Loss of heterozygosity for defined regions on chromosomes 3, 11 and 17 in carcinomas of the uterine cervix

Abstract

Summary Loss of heterozygosity (LOH) frequently occurs in squamous cell carcinomas of the uterine cervix and indicates the probable sites of tumour-suppressor genes that play a role in the development of this tumour. To define the localization of these tumour-suppressor genes, we studied loss of heterozygosity in 64 invasive cervical carcinomas (stage IB and IIA) using the polymerase chain reaction with 24 primers for polymorphic repeats of known chromosomal localization. Chromosomes 3, 11, 13, 16 and 17, in particular, were studied. LOH was frequently found on chromosome 11, in particular at 11 q22 (46%) and 11 q23.3 (43%). LOH on chromosome 11p was not frequent. On chromosome 17p1 3.3, a marker (Dl 7S513) distal to p53 showed 38% LOH, whereas p53 itself showed only 20% LOH. On the short arm of chromosome 3, LOH was frequently found (41%) at 3p21.1. The f-catenin gene is located in this chromosomal region. Therefore, expression of f-catenin protein was studied in 39 cases using immunohistochemistry. Staining of 1-catenin at the plasma membrane of tumour cells was present in 38 cases and completely absent in only one case. The tumour-suppressor gene on chromosome 3p21.1 may be ,B-catenin in this one case, but (an)other tumour-suppressor gene(s) must also be present in this region. For the other chromosomes studied, 1 3q (BRCA-2) and 16q (E-cadherin), only sporadic losses (< 15% of cases) were found. Expression of E-cadherin was found in all of 37 cases but in six cases the staining was very weak. No correlation was found between clinical and histological parameters and losses on chromosome 3p, 1 1 q and 1 7p. In addition to LOH, microsatellite instability was found in one tumour for almost all loci and in eight tumours for one to three loci. In conclusion, we have identified three loci with frequent LOH, which may harbour new tumour-suppressor genes, and found microsatellite instability in 14% of cervical carcinomas.

Progressive genetic aberrations detected by comparative genomic hybridization in squamous cell cervical cancer

“…Several recurrent chromosomal aberrations have been described for cervical cancer, detected either by CGH or allelic imbalance (Hampton et al, 1994;Heselmeyer et al, 1996Heselmeyer et al, , 1997Larson et al, 1997;Kersemaekers et al, 1998;Dellas et al, 1999;Kirchhoff et al, 1999). These regions include gain of 3q and losses of 3p, 11q, and 6q as observed in the current series.…”

Genetic aberrations detected by comparative genomic hybridisation in vulvar cancers

“…Furthermore, two of the microsatellite markers showing LOH which were used in the previous studies were mapped to the region of 3p24, which was the smallest Comparative genomic hybridisation in vulvar cancer DG Allen et al region of chromosome loss detected by CGH in the current study. Loss of 3p is also frequently seen in cervical SCC, by CGH and LOH analysis (Heselmeyer et al, 1996(Heselmeyer et al, , 1997bLarson et al, 1997;Wistuba et al, 1997;Kersemaekers et al, 1998;Steenbergen et al, 1998;Dellas et al, 1999;Kirchoff et al, 1999;Allen et al, 2000). Loss of 11q has been documented in cervical and other malignancies not related to HPV infection, including breast, colorectal and ovarian cancers and malignant melanoma (Hampton et al, 1994;Kersemaekers et al, 1998;Allen et al, 2000).…”

Loss of heterozygosity on chromosome arms 3p and 6q in microdissected adenocarcinomas of the uterine cervix and adenocarcinoma in situ

“…22 Most of the reports have analyzed LOH in squamous carcinomas and have included in addition few glandular lesions. [7][8][9] Ferguson et al reported a low frequency of deletions in glandular lesions, suggesting that most endocervical adenocarcinomas lack the molecular alterations characteristic of other gynecologic malignancies, including LOH. 6 Larson et al identified LOH in 10 of 13 cell lines derived from squamous cell carcinomas of the cervix, whereas the deletions were not detected in cell lines derived from adenocarcinomas (HeLa and JE6), or adenosquamous carcinoma (XH1).…”

“…[5][6][7][8] However, most of these studies have focused on LOH detection in squamous carcinomas and have included only a few cases of adenocarcinomas. A major challenge in identifying allelic deletions in microscopic lesions such as adenocarcinomas or their precursor lesions with a complex pattern of glands admixed with reactive/inflammatory stroma is the need to obtain pure tumor cell populations, because contaminating nonlesional cells can mask the detection of LOH.…”