title: The Distinctive Mutational Spectra of Polyomavirus-Negative Merkel Cell Carcinoma.
abstract: Merkel cell carcinoma (MCC) is a rare but highly aggressive cutaneous neuroendocrine tumor. Merkel cell polyomavirus (MCPyV) may contribute to tumorigenesis in a subset of tumors via inhibition of tumor suppressors such as retinoblastoma (RB1) by mutated viral T antigens, but the molecular pathogenesis of MCPyV-negative MCC is largely unexplored. Through our MI-ONCOSEQ precision oncology study, we performed integrative sequencing on two cases of MCPyV-negative MCC, as well as a validation cohort of 14 additional MCC cases (n = 16). In addition to previously identified mutations in TP53, RB1, and PIK3CA, we discovered activating mutations of oncogenes, including HRAS and loss-of-function mutations in PRUNE2 and NOTCH family genes in MCPyV-negative MCC. MCPyV-negative tumors also displayed high overall mutation burden (10.09 ± 2.32 mutations/Mb) and were characterized by a prominent UV-signature pattern with C > T transitions comprising 85% of mutations. In contrast, mutation burden was low in MCPyV-positive tumors (0.40 ± 0.09 mutations/Mb) and lacked a UV signature. These findings suggest a potential ontologic dichotomy in MCC, characterized by either viral-dependent or UV-dependent tumorigenic pathways.
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School.|Department of Pathology, University of Michigan Medical School.|Department of Dermatology, University of Michigan Medical School.
authors.forename: Paul William
authors.initials: PW
authors.lastname: Harms
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School.|Department of Biomedical Science, Bharathidasan University, Tiruchirappalli, India.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Vats
authors.affiliation: Department of Dermatology, University of Michigan Medical School.
authors.forename: Monique Elise
authors.initials: ME
authors.lastname: Verhaegen
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School.
authors.forename: Dan R
authors.initials: DR
authors.lastname: Robinson
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School.|Department of Pathology, University of Michigan Medical School.
authors.forename: Yi-Mi
authors.initials: YM
authors.lastname: Wu
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School.
authors.forename: Saravana Mohan
authors.initials: SM
authors.lastname: Dhanasekaran
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School.|Department of Pathology, University of Michigan Medical School.|Department of Urology, Henry Ford Health System, Detroit, MI.
authors.forename: Nallasivam
authors.initials: N
authors.lastname: Palanisamy
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School.|Department of Pathology, University of Michigan Medical School.
authors.forename: Javed
authors.initials: J
authors.lastname: Siddiqui
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School.|Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI 48109,USA.
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cao
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School.
authors.forename: Fengyun
authors.initials: F
authors.lastname: Su
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School.|Department of Pathology, University of Michigan Medical School.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School.|Department of Pathology, University of Michigan Medical School.|Department of Urology, Henry Ford Health System, Detroit, MI.
authors.forename: Hong
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School.|Department of Pathology, University of Michigan Medical School.
authors.forename: Lakshmi P
authors.initials: LP
authors.lastname: Kunju
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School.|Department of Pathology, University of Michigan Medical School.|Department of Urology, Henry Ford Health System, Detroit, MI.
authors.forename: Rohit
authors.initials: R
authors.lastname: Mehra
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School.|Department of Pathology, University of Michigan Medical School.|Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.|Department of Urology, University of Michigan Medical School, Ann Arbor, MI 48109 USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
authors.affiliation: Department of Pathology, University of Michigan Medical School.|Department of Dermatology, University of Michigan Medical School.
authors.forename: Douglas Randall
authors.initials: DR
authors.lastname: Fullen
authors.affiliation: Department of Dermatology, University of Michigan Medical School.
authors.forename: Christopher Keram
authors.initials: CK
authors.lastname: Bichakjian
authors.affiliation: Department of Dermatology, University of Michigan Medical School.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Johnson
authors.affiliation: Department of Dermatology, University of Michigan Medical School.|Department of Cell and Developmental Biology, University of Michigan Medical Center, Ann Arbor, USA.
authors.forename: Andrzej Antoni
authors.initials: AA
authors.lastname: Dlugosz
authors.affiliation: Michigan Center for Translational Pathology, University of Michigan Medical School.|Department of Pathology, University of Michigan Medical School.|Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI 48109,USA.|Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.|Department of Urology, University of Michigan Medical School, Ann Arbor, MI 48109 USA.
authors.forename: Arul M
authors.initials: AM
authors.lastname: Chinnaiyan
mesh_terms: D000368:Aged; D015266:Carcinoma, Merkel Cell / Q000235:genetics* / Q000556:secondary; D002352:Carrier Proteins / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000528:radiation effects; D004252:DNA Mutational Analysis / Q000379:methods; D004273:DNA, Neoplasm / Q000235:genetics; D059472:Exome / Q000235:genetics; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D059965:Merkel cell polyomavirus; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D009381:Neoplasms, Radiation-Induced / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D009857:Oncogenes; D010307:Parotid Neoplasms / Q000235:genetics / Q000556:secondary; D017354:Point Mutation; D051880:Receptors, Notch / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics*; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D002352:Carrier Proteins; D004273:DNA, Neoplasm; C496662:GPRIN2 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D015514:Oncogene Proteins, Fusion; C509845:PRUNE2 protein, human; D051880:Receptors, Notch