Recurrent NMYC copy number gain and high protein expression in basal cell carcinoma.
Formation of basal cell carcinoma (BCC) has been linked to deregulation in the sonic hedgehogh (Shh) signalling pathway. Though mutations of the genes, PTCH1 and SMO, are known to be involved in aberrant Shh signalling, the distinct downstream effectors of these genes are poorly described. Studies have indicated that the NMYC oncogene is a potential Shh downstream effector. To assess the expression of Nmyc protein and gene copy numbers of the NMYC gene locus in a representative BCC tumour collection, immunohistochemistry (IHC) and fluorescence in situ hybridisation (FISH) were performed on 273 BCC specimens of different growth patterns and anatomic localisations on tissue microarray (TMA) sections. High Nmyc protein expression was detected in 72.7% (160/220) of all BCC specimens. Strong Nmyc immunopositivity was more frequently found in infiltrative BCCs compared to nodular/superficial BCCs (p=0.005), and in BCCs of the head compared to BCCs of other anatomic localisations (p=0.021). The prevalence of NMYC copy number gains was 17.5% (37/211), including three tumours with nodular differentiation that exhibited a distinct high-level amplification of the NMYC locus. These data indicate that high expression of the Shh downstream mediator, Nmyc, is a frequent event in BCC, predominantly in more aggressive subtypes. Although the NMYC copy number gain found in a subset of cases might contribute to this aberrant Nmyc protein expression by a gene dosage effect, our data suggests that Nmyc protein can also be induced by aberrant Shh signalling, acting as an effector molecule of the Shh pathway. Novel systemic anti-sense NMYC inhibition strategies could be a promising option for therapy-refractory BCC.
Freier
Kolja
K
Abteilung Molekulare Genetik, Deutsches Krebsforschungszentrum, D-69120 Heidelberg, Germany.
Flechtenmacher
Christa
C
Devens
Frauke
F
Hartschuh
Wolfgang
W
Hofele
Christof
C
Lichter
Peter
P
Joos
Stefan
S
D002280:Basal Cell Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D018628:Gene Dosage; D016259:Genes, myc / Q000235:genetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D017404:In Situ Hybridization, Fluorescence; D012867:Skin / Q000378:metabolism; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D046888:Tissue Array Analysis