Frequent epigenetic silencing of the FHIT gene in penile squamous cell carcinomas

Abstract

Methylation of normally unmethylated CpG-rich islands in or near the promoter region has been associated with transcriptional inactivation of tumor-suppressor and tumor-related genes in human cancers. However, so far, only a few studies have searched for DNA methylation in penile carcinoma (PC). On the other hand, human papillomavirus (HPV) has been reported to be associated with the pathogenesis of PC. To elucidate the methylation status of PC and HPV infection, the methylation status of eight genes (DAPK, FHIT, MGMT, p14, p16, RAR-beta, RASSF1A, and RUNX3), the incidences of the HPV status, and the expression of Fhit protein were examined in 25 PCs. The frequencies of methylation were: 28% for DAPK, 92% for FHIT, 20% for MGMT, 4% for p14, 24% for p16, 24% for RAR-beta, 12% for RASSF1A, and 44% for RUNX3. Negative expression of Fhit protein was observed in 22 of the 25 cancers (88%). Among those 22, 20 showed methylation of the FHIT gene. HPV-DNA was detected in three of the 25 cancers (12%). Methylation of FHIT gene was frequently found than HPV infection, therefore methylation of the FHIT gene is suggested to play an important role in the pathogenesis of penile squamous cell carcinoma.

Epigenetics Markers of Metastasis and HPV-Induced Tumorigenesis in Penile Cancer

“…Previous studies have identified differentially methylated genes in penile cancer (14,15). These have been targeted studies in which candidate epigenetic-regulated genes have been identified, including RAS and THBS1.…”

“…However, little is known about the molecular genetics or epigenetics driving the development and progression of penile cancer. Aberrant methylation of a handful of candidate genes has previously been identified, including CDKN2A and RASSF1A (13)(14)(15)(16). Recently, epigenetic changes in both host and virus epigenomes have been reported in other HPV-induced cancers (17)(18)(19)(20).…”

Human papillomavirus prevalence and type distribution in penile carcinoma

“…Publications containing less than five cases were also excluded from the analysis. A final total of 31 articles were included in this review12 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 45 (see table 1). …”

Relationship between FHIT expression and HPV status in vulvar squamous cell carcinomas

“…The FHIT gene, which spans the FRA3B fragile site at chromosome 3p14.2 [2] , has been found as an early and frequent event in a variety of malignant tumors [3][4][5] .…”