Abstract
Investigation of genetic changes in tumours by loss of heterozygosity (LOH) is a powerful technique for identifying chromosomal regions that may contain tumour suppressor genes. LOH has been described on chromosome 6 in ovarian carcinoma using restriction fragment length polymorphism analysis with a small number of probes. We studied 29 ovarian carcinomas with 19 probes mapping to chromosome 6. Sixteen of the 29 tumours showed LOH on 6q (55%). Of these 16, 63% showed loss of all informative markers on that arm. One tumour showed loss of 6q24-qter, localising the putative tumour suppressor gene to that region. Loss on 6p was 28% overall. However, using three dinucleotide repeat primer pairs from 6p to study LOH in seven selected tumours, LOH was demonstrated at both 6p22.3-pter and at 6p12-6p22. These results confirm that 6q harbours a tumour suppressor gene of relevance to ovarian carcinoma and suggest that there may also be a similar gene(s) on 6p. By Southern analysis, there was no evidence of genomic rearrangements of the oestrogen receptor gene, located at 6q25.1. LOH on 6q was more common in high than low grade tumours. The relevance of our findings to previous work in ovarian cancer and other solid tumours is discussed.
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- Atkin N. B., Baker M. C., Ferti-Passantonopoulou A. Chromosome changes in early gynecologic malignancies. Acta Cytol. 1983 Jul-Aug;27(4):450–453. [PubMed] [Google Scholar]
- Blanché H., Wright L. G., Vergnaud G., de Gouyon B., Lauthier V., Silver L. M., Dausset J., Cann H. M., Spielman R. S. Genetic mapping of three human homologues of murine t-complex genes localizes TCP10 to 6q27, 15 cM distal to TCP1 and PLG. Genomics. 1992 Apr;12(4):826–828. doi: 10.1016/0888-7543(92)90317-l. [DOI] [PubMed] [Google Scholar]
- Blanché H., Zoghbi H. Y., Jabs E. W., de Gouyon B., Zunec R., Dausset J., Cann H. M. A centromere-based genetic map of the short arm of human chromosome 6. Genomics. 1991 Mar;9(3):420–428. doi: 10.1016/0888-7543(91)90407-6. [DOI] [PubMed] [Google Scholar]
- Boyle J. M., Hey Y., Myers K., Stern P. L., Grzeschik F. H., Ikehara Y., Misumi Y., Fox M. Regional localization of a trophoblast antigen-related sequence and 16 other sequences to human chromosomes 6q using somatic cell hybrids. Genomics. 1992 Apr;12(4):693–698. doi: 10.1016/0888-7543(92)90296-5. [DOI] [PubMed] [Google Scholar]
- Cavenee W. K., Dryja T. P., Phillips R. A., Benedict W. F., Godbout R., Gallie B. L., Murphree A. L., Strong L. C., White R. L. Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. 1983 Oct 27-Nov 2Nature. 305(5937):779–784. doi: 10.1038/305779a0. [DOI] [PubMed] [Google Scholar]
- Devilee P., van Vliet M., van Sloun P., Kuipers Dijkshoorn N., Hermans J., Pearson P. L., Cornelisse C. J. Allelotype of human breast carcinoma: a second major site for loss of heterozygosity is on chromosome 6q. Oncogene. 1991 Sep;6(9):1705–1711. [PubMed] [Google Scholar]
- Ehlen T., Dubeau L. Loss of heterozygosity on chromosomal segments 3p, 6q and 11p in human ovarian carcinomas. Oncogene. 1990 Feb;5(2):219–223. [PubMed] [Google Scholar]
- Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
- Friend S. H., Bernards R., Rogelj S., Weinberg R. A., Rapaport J. M., Albert D. M., Dryja T. P. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature. 1986 Oct 16;323(6089):643–646. doi: 10.1038/323643a0. [DOI] [PubMed] [Google Scholar]
- Futreal P. A., Söderkvist P., Marks J. R., Iglehart J. D., Cochran C., Barrett J. C., Wiseman R. W. Detection of frequent allelic loss on proximal chromosome 17q in sporadic breast carcinoma using microsatellite length polymorphisms. Cancer Res. 1992 May 1;52(9):2624–2627. [PubMed] [Google Scholar]
- Garcia T., Sanchez M., Cox J. L., Shaw P. A., Ross J. B., Lehrer S., Schachter B. Identification of a variant form of the human estrogen receptor with an amino acid replacement. Nucleic Acids Res. 1989 Oct 25;17(20):8364–8364. doi: 10.1093/nar/17.20.8364. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Goelz S. E., Hamilton S. R., Vogelstein B. Purification of DNA from formaldehyde fixed and paraffin embedded human tissue. Biochem Biophys Res Commun. 1985 Jul 16;130(1):118–126. doi: 10.1016/0006-291x(85)90390-0. [DOI] [PubMed] [Google Scholar]
- Knudson A. G., Jr Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971 Apr;68(4):820–823. doi: 10.1073/pnas.68.4.820. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Le Borgne-Demarquoy F., Kwiatowski T. J., Jr, Zoghbi H. Y. Two dinucleotide repeat polymorphisms at the D6S202 locus. Nucleic Acids Res. 1991 Nov 11;19(21):6060–6060. doi: 10.1093/nar/19.21.6060-a. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lee J. H., Kavanagh J. J., Wildrick D. M., Wharton J. T., Blick M. Frequent loss of heterozygosity on chromosomes 6q, 11, and 17 in human ovarian carcinomas. Cancer Res. 1990 May 1;50(9):2724–2728. [PubMed] [Google Scholar]
- Litt M., Luty J. A. Dinucleotide repeat polymorphism at the D6S89 locus. Nucleic Acids Res. 1990 Jul 25;18(14):4301–4301. doi: 10.1093/nar/18.14.4301. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mauvieux V., Jouanolle A. M., el Kahloun A., Blayau M., Le Gall J. Y., David V. Dinucleotide repeat polymorphism at the FTHPI locus of chromosome 6. Nucleic Acids Res. 1991 Dec 25;19(24):6969–6969. doi: 10.1093/nar/19.24.6969. [DOI] [PMC free article] [PubMed] [Google Scholar]
- McGuire W. L., Chamness G. C., Fuqua S. A. The importance of normal and abnormal oestrogen receptor in breast cancer. Cancer Surv. 1992;14:31–40. [PubMed] [Google Scholar]
- Millikin D., Meese E., Vogelstein B., Witkowski C., Trent J. Loss of heterozygosity for loci on the long arm of chromosome 6 in human malignant melanoma. Cancer Res. 1991 Oct 15;51(20):5449–5453. [PubMed] [Google Scholar]
- Morita R., Saito S., Ishikawa J., Ogawa O., Yoshida O., Yamakawa K., Nakamura Y. Common regions of deletion on chromosomes 5q, 6q, and 10q in renal cell carcinoma. Cancer Res. 1991 Nov 1;51(21):5817–5820. [PubMed] [Google Scholar]
- Müllenbach R., Lagoda P. J., Welter C. An efficient salt-chloroform extraction of DNA from blood and tissues. Trends Genet. 1989 Dec;5(12):391–391. [PubMed] [Google Scholar]
- Oka K., Ishikawa J., Bruner J. M., Takahashi R., Saya H. Detection of loss of heterozygosity in the p53 gene in renal cell carcinoma and bladder cancer using the polymerase chain reaction. Mol Carcinog. 1991;4(1):10–13. doi: 10.1002/mc.2940040104. [DOI] [PubMed] [Google Scholar]
- Pejovic T., Heim S., Mandahl N., Baldetorp B., Elmfors B., Flodérus U. M., Furgyik S., Helm G., Himmelmann A., Willén H. Chromosome aberrations in 35 primary ovarian carcinomas. Genes Chromosomes Cancer. 1992 Jan;4(1):58–68. doi: 10.1002/gcc.2870040108. [DOI] [PubMed] [Google Scholar]
- Ponglikitmongkol M., Green S., Chambon P. Genomic organization of the human oestrogen receptor gene. EMBO J. 1988 Nov;7(11):3385–3388. doi: 10.1002/j.1460-2075.1988.tb03211.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ranum L. P., Chung M. Y., Duvick L. A., Zoghbi H. Y., Orr H. T. Dinucleotide repeat polymorphism at the D6S109 locus. Nucleic Acids Res. 1991 Mar 11;19(5):1171–1171. doi: 10.1093/nar/19.5.1171-a. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Russell S. E., Hickey G. I., Lowry W. S., White P., Atkinson R. J. Allele loss from chromosome 17 in ovarian cancer. Oncogene. 1990 Oct;5(10):1581–1583. [PubMed] [Google Scholar]
- Saito S., Saito H., Koi S., Sagae S., Kudo R., Saito J., Noda K., Nakamura Y. Fine-scale deletion mapping of the distal long arm of chromosome 6 in 70 human ovarian cancers. Cancer Res. 1992 Oct 15;52(20):5815–5817. [PubMed] [Google Scholar]
- Sato T., Saito H., Morita R., Koi S., Lee J. H., Nakamura Y. Allelotype of human ovarian cancer. Cancer Res. 1991 Oct 1;51(19):5118–5122. [PubMed] [Google Scholar]
- Sato T., Tanigami A., Yamakawa K., Akiyama F., Kasumi F., Sakamoto G., Nakamura Y. Allelotype of breast cancer: cumulative allele losses promote tumor progression in primary breast cancer. Cancer Res. 1990 Nov 15;50(22):7184–7189. [PubMed] [Google Scholar]
- Stenman G., Sandros J., Mark J., Edström S. Partial 6q deletion in a human salivary gland adenocarcinoma. Cancer Genet Cytogenet. 1989 Jun;39(2):153–156. doi: 10.1016/0165-4608(89)90180-5. [DOI] [PubMed] [Google Scholar]
- Thomas G. A., Raffel C. Loss of heterozygosity on 6q, 16q, and 17p in human central nervous system primitive neuroectodermal tumors. Cancer Res. 1991 Jan 15;51(2):639–643. [PubMed] [Google Scholar]
- Trent J. M., Stanbridge E. J., McBride H. L., Meese E. U., Casey G., Araujo D. E., Witkowski C. M., Nagle R. B. Tumorigenicity in human melanoma cell lines controlled by introduction of human chromosome 6. Science. 1990 Feb 2;247(4942):568–571. doi: 10.1126/science.2300817. [DOI] [PubMed] [Google Scholar]
- Vogelstein B., Fearon E. R., Kern S. E., Hamilton S. R., Preisinger A. C., Nakamura Y., White R. Allelotype of colorectal carcinomas. Science. 1989 Apr 14;244(4901):207–211. doi: 10.1126/science.2565047. [DOI] [PubMed] [Google Scholar]
- Wake N., Hreshchyshyn M. M., Piver S. M., Matsui S., Sandberg A. A. Specific cytogenetic changes in ovarian cancer involving chromosomes 6 and 14. Cancer Res. 1980 Dec;40(12):4512–4518. [PubMed] [Google Scholar]
- Weber J. L., Kwitek A. E., May P. E., Zoghbi H. Y. Dinucleotide repeat polymorphism at the D6S105 locus. Nucleic Acids Res. 1991 Feb 25;19(4):968–968. doi: 10.1093/nar/19.4.968. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Weinberg R. A. Tumor suppressor genes. Science. 1991 Nov 22;254(5035):1138–1146. doi: 10.1126/science.1659741. [DOI] [PubMed] [Google Scholar]
- Zheng J. P., Robinson W. R., Ehlen T., Yu M. C., Dubeau L. Distinction of low grade from high grade human ovarian carcinomas on the basis of losses of heterozygosity on chromosomes 3, 6, and 11 and HER-2/neu gene amplification. Cancer Res. 1991 Aug 1;51(15):4045–4051. [PubMed] [Google Scholar]
- Zoghbi H. Y., Ballantyne C. M., O'Brien W. E., McCall A. E., Kwiatkowski T. J., Jr, Ledbetter S. A., Beaudet A. L. Deletion and linkage mapping of eight markers from the proximal short arm of chromosome 6. Genomics. 1990 Feb;6(2):352–357. doi: 10.1016/0888-7543(90)90576-g. [DOI] [PubMed] [Google Scholar]
- Zuppan P., Hall J. M., Lee M. K., Ponglikitmongkol M., King M. C. Possible linkage of the estrogen receptor gene to breast cancer in a family with late-onset disease. Am J Hum Genet. 1991 Jun;48(6):1065–1068. [PMC free article] [PubMed] [Google Scholar]



