Monoclonality and surface lesion-specific microsatellite alterations in premalignant and malignant neoplasia of uterine cervix: A local field effect of genomic instability and clonal evolution

Invasive squamous carcinoma of the uterine cervix (CC) arises from sequenti al progression of low-grade (L) and high-grade (H) squamous intraepithelial lesions (SILs). In clinical observations, these lesions are frequently fou nd as synchronous multiple foci. The nature and evolutionary mechanism of t hese lesions are largely unknown. We have performed allelotyping of three 3 p markers (at 3p 14, 3p22-24, and 3p25) on 22 LSILs and 15 HSILs microdisse cted from patients with multiple(n = 21) or uniform (n = 6) cervical lesion s. The results were analyzed together with our previous allelotyping of 57 deeply invasive CCs. Loss of heterozygosity at one of the three markers was observed in 23%, 27%, and 31% of LSILs, HSILs, and CCs, respectively Frequ ent and early allelic loss was noted (in 30% of LSILs and 50% of HSILs) at 3p 14, which may harbor tumor suppressor genes involved in early stages of cervical carcinogenesis. A high frequency of microsatellite alteration (MA) was found in LSIL (41%) and HSIL (67%) but not in CC (5.3%), In particular , MA was more frequently found in low-grade lesions in association with inv asive cancers (75%, 6/8) than in those associated with SILs (29%, 4/14) (P < 0.05). Together with the finding of a monoclonal origin of premalignant a nd malignant cervical lesions, the present results allow us to propose a mo del of local field effect of genomic instability that progressively affects the clonal evolution of SIL of uterine cervix, (C) 1999 Wiley-Liss, Inc.