Shared Oncogenic Pathways Implicated in Both Virus-Positive and UV-Induced Merkel Cell Carcinomas.
Merkel cell carcinoma (MCC) is a highly malignant neuroendocrine tumor of the skin whose molecular pathogenesis is not completely understood, despite the role that Merkel cell polyomavirus can play in 55-90% of cases. To study potential mechanisms driving this disease in clinically characterized cases, we searched for somatic mutations using whole-exome sequencing, and extrapolated our findings to study functional biomarkers reporting on the activity of the mutated pathways. Confirming previous results, Merkel cell polyomavirus-negative tumors had higher mutational loads with UV signatures and more frequent mutations in TP53 and RB compared with their Merkel cell polyomavirus-positive counterparts. Despite important genetic differences, the two Merkel cell carcinoma etiologies both exhibited nuclear accumulation of oncogenic transcription factors such as NFAT or nuclear factor of activated T cells (NFAT), P-CREB, and P-STAT3, indicating commonly deregulated pathogenic mechanisms with the potential to serve as targets for therapy. A multivariable analysis identified phosphorylated CRE-binding protein as an independent survival factor with respect to clinical variables and Merkel cell polyomavirus status in our cohort of Merkel cell carcinoma patients.
Pathology Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain; Cancer Genomics Laboratory, Instituto de Investigación Marqués de Valdecilla, IDIVAL, Santander, Spain.
María Del Carmen
MDC
González-Vela
Cancer Genomics Laboratory, Instituto de Investigación Marqués de Valdecilla, IDIVAL, Santander, Spain.
Soraya
S
Curiel-Olmo
CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
Sophia
S
Derdak
CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
Sergi
S
Beltran
Universidad de Cantabria-IDIVAL, Santander, Spain.
Miguel
M
Santibañez
Cancer Genomics Laboratory, Instituto de Investigación Marqués de Valdecilla, IDIVAL, Santander, Spain.
Nerea
N
Martínez
Oncology Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain.
Alfredo
A
Castillo-Trujillo
CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
Martha
M
Gut
Pathology Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain.
Roxana
R
Sánchez-Pacheco
Cancer Genomics Laboratory, Instituto de Investigación Marqués de Valdecilla, IDIVAL, Santander, Spain.
Carmen
C
Almaraz
Cancer Genomics Laboratory, Instituto de Investigación Marqués de Valdecilla, IDIVAL, Santander, Spain.
Laura
L
Cereceda
Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain.
Beatriz
B
Llombart
IBBTEC-UC-CSIC-SODERCAN Instituto de Biomedicina y Biotecnología de Cantabria, Santander, Spain; Josep Carreras Leukemia Research Institute and School of Medicine, University of Barcelona, Barcelona, Spain.
Antonio
A
Agraz-Doblas
Cancer Genomics Laboratory, Instituto de Investigación Marqués de Valdecilla, IDIVAL, Santander, Spain.
José
J
Revert-Arce
Biobanco -Fundación Instituto Valenciano de Oncología, Valencia, Spain.
José Antonio
JA
López Guerrero
Hospital Universitario Virgen de la Salud, Toledo, Spain.
Manuela
M
Mollejo
Biobanco-Hospital Universitario Central de Asturias, Oviedo, Spain.
Pablo Isidro
PI
Marrón
Dermatology Service, Instituto I+12, Hospital Universitario 12 de Octubre, Madrid, Spain.
Pablo
P
Ortiz-Romero
International Agency for Research on Cancer (IARC-WHO), Lyon, France; Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany.
Lynnette
L
Fernandez-Cuesta
IBBTEC-UC-CSIC-SODERCAN Instituto de Biomedicina y Biotecnología de Cantabria, Santander, Spain.
Ignacio
I
Varela
CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 4, 08028, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
Ivo
I
Gut
Department of Dermatology Medical University of Graz, Austria.
Lorenzo
L
Cerroni
Pathology Department, Hospital Universitario Marqués de Valdecilla, Santander, Spain; Cancer Genomics Laboratory, Instituto de Investigación Marqués de Valdecilla, IDIVAL, Santander, Spain.
Miguel Ángel
MÁ
Piris
Cancer Genomics Laboratory, Instituto de Investigación Marqués de Valdecilla, IDIVAL, Santander, Spain; IBBTEC-UC-CSIC-SODERCAN Instituto de Biomedicina y Biotecnología de Cantabria, Santander, Spain. Electronic address: vaquej@unican.es.
José Pedro
JP
Vaqué
D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D001707:Biopsy, Needle; D063646:Carcinogenesis / Q000235:genetics; D015266:Carcinoma, Merkel Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000821:virology*; D015331:Cohort Studies; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D059965:Merkel cell polyomavirus / Q000235:genetics* / Q000302:isolation & purification; D015999:Multivariate Analysis; D009154:Mutation; D009857:Oncogenes / Q000235:genetics; D011379:Prognosis; D018570:Risk Assessment; D015398:Signal Transduction / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000821:virology*; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014412:Tumor Virus Infections / Q000401:mortality / Q000473:pathology; D014466:Ultraviolet Rays / Q000009:adverse effects
D014408:Biomarkers, Tumor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53