: AZ
authors.lastname: Weizer
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Rohit
authors.initials: R
authors.lastname: Mehra
authors.affiliation: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan. Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors.forename: Felix Y
authors.initials: FY
authors.lastname: Feng
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Ajjai S
authors.initials: AS
authors.lastname: Alva
authors.affiliation: Department of Urology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Morgan
authors.affiliation: Department of Urology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Montgomery
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Javed
authors.initials: J
authors.lastname: Siddiqui
authors.affiliation: Thermo Fisher Scientific, Ann Arbor, Michigan.
authors.forename: Seth
authors.initials: S
authors.lastname: Sadis
authors.affiliation: Thermo Fisher Scientific, Ann Arbor, Michigan.
authors.forename: Santhoshi
authors.initials: S
authors.lastname: Bandla
authors.affiliation: Thermo Fisher Scientific, Ann Arbor, Michigan.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Williams
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan. Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan.
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Cho
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan. Thermo Fisher Scientific, Ann Arbor, Michigan.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Rhodes
authors.affiliation: Department of Pathology, Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, Michigan. Department of Urology, University of Michigan, Ann Arbor, Michigan. Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan. tomlinss@umich.edu.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality / Q000821:virology; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005784:Gene Amplification; D018773:Genes, erbB-1 / Q000235:genetics; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D030361:Papillomavirus Infections / Q000150:complications / Q000453:epidemiology; D010412:Penile Neoplasms / Q000235:genetics* / Q000401:mortality / Q000821:virology; D012189:Retrospective Studies; D059467:Transcriptome
chemical_list: C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4