title: Molecular Profiling of Multiple Primary Merkel Cell Carcinoma to Distinguish Genetically Distinct Tumors From Clonally Related Metastases.
abstract: Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma. In rare cases, the development of an additional cutaneous MCC tumor is clinically consistent with a second primary MCC tumor rather than a cutaneous metastasis, which has important treatment and prognostic implications.
  
  
  
  To evaluate genetic relatedness in 4 cases with the clinical diagnosis of multiple primary MCCs.
  
  
  
  In this case series, 7 cases of clinically designated multiple primary MCC were identified; 4 cases met inclusion criteria for next-generation sequencing (NGS) analysis. Mutations, copy number alterations, and Merkel cell polyomavirus (MCPyV) sequence were analyzed and compared between clinically designated multiple primary tumors to characterize genetic relatedness and hence assess clonality. Patients with clinically designated multiple primary MCC were identified from the multidisciplinary MCC Program at the University of Michigan, a tertiary care center.
  
  
  
  Four cases of clinically designated multiple primary MCC were characterized by tumor sequencing and targeted MCPyV sequencing to distinguish independent primary tumors from related metastases.
  
  
  
  Overall, 4 patients in their 70s or 80s were included and analyzed. Cases 1 and 4 were verified as genetically distinct primary tumors and did not harbor similar copy number alterations or demonstrate significant mutational overlap. Cases 2 and 3 were designated as clonally related based on overlapping copy number alterations. In clonally related tumors, chromosomal copy number changes were more reliable than mutations for demonstrating clonality. Regardless of clonality, we found that MCPyV status was concordant for all tumor pairs and MCPyV positive tumors harbored predominatly subclonal mutations.
  
  
  
  Our findings suggest that patients with MCC may develop a second genetically distinct primary tumor; in this case, the subsequent tumor is likely to develop through similar mechanisms of pathogenesis, either MCPyV-mediated or ultraviolet light-mediated. Next-generation sequencing analysis of chromosomal copy number changes and mutations is useful in distinguishing multiple primary MCCs from progression of MCC clinically resembling multiple primaries, allowing appropriate staging of the patient.
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor2Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Harms
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor4Department of Pathology, University of Michigan Medical School, Ann Arbor.
authors.forename: Lorena
authors.initials: L
authors.lastname: Lazo de la Vega
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor4Department of Pathology, University of Michigan Medical School, Ann Arbor.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Hovelson
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor4Department of Pathology, University of Michigan Medical School, Ann Arbor.
authors.forename: Samantha
authors.initials: S
authors.lastname: Rahrig
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor4Department of Pathology, University of Michigan Medical School, Ann Arbor.
authors.forename: Andi K
authors.initials: AK
authors.lastname: Cani
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor4Department of Pathology, University of Michigan Medical School, Ann Arbor.
authors.forename: Chia-Jen
authors.initials: CJ
authors.lastname: Liu
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor4Department of Pathology, University of Michigan Medical School, Ann Arbor.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Fullen
authors.affiliation: Department of Pathology, University of Michigan Medical School, Ann Arbor.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor4Department of Pathology, University of Michigan Medical School, Ann Arbor.
authors.forename: Aleodor A
authors.initials: AA
authors.lastname: Andea
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor2Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Bichakjian
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor2Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Johnson
authors.affiliation: Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor3Michigan Center for Translational Pathology, University of Michigan, Ann Arbor4Department of Pathology, University of Michigan Medical School, Ann Arbor5Department of Urology, University of Michigan Medical School, Ann Arbor.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
authors.affiliation: Department of Dermatology, University of Michigan Medical School, Ann Arbor3Michigan Center for Translational Pathology, University of Michigan, Ann Arbor4Department of Pathology, University of Michigan Medical School, Ann Arbor.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Harms
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015266:Carcinoma, Merkel Cell / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D056915:DNA Copy Number Variations; D005260:Female; D006801:Humans; D008297:Male; D059965:Merkel cell polyomavirus / Q000235:genetics*; D009154:Mutation; D009367:Neoplasm Staging; D009378:Neoplasms, Multiple Primary / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D015203:Reproducibility of Results; D012878:Skin Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology