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Loss of Heterozygosity for Defined Regions on Uterine Cervix

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Loss of Heterozygosity for Defined Regions on Uterine Cervix British Joumal of Cancer (1998) 77(2), 192-200 © 1998 Cancer Research Campaign Loss of heterozygosity for defined regions on chromosomes 3, 11 and 17 in carcinomas of the uterine cervix AMF Kersemaekers1, J Hermans2, GJ Fleuren1 and MJ van de Vijver' Departments of 'Pathology and 2Statistics, Leiden University Hospital, PO Box 9600, Building 1, L1-Q, 2300 RC Leiden, The Netherlands 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 17p13.3, 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. Keywords: cervical carcinoma; allelic imbalance; 1-catenin; microsatellite instability; tumour-suppressor gene; E-cadherin The involvement of human papillomavirus (HPV) in the develop- the ,-catenin gene is located (Kraus et al 1994; Bailey et al, 1995; ment of carcinomas of the uterine cervix has been firmly estab- Hengel et al, 1995; Trent et al, 1995; Nollet et al, 1996). O-Catenin lished. Because HPV infection does not always lead to cervical is a structural mediator for the attachment of the cytoskeletal actin cancer, other genetic alterations must also play a role in tumour filaments to cellular adhesion molecules, i.e. cadherins, in partic- development. Loss of heterozygosity (LOH), pointing to a role for ular E-cadherin (Jou et al 1995; Kawanishi et al, 1995; Rubinfeld tumour-suppressor genes, oncogene amplification and point muta- et al, 1995). O-Catenin also complexes with the APC gene product, tions are all thought to be involved, but there is as yet no complete a tumour-suppressor gene mutated in hereditary polyposis coli and picture of the relative role for each of these genetic changes in sporadic colorectal tumours (Rubinfeld et al, 1993; Su et al, 1993; cervical carcinomas. To play a role in tumorigenesis, both copies Hulsken et al, 1994). In normal cells, APC binds together with of a tumour-suppressor gene have to be inactivated. Usually, one GSK-3, to ,-catenin and degrades it. O-Catenin can be deregu- allele is lost by a small inactivating mutation and the second by lated by mutations in APC or in P-catenin itself. This results in the loss of heterozygosity. Loss of one allele in a chromosome region accumulation of ,-catenin, activating its role in signalling may therefore point to the presence of a tumour-suppressor gene in (Korinek et al, 1997; Morin et al, 1997; Rubinfeld et al, 1997). that region. Such chromosome losses can be detected by polymor- The involvement of chromosome 11 in cervical cancer has been phic markers. Different studies have reported a high incidence of reported by several groups. Hampton et al (1994) found the LOH on chromosomes 3p, lIp and 1 lq. However, a detailed dele- smallest region of overlapping LOH at 1 lq22-24. Bethwaite et al tion map of these areas has not been made yet. (1995) found LOH on 1 1q23, but only with one marker in this Seven different groups (Yokota et al, 1989; Chung et al, 1992; region. Misra and Saxon (Misra and Srivatsan, 1989; Saxon et al, Jones and Nakamura, 1992; Kohno et al, 1993; Karlsen et al, 1994; 1986) used HeLa cells, which had lost part of chromosome 11, to Mitra et al, 1994; Mullokandov et al, 1996; Rader et al, 1996) fuse them with fibroblast hybrids that contained part or all of chro- found LOH on chromosome 3 in cervical carcinomas. The mosome 11. By transferring a normal complete copy of chromo- regions mapped by these investigators include 3p2l-p22, where some 11, the HeLa cells became non-tumorigenic. This suggests that chromosome 11 harbours genes that are involved in the suppression of HeLa cell tumorigenicity. Received 12 February 1997 Many investigators (Kaelbling et al, 1992; Mitra et al, 1994; Revised 1 July 1997 Accepted 8 July 1997 Havre et al, 1995; Hoppe-Seyler and Butz, 1995; Mansur et al, 1995; Mullokandov et al, 1996) have studied the short arm of Correspondence to: MJ van de Vijver chromosome 17 for the p53 gene, which may be involved in 192 Loss of heterozygosity in carcinomas of the uterine cervix 193 Table 1 Frequency of LOH observed with 24 PCR primers for tumours were clinically staged as class IA (2), IB (48) and IIA chromosomes 3,11,13,16 and 17 in 64 cervical cancers (14), and were treated with radical hysterectomy. The ages of the Locus Map position Cases studied LOH (%) patients ranged from 22 to 76 years with a median of 45 years. All (informative cases) material consisted of formalin-fixed paraffin-embedded tissue. Haematoxylin & eosin sections were screened and tissue blocks D3S1270 3pter-p25 61 (38) 7 (18%) were selected if they contained 50% or more tumour tissue. D3S1211 3p24.2-p22 55 (29) 6 (20%) Constitutional DNA was extracted D3S11 3p23 62 (39) 5 (13%) from the uterus wall, which did D3S1768 3p23 57 (40) 11 (28%) not contain tumour tissue. J-catenin 3p22 62 (35) 13 (37%) D3S2456 3p21 58 (44) 18 (41%) D3S1289 3p21.2-p21.1 57(43) 17 (40%) DNA extraction D3S196 61 3 3q27-q28 (43) (7%) DNA extraction was performed according to the protocol described D11S865 11p15.1 59(47) 6 (13%) by Isola et al (1994) with some adjustments. Ten 16-jim sections D11S875 11p15.4-p13 63(46) 3 (7%) D11S554 11p12-p11.2 47(33) 4 (12%) were cut from the tissue blocks. Tumour-rich areas were identified D11S35 11q22 57 (41) 19 (46%) using a consecutive haematoxylin and eosin-stained section for DRD-2 11q23.1 61 (21) 5(24%) guidance. The area that contained 50% or more tumour cells was cut D11S528 11 q23.3 63(47) 20 (43%) away with a clean knife and put in sterile microcentrifuge tubes. D17S513 17p13.3 62 (42) 16 (38%) This enrichment resulted in isolation of DNA from material D17S1537 17p13.3 58 (31) 10 (32%) containing at least 50% tumour cells. The tissue was deparaffinated TP53 17p13.1 63 (44) 9 (20%) in xylene, centrifuged and subsequently washed twice in 100% D17S520 17p12 58 (41) 4 (10%) D17S578 17q11.2 53(28) 2 (7%) ethanol. DNA was isolated by incubation for 72 h at 55°C in 1 ml of D17S855 17q21 (BRCA1) 57 (41) 2 (4%) isolation buffer containing 100 mm sodium chloride, 10 mm Tris- D13S153 13q1 3-14 (RB) 61 (50) 2 (4%) HCI (pH 8), 25 mm EDTA (pH 8) and 0.5% sodium dodecyl D13S289 13q12.3 (BRCA2) 62 (44) 6 (13%) sulphate. An aliquot (30 ,ul) of proteinase K (10 jg il-1) was then added to the and D16S752 16q22.1 57 (47) 7 (14%) mixture, fresh 15-jl aliquots of proteinase K were D16S2624 16q22.1 56 (47) 5 (10%) added after 24 and 48 h. DNA was extracted by phenol/chloroform and precipitated with 1 ml of 100% ethanol, 20 jg ml-' glycogen and 250 jil 7.5 M ammonium actinium. DNA was dissolved in Tris- EDTA (10 mm Tris, 0.1 mm EDTA, pH 7.6). cervical carcinomas through its interaction with HPV-E6 oncopro- Polymerase chain reaction (PCR) technique teins. p53 point mutations are infrequent (< 10%) in clinical Primers for polymorphic repeats (Table samples of squamous cell carcinomas of the uterine cervix, 1, mostly CA repeats and some tetranucleotide were chosen on the basis of whereas p53 point mutations were seen more often in adenocarci- repeats) their heterozygosity percentage, location and allele from noma (30%) (Fujita et al, 1992; Jiko et al, 1994; Schneider et al, length the genome database. The intragenic ,B-catenin were 1994). Park et al (1995) detected LOH at l7pl3.3 in eight (40%) primers kindly provided by F Nollet, University of Ghent, Belgium. A standard out of 20 heterozygous cervical carcinomas, with at least one of PCR was carried out in a 12-jil reaction volume containing ng the two markers D17S34 or D17S5.
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