Fragile histidine triad transcription abnormalities and human papillomavirus E6-E7 mRNA expression in the development of cervical carcinoma

BACKGROUND. Human papillomaviruses (HPV) are the most important etiologic f actor for cervical carcinoma. However, additional cellular events may be ne cessary for malignant progression in the cenix. Recently, the fragile histi dine triad (FHIT) gene, which is frequently lost in many cancers, was ident ified as a candidate tumor suppressor gene at chromosome 3p locus 14.2. METHODS. Thirty-five invasive cervical carcinomas (ICC), 13 Grade 2-3 cervi cal intraepithelial neoplasia specimens thigh grade CIM, and 21 normal cerv ices were examined for expression of the FHIT gene and oncogenic HPV E6-E7 mRNA by reverse transcription-polymerase chain reaction (RT-PCR), and all o f these FHIT cDNA were directly sequenced. RESULTS. Fourteen of 35 ICC (40%) showed abnormal FHIT transcription, where as none of the high grade CIN or normal cervices had FHIT abnormalities. FH IT abnormalities included 13 short transcripts that were variously truncate d between exons 4 and 8, 3 short transcripts with unknown sequences inserte d, and 1 with no transcription. FHIT abnormalities were observed in all the small cell carcinomas, 4 of 7 adenocarcinomas and adenosquamous cell carci nomas (57%), and 7 of 25 squamous cell carcinomas (28%). Small cell carcino ma appeared to express the aberrant transcripts more frequently than squamo us cell carcinoma (P = 0.037). Immunohistochemical analysis showed that fou r ICCs with abnormal FHIT transcription did not express FHIT protein, where as five of six CIN and ICC with no FHIT abnormality did express it. When ex pression 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 expres sion between CIN and ICC. In contrast, HPV E6-E7 expression was repressed i n 8 of 10 (80%) ICC with FHIT abnormalities and in 2 of 18 (11%) in ICC wit h no FHIT abnormalities. CONCLUSIONS. Although E6-E7 genes of oncogenic HPV are important for the de velopment of CIN and ICC, they may not be required for the development of c arcinoma cells that have abnormal FHIT genes. (C) 1999 American Cancer Soci ety.