Background: Human papillomaviruses (HPV) are the most important etiologic factor for cervical carcinoma. However, additional cellular events may be necessary for malignant progression in the cervix. Recently, the fragile histidine triad (FHIT) gene, which is frequently lost in many cancers, was identified as a candidate tumor suppressor gene at chromosome 3p locus 14.2.
Methods: Thirty-five invasive cervical carcinomas (ICC), 13 Grade 2-3 cervical intraepithelial neoplasia specimens (high grade CIN), and 21 normal cervices were examined for expression of the FHIT gene and oncogenic HPV E6-E7 mRNA by reverse transcription-polymerase chain reaction (RT-PCR), and all of these FHIT cDNA were directly sequenced.
Results: Fourteen of 35 ICC (40%) showed abnormal FHIT transcription, whereas none of the high grade CIN or normal cervices had FHIT abnormalities. FHIT abnormalities included 13 short transcripts that were variously truncated between exons 4 and 8, 3 short transcripts with unknown sequences inserted, and 1 with no transcription. FHIT abnormalities were observed in all the small cell carcinomas, 4 of 7 adenocarcinomas and adenosquamous cell carcinomas (57%), and 7 of 25 squamous cell carcinomas (28%). Small cell carcinoma appeared to express the aberrant transcripts more frequently than squamous cell carcinoma (P=0.037). Immunohistochemical analysis showed that four ICCs with abnormal FHIT transcription did not express FHIT protein, whereas five of six CIN and ICC with no FHIT abnormality did express it. When expression of HPV E6-E7 mRNA was examined in the samples positive for HPV-DNA, E6-E7 transcripts were expressed in 7 of 9 high grade CIN (78%) and 18 of 28 ICC (64%). There was no difference in the frequency of HPV E6-E7 expression between CIN and ICC. In contrast, HPV E6-E7 expression was repressed in 8 of 10 (80%) ICC with FHIT abnormalities and in 2 of 18 (11%) in ICC with no FHIT abnormalities.
Conclusions: Although E6-E7 genes of oncogenic HPV are important for the development of CIN and ICC, they may not be required for the development of carcinoma cells that have abnormal FHIT genes.