Comparison of molecular changes in cervical intraepithelial neoplasia in HIV-positive and HIV-indeterminate subjects.
OBJECTIVE
HIV infection is associated with an increased incidence of cervical malignancy and its precursor lesions (CIN, cervical intraepithelial neoplasia) compared with the general population. We studied the molecular abnormalities in the development of HIV-associated CIN and compared them with those present in CINs arising in HIV-indeterminate subjects ("sporadic CIN").


METHODS
We investigated the presence of human papilloma virus (HPV) sequences, loss of heterozygosity (LOH), and microsatellite alterations (MAs) at five 3p chromosomal regions using 17 polymorphic markers in precisely microdissected archival tissues from 16 HIV-positive CINs and compared them with those present in 39 sporadic CINs.


RESULTS
HPV sequences were detected in 36 of 55 (66%) CIN lesions, and high-risk oncogenic strains (HPV 16 and 18) accounted for 15 of them. No differences in the HPV frequencies were found between HIV-associated and sporadic CINs. Allelic losses at one or more chromosome 3p regions were frequently detected in CIN lesions (49%). The overall frequency of 3p LOH and the frequencies at all individual regions were similar in HIV-associated and sporadic CINs. The frequency of MA present in the HIV-associated CIN cases (0.093) was sixfold greater than in sporadic CINs (0.014; P = 0.0001). At least 1 MA was present in 11 (69%) of 16 HIV-associated vs. 5 of 39 (13%) sporadic CIN (P = 0.0006). Molecular changes were independent of the presence of HPV sequences.


CONCLUSIONS
Chromosome 3p deletions are frequently detected in the precursor lesions of cervical carcinoma (CIN) and there are no differences in the 3p LOH frequencies between HIV-associated and sporadic CIN lesions. Microsatellite alterations, which reflect widespread genomic instability, occur at greatly increased frequency in HIV-associated CIN. Although the mechanism underlying the development of increased MAs is unknown, it may play a crucial role in the development of many HIV-associated neoplasias.
Wistuba
I I
II
Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, Texas, 75235-8593, USA.
Syed
S
S
Behrens
C
C
Duong
M
M
Milchgrub
S
S
Muller
C Y
CY
Jagirdar
J
J
Gazdar
A F
AF
D015344:DNA Probes, HPV; D004279:DNA, Viral / Q000032:analysis*; D005260:Female; D006679:HIV Seropositivity / Q000150:complications*; D006801:Humans; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats; D027383:Papillomaviridae / Q000235:genetics*; D017422:Sequence Analysis, DNA; D002583:Uterine Cervical Neoplasms / Q000150:complications / Q000235:genetics / Q000821:virology*; D002578:Uterine Cervical Dysplasia / Q000150:complications / Q000235:genetics / Q000821:virology*
D015344:DNA Probes, HPV; D004279:DNA, Viral