Fhit alterations in cancerous and non-cancerous cervical epithelium

We have reported a significant frequency of an alteration of the fragile hi stidine triad (fhit) gene in squamous-cell carcinoma of the uterine cervix (series I). To further define the role of Fit alteration in the development of cervical carcinoma, we surveyed 36 normal cervical epithelium, 22 cervi cal intra-epithelial neoplasias (CINs) and 20 additional cases of invasive cervical carcinomas (series 2). Fit transcripts were analyzed using reverse -transcription-polymerase-chain-reaction amplification and sequencing. Loss of expression of Fit was observed in 14 of 48 (29%) invasive carcinomas (8 /28, series 1; 6/20, series 2) but not in any normal squamous epithelia or CINs analyzed. Abnormal Fit transcripts, including deletions and/or inserti ons, were observed in 12 of 48 (25%) invasive carcinomas (9/28, series 1; 3 /20, series 2), 6 of 22 (27%) CINs, and 10 of 40 (25%) normal squamous epit helia (0/4, series 1; 10/36, series 2). Point mutation was detected in 9 of 48 (19%) cervical carcinomas (8/28, series 1; 1/20, series 2). Inactivatio n in both alleles was observed in 18 of 48 cervical carcinomas (38%), but n ot in any of 22 CINs or 40 normal squamous epithelia. Loss or impaired expr ession of the Fit-gene product was detected in 13 of 30 (43%) cervical carc inomas by immunohistochemistry, whereas all 6 normal cervical epithelia, or 22 CINs, expressed fhit protein. There was a strong association of impaire d fhit protein expression with the disruption of normal Fit transcript in c ervical carcinoma. No apparent correlation was observed between Fit inactiv ation and HPV infection. Our results suggest that Fit-gene inactivation occ urs, not as an initiating event, but rather as a later event in cervical ca rcinogenesis, when the cervical tumor has acquired an invasive character. ( C) 2000 Wiley-Liss, Inc.