Allelic deletion mapping on chromosome 6q and X chromosome inactivation clonality patterns in cervical intraepithelial neoplasia and invasive carcinoma

Objective. Loss of heterozygosity (LOH) profiles and X chromosome inactivat ion patterns are analyzed in 42 patients with cervical intraepithelial neop lasias (CIN), including low-grade (CIN1) and high-grade (CIN2, CIN3) lesion s, and 22 patients with invasive cervical carcinomas. Method. Laser capture microdissection was utilized to procure pure matched normal and lesional cells from each case. Sixteen microsatellite markers on four chromosomal arms, 6q21-q25.1, 8p21, 13q12.3-q13, and 17q12-q21, were amplified for LOH, as well as the HUMARA locus for X chromosome inactivatio n analysis. Eight additional markers spanning the long arm of chromosome 6 were utilized in all cases showing LOH on this arm and in which further tis sue material was available for microdissection. Results. Fifty-five percent of carcinomas showed deletions on chromosome ba nds 6q21-q25.1, 43% on 13q12.3-q13, and 40% on 17q12-q21. Deletions on 6q w ere identified in CIN3 (40%), CIN2 (37%), and CIN1 (10%), on 13q in CIN3 (3 3%) and CIN2 (33%), and rarely on chromosomal arm 17q. Finer 6q mapping rev ealed that marker D6S310 (q22) represented the centromeric and marker D6S25 5 (q25-q16) the telomeric boundary of deletion. A second, telomeric area of deletion at marker D6S281 (q27) was also identified. Monoclonal X chromoso me inactivation patterns were identified in 12/13 cancers, 13/14 CIN3, 5/10 CIN2, and 0/6 CIN1. Conclusions. Two areas of deletion on chromosome 6q were identified in cerv ical tumors, suggesting the presence of tumor suppressor gene(s) inactivate d in this neoplasia. LOH on this arm were identified early during cervical tumor progression. LOH on 13q and 17q also occur in cervical cancers. X chr omosome inactivation patterns suggest that CIN develops into a monoclonal l esion during progression from CIN1 to CIN3. (C) 2001 Academic Press.