Hypermethylation of the thrombospondin-1 gene is associated with poor prognosis in penile squamous cell carcinoma.
OBJECTIVE
To evaluate the presence of human papillomavirus (HPV) infection, the methylation status in the promoter region of thrombospondin-1 (TSP-1), RAS association domain family 1A (RASSF1-A) and p16 genes, and the expression of TSP-1, CD31, p16 and p53 proteins in patients diagnosed with penile cancer, and the possible associations between these variables and clinical and pathological features.


METHODS
HPV types, gene promoter hypermethylation and protein expression were analysed by reverse line blot, methylation-specific polymerase chain reaction, and immunohistochemistry, respectively, in 24 penile squamous cell carcinomas.


RESULTS
HPV infection was detected in 11 of 24 cases (46%), and TSP-1, RASSF1-A and p16 genes were hypermethylated in 46%, 42% and 38% of the tumours, respectively. TSP-1 hypermethylation was associated with unfavourable histological grade (grade 3; P = 0.033), vascular invasion (P = 0.023), weak expression of TSP-1 protein (P = 0.041), and shorter overall survival (P = 0.04). TSP-1 expression was not associated with microvessel density. However, RASSF1-A hypermethylation was more frequent in T1 tumours (P = 0.01), and p16 hypermethylation was not associated with any of the tested variables except for absence of p16 expression (P = 0.022).


CONCLUSIONS
In summary, the epigenetic inactivation of TSP-1 and RASSF1-A genes is associated with pathological variables and seems to be of prognostic significance in penile cancer.
Guerrero
David
D
Biomedical Research Center, Navarra Health Service, Pamplona, Navarra, Spain. dguerres@cfnavarra.es
Guarch
Rosa
R
Ojer
Amaya
A
Casas
Juan Manuel
JM
Ropero
Santiago
S
Mancha
Ana
A
Pesce
Carlo
C
Lloveras
Belen
B
Garcia-Bragado
Federico
F
Puras
Ana
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D019942:Genes, p16; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010412:Penile Neoplasms / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012189:Retrospective Studies; D019700:Thrombospondin 1 / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
C411762:RASSF1 protein, human; D019700:Thrombospondin 1; D025521:Tumor Suppressor Proteins