Deletion of the FHIT gene in neoplastic and invasive cervical lesions is related to high-risk HPV infection but is independent of histopathological features

The fragile histidine triad (FHIT) gene encompasses the common chromosomal fragile site FRA3B, Human papilloma virus (HPV), which is the main aetiolog ical agent in cervical cancers, has been found to be able to integrate its genes into the chromosome 3 fragile site of cultured cells, deleting a piec e of DNA which includes the FHIT gene. Eighty-six microdissected archival c ervical LLETZ biopsies comprising cases of cervical intraepithelial neoplas ia (CIN) 1 (n = 27), CIN3 (n = 30) and microinvasive carcinoma (n = 29) wer e evaluated for HPV infection and FHIT gene loss of heterozygosity (LOH). F HIT gene LOH was detected by polymerase chain reaction (PCR) using fluoresc ently labelled intragenic microsatellite markers D3S1300 and D3S4103. PCR p roducts were analysed on a semi-automated DNA sequencer using Fragment Mana ger(TM) software to determine allele loss. The HPV status of the lesions wa s determined by PCR using generic and type-specific primers in conjunction with restriction endonuclease digestion. The results were analysed using Ep i-Info and SPSS-PC statistical analysis software, Haematoxylin and eosin-st ained sections from the 86 cases were profiled for six histopathological fe atures, some of which have been previously shown to be associated with micr oinvasive cancer. FHIT gene LOH was found in 36% of CIN1 cases, 52% of CIN3 cases and 73% of microinvasive cases (p=0.029). HPV 16 DNA was found in 68 % of CIN3 cases and 93% of microinvasive cases (p<.0.001). The second most prevalent HPV type found was HPV 31, which was present in only four lesions , three of which had FHIT gene LOH. When FHIT gene LOH was evaluated versus HPV 16 and 31 infection using the chi-square test, a statistically signifi cant relationship was found (p=0.014). FHIT gene LOH was found to be indepe ndent of the histopathological features evaluated. The finding of a statist ically significant relationship between FHIT gene LOH and oncogenic HPV inf ection suggests a link between the integration of viral DNA and subsequent gene deletion in the progression of cervical cancer. FHIT gene anomalies ma y prove to be excellent markers of progression in early uterine cervical ca ncers, Copyright (C) 2000 John Wiley & Sons, Ltd.