Prognostic relevance of high atonal homolog-1 expression in Merkel cell carcinoma.
BACKGROUND
It has recently been reported that atonal homolog 1 (ATOH1) gene is down-regulated in Merkel cell carcinoma (MCC) and thus may represent a tumor suppressor gene.


OBJECTIVE
We aimed to test for ATOH1 gene mutations and expression levels in MCC tissues and cell lines.


METHODS
Genomic DNA isolation and amplification via PCR was successfully performed in 33 MCCs on formalin-fixed paraffin-embedded tissue and three MCC cell lines, followed by Sanger sequencing of the whole ATOH1 gene to detect genomic aberrations. ATOH1 mRNA levels were determined by RT-PCR. Immunohistochemistry of ATOH1 was performed to quantify protein expression in tumor samples and cell lines.


RESULTS
Neither in any of the 33 MCC tissue samples nor in the three cell lines ATOH1 mutations were present. ATOH1 was expressed in all lesions, albeit at different expression levels. Univariate analysis revealed that the total immunohistology score significantly correlated with the occurrence of tumor relapse (r = 0.57; P = 0.0008). This notion was confirmed in multivariate analysis suggesting that ATOH1 expression is a potential independent predictor for tumor relapse in MCC patients (P = 0.028). MCC-related death also correlated with ATOH1 expression (r = 0.4; P = 0.025); however, ATOH1 expression did not retain its predictive value in the regression model.


CONCLUSIONS
In contrast to anecdotal reports ATOH1 expression is not lost by genetic alterations in MCC. However, protein expression of ATOH1 is increased in advanced MCC indicating that ATOH1 is involved in MCC progression.
Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Gudrunstrasse 56, 44791, Bochum, Germany. t.gambichler@klinikum-bochum.de.
T
T
Gambichler
Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Gudrunstrasse 56, 44791, Bochum, Germany.
S
S
Mohtezebsade
National Reference Center for Papilloma- and Polyomaviruses, Institute of Virology, University of Cologne, Cologne, Germany.
U
U
Wieland
National Reference Center for Papilloma- and Polyomaviruses, Institute of Virology, University of Cologne, Cologne, Germany.
S
S
Silling
Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Gudrunstrasse 56, 44791, Bochum, Germany.
A-K
AK
Höh
Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Gudrunstrasse 56, 44791, Bochum, Germany.
M
M
Dreißigacker
Dermatopathology Duisburg, Duisburg, Germany.
J
J
Schaller
Department of Dermatology and Dermato-Histo-Pathology, Skin Cancer Center, Fachklinik Hornheide, Münster, Germany.
H-J
HJ
Schulze
Institute for Pathology, Mülheim/Ruhr, Germany.
F
F
Oellig
Department of Dermatology, Venereology and Allergology, HELIOS St. Elisabeth Hospital Oberhausen, Oberhausen, Germany.
A
A
Kreuter
Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Gudrunstrasse 56, 44791, Bochum, Germany.
E
E
Stockfleth
Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Gudrunstrasse 56, 44791, Bochum, Germany.
M
M
Stücker
Department of Dermatology, Skin Cancer Center, Ruhr-University Bochum, Gudrunstrasse 56, 44791, Bochum, Germany.
F G
FG
Bechara
Translational Skin Cancer Research, DKTK Partner Site Essen/Düsseldorf, West German Cancer Center, Dermatology, University Duisburg-Essen, Essen, Germany.
J C
JC
Becker
D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015266:Carcinoma, Merkel Cell / Q000378:metabolism* / Q000821:virology; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D059965:Merkel cell polyomavirus / Q000235:genetics; D009364:Neoplasm Recurrence, Local / Q000378:metabolism*; D011379:Prognosis; D012878:Skin Neoplasms / Q000378:metabolism* / Q000821:virology
D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; C500942:ATOH1 protein, human
ATOH1; Atonal homolog-1; Merkel cell carcinoma