Abnormal fragile histidine triad transcripts were found in 20 -30% of CIN2/3 lesions and 11% of normal cervical biopsies by RT -PCR. Bi-allelic loss of the fragile histidine triad gene and the loss of fragile histidine triad protein expression detectable by immunochemical staining with a polyclonal fragile histidine triad specific antibody was rare. The genomic changes showed no association with the presence of human papillomavirus types which carry high risk for cervical cancer (high risk human papillomavirus) as assessed by a type-specific multiplex PCR. The presence of abnormal fragile histidine triad transcripts in a subset of CIN2/3 lesions with no high risk human papillomavirus suggests that this could be an independent risk factor associated with an alternative carcinogenic pathway. Cervical cancer is the second most common malignancy in women worldwide. It is generally accepted that the development of cervical cancer from precancers (CIN2/3) involves multistep molecular changes and is therefore a preventable disease if precancers are detected and treated early.The major risk factor for CIN2/3 and cancer is infection with high risk human papillomavirus (HR HPV) types which include HPV16, HPV18, HPV31, HPV33, HPV35, HPV45, HPV51, HPV52, HPV56, HPV58, HPV59 and HPV68. One or more of these virus types have been reported to be present in 90 -95% of CIN2/3 lesions and in nearly all cancers (Lorincz et al, 1992;Bosch et al, 1995; Walboomers et al, 1996). However, infection with HR HPV does not invariably lead to the development of high grade cervical lesions and there is a clear requirement for other cofactors, presumably to advance the oncogenic process initiated by HR HPV (zur Hausen, 1999). The effects of co-factors are difficult to measure objectively because of the dominant effects of HR HPV infection but tobacco smoking has consistently been associated with cervical cancer (Szarewski et al, 1996) and has been found recently to induce genomic instability in head and neck cancers (Schantz et al, 2000). Other potential co-factors include oral contraceptive use and other sexually transmitted diseases.Genomic instability has been found in cervical neoplasia and commonly involves the short arm of chromosome 3. Results reported so far are based on small numbers of samples and show no clear correlation between genomic changes and lesion grades (Butler et al, 2000;Yoshino et al, 2000). Allelic loss and microsatellite instability were found to occur in lesions with or without malignant potential in similar proportion Chu et al, 1998;Yoshino et al, 1998;Butler et al, 2000;Lin et al, 2000). Inconsistent results were also obtained in the analysis of abnormal transcripts encoded by the fragile histidine triad (FHIT) gene at chromosome 3p14.2. These are also indicative of genomic instability (Sozzi et al, 1996) but the incidence reported varies from 30 to 80% in cervical cancer and 0 to 40% in normal tissue (Greenspan et al, 1997;Chu et al, 1998;Muller et al, 1998;Su et al, 1998;Yoshino et al, 1998;Nakagawa et al, 1999;...