Epigenetic silencing contributes to frequent loss of the fragile histidine triad tumour suppressor in basal cell carcinomas.
BACKGROUND
Extensive exposure to ultraviolet radiation is associated with genetic alterations in basal cell carcinomas (BCCs), which represent some 75% of skin cancers.


OBJECTIVE
As recent data suggested the fragile histidine triad (FHIT) gene product to participate in DNA damage responses we wished to address whether functional deletion of this tumour suppressor participates in the development of BCC. Our study focused on epigenetic inactivation of the FHIT gene.


METHODS
Paraffin-embedded specimens from 17 patients with BCC were available for methylation-specific polymerase chain reaction (MSP), combined bisulphite-dependent restriction analysis (COBRA) of the FHIT gene and immunohistochemistry of its product.


RESULTS
We report for the first time that 100% of BCCs are negative for FHIT by immunostaining. Aberrant methylation of the FHIT promoter occurred in a significant portion of BCCs. MSP detected hypermethylation of the FHIT/FRA3B locus in nine of nine (100%) periocular BCCs and in six of eight (75%) BCCs from other body regions. COBRA yielded similar results, confirming that some 88% of the 17 BCCs analysed harbour epigenetic silencing of the FHIT gene. Loss of FHIT protein was demonstrated immunohistochemically, confirming that promoter hypermethylation correlated with loss of gene expression.


CONCLUSIONS
We have identified epigenetic silencing of the FHIT tumour suppressor gene as a frequent inactivation mechanism which is likely to contribute to functional deficiencies in DNA damage response of BCCs.
Goldberg
M
M
Section of Molecular Gastroenterological Oncology of the First Department of Medicine, Martin-Luther University Halle-Wittenberg, Halle (Saale), Germany.
Rummelt
C
C
Laerm
A
A
Helmbold
P
P
Holbach
L M
LM
Ballhausen
W G
WG
D017766:Acid Anhydride Hydrolases / Q000235:genetics*; D000368:Aged; D000369:Aged, 80 and over; D002280:Basal Cell Carcinoma / Q000235:genetics*; D015331:Cohort Studies; D019175:DNA Methylation; D005260:Female; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D012878:Skin Neoplasms / Q000235:genetics*; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D009363:Neoplasm Proteins; D000099170:Bis(5'-adenosyl)triphosphatase