Skip to main content
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 Oct;81(3):503–509. doi: 10.1038/sj.bjc.6690722

Detection of loss of heterozygosity at RAD51, RAD52, RAD54 and BRCA1 and BRCA2 loci in breast cancer: pathological correlations

R Gonzalez 1, J M Silva 1, G Dominguez 1, J M Garcia 1, G Martinez 2, J Vargas 3, M Provencio 1, P España 1, F Bonilla 1
PMCID: PMC2362917  PMID: 10507777

Abstract

Loss of heterozygosity (LOH) in loci of the 15q15.1, 12p13, 1p32, 17q21 and 13q12–13 regions may collaborate in the inactivation of RAD51, RAD52, RAD54, BRCA1, BRCA2 and possibly other genes implicated in the repair of double-stranded DNA and in DNA recombination. We investigate allelic losses in microsatellites of the RAD51, RAD52, RAD54, BRCA1 and BRCA2 regions, and their correlations with nine pathologic parameters in 127 breast carcinomas. The LOH analysis was performed by amplifying DNA by PCR, using 15 markers of the 15q15.1, 12p13.3, 1p32, 17q21 and 13q12–13 regions. LOH was found in the RAD51 region in 32% of tumours, in the RAD52 region in 16%, in RAD54 in 20% and in the BRCA1 and BRCA2 regions in 49% and 44% respectively. Significant correlations between one or more regions with concomitant LOH and pathologic parameters were observed with respect to age (P = 0.008), oestrogen receptor content (P = 0.03), progesterone receptors (P = 0.003), higher grade (P = 0.001), more advanced stage (P = 0.004) and peritumoural vessel involvement (P < 0.0001). The number of cases in which LOH was observed simultaneously in two or more regions was always higher than expected on the basis of their statistical probability, and curiously, the three patients with LOH at five regions concomitantly were under the age of 30 years. These results suggest that LOH at these regions could be related to breast cancer, and probably to a poor tumour prognosis. © 1999 Cancer Research Campaign

Keywords: RAD51, RAD52, RAD54, BRCA1, BRCA2, LOH

Full Text

The Full Text of this article is available as a PDF (99.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Beckmann M. W., Picard F., An H. X., van Roeyen C. R., Dominik S. I., Mosny D. S., Schnürch H. G., Bender H. G., Niederacher D. Clinical impact of detection of loss of heterozygosity of BRCA1 and BRCA2 markers in sporadic breast cancer. Br J Cancer. 1996 May;73(10):1220–1226. doi: 10.1038/bjc.1996.234. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Benson F. E., Stasiak A., West S. C. Purification and characterization of the human Rad51 protein, an analogue of E. coli RecA. EMBO J. 1994 Dec 1;13(23):5764–5771. doi: 10.1002/j.1460-2075.1994.tb06914.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bièche I., Lidereau R. Genetic alterations in breast cancer. Genes Chromosomes Cancer. 1995 Dec;14(4):227–251. doi: 10.1002/gcc.2870140402. [DOI] [PubMed] [Google Scholar]
  4. Chapman M. S., Verma I. M. Transcriptional activation by BRCA1. Nature. 1996 Aug 22;382(6593):678–679. doi: 10.1038/382678a0. [DOI] [PubMed] [Google Scholar]
  5. Cleton-Jansen A. M., Collins N., Lakhani S. R., Weissenbach J., Devilee P., Cornelisse C. J., Stratton M. R. Loss of heterozygosity in sporadic breast tumours at the BRCA2 locus on chromosome 13q12-q13. Br J Cancer. 1995 Nov;72(5):1241–1244. doi: 10.1038/bjc.1995.493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Connor F., Bertwistle D., Mee P. J., Ross G. M., Swift S., Grigorieva E., Tybulewicz V. L., Ashworth A. Tumorigenesis and a DNA repair defect in mice with a truncating Brca2 mutation. Nat Genet. 1997 Dec;17(4):423–430. doi: 10.1038/ng1297-423. [DOI] [PubMed] [Google Scholar]
  7. Devilee P., Cornelisse C. J. Somatic genetic changes in human breast cancer. Biochim Biophys Acta. 1994 Dec 30;1198(2-3):113–130. doi: 10.1016/0304-419x(94)90009-4. [DOI] [PubMed] [Google Scholar]
  8. Ellis N. A., Groden J., Ye T. Z., Straughen J., Lennon D. J., Ciocci S., Proytcheva M., German J. The Bloom's syndrome gene product is homologous to RecQ helicases. Cell. 1995 Nov 17;83(4):655–666. doi: 10.1016/0092-8674(95)90105-1. [DOI] [PubMed] [Google Scholar]
  9. Kerangueven F., Noguchi T., Coulier F., Allione F., Wargniez V., Simony-Lafontaine J., Longy M., Jacquemier J., Sobol H., Eisinger F. Genome-wide search for loss of heterozygosity shows extensive genetic diversity of human breast carcinomas. Cancer Res. 1997 Dec 15;57(24):5469–5474. [PubMed] [Google Scholar]
  10. Lancaster J. M., Wooster R., Mangion J., Phelan C. M., Cochran C., Gumbs C., Seal S., Barfoot R., Collins N., Bignell G. BRCA2 mutations in primary breast and ovarian cancers. Nat Genet. 1996 Jun;13(2):238–240. doi: 10.1038/ng0696-238. [DOI] [PubMed] [Google Scholar]
  11. Ludwig T., Chapman D. L., Papaioannou V. E., Efstratiadis A. Targeted mutations of breast cancer susceptibility gene homologs in mice: lethal phenotypes of Brca1, Brca2, Brca1/Brca2, Brca1/p53, and Brca2/p53 nullizygous embryos. Genes Dev. 1997 May 15;11(10):1226–1241. doi: 10.1101/gad.11.10.1226. [DOI] [PubMed] [Google Scholar]
  12. Marmorstein L. Y., Ouchi T., Aaronson S. A. The BRCA2 gene product functionally interacts with p53 and RAD51. Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13869–13874. doi: 10.1073/pnas.95.23.13869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Matson S. W., Kaiser-Rogers K. A. DNA helicases. Annu Rev Biochem. 1990;59:289–329. doi: 10.1146/annurev.bi.59.070190.001445. [DOI] [PubMed] [Google Scholar]
  14. Miki Y., Katagiri T., Kasumi F., Yoshimoto T., Nakamura Y. Mutation analysis in the BRCA2 gene in primary breast cancers. Nat Genet. 1996 Jun;13(2):245–247. doi: 10.1038/ng0696-245. [DOI] [PubMed] [Google Scholar]
  15. Milner J., Ponder B., Hughes-Davies L., Seltmann M., Kouzarides T. Transcriptional activation functions in BRCA2. Nature. 1997 Apr 24;386(6627):772–773. doi: 10.1038/386772a0. [DOI] [PubMed] [Google Scholar]
  16. Muris D. F., Bezzubova O., Buerstedde J. M., Vreeken K., Balajee A. S., Osgood C. J., Troelstra C., Hoeijmakers J. H., Ostermann K., Schmidt H. Cloning of human and mouse genes homologous to RAD52, a yeast gene involved in DNA repair and recombination. Mutat Res. 1994 Nov;315(3):295–305. doi: 10.1016/0921-8777(94)90040-x. [DOI] [PubMed] [Google Scholar]
  17. Oto M., Miyake S., Yuasa Y. Optimization of nonradioisotopic single strand conformation polymorphism analysis with a conventional minislab gel electrophoresis apparatus. Anal Biochem. 1993 Aug 15;213(1):19–22. doi: 10.1006/abio.1993.1379. [DOI] [PubMed] [Google Scholar]
  18. Park M. S. Expression of human RAD52 confers resistance to ionizing radiation in mammalian cells. J Biol Chem. 1995 Jun 30;270(26):15467–15470. doi: 10.1074/jbc.270.26.15467. [DOI] [PubMed] [Google Scholar]
  19. Park M. S., Ludwig D. L., Stigger E., Lee S. H. Physical interaction between human RAD52 and RPA is required for homologous recombination in mammalian cells. J Biol Chem. 1996 Aug 2;271(31):18996–19000. doi: 10.1074/jbc.271.31.18996. [DOI] [PubMed] [Google Scholar]
  20. Phelan C. M., Borg A., Cuny M., Crichton D. N., Baldersson T., Andersen T. I., Caligo M. A., Lidereau R., Lindblom A., Seitz S. Consortium study on 1280 breast carcinomas: allelic loss on chromosome 17 targets subregions associated with family history and clinical parameters. Cancer Res. 1998 Mar 1;58(5):1004–1012. [PubMed] [Google Scholar]
  21. Rasio D., Murakumo Y., Robbins D., Roth T., Silver A., Negrini M., Schmidt C., Burczak J., Fishel R., Croce C. M. Characterization of the human homologue of RAD54: a gene located on chromosome 1p32 at a region of high loss of heterozygosity in breast tumors. Cancer Res. 1997 Jun 15;57(12):2378–2383. [PubMed] [Google Scholar]
  22. Scully R., Chen J., Plug A., Xiao Y., Weaver D., Feunteun J., Ashley T., Livingston D. M. Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell. 1997 Jan 24;88(2):265–275. doi: 10.1016/s0092-8674(00)81847-4. [DOI] [PubMed] [Google Scholar]
  23. Sharan S. K., Morimatsu M., Albrecht U., Lim D. S., Regel E., Dinh C., Sands A., Eichele G., Hasty P., Bradley A. Embryonic lethality and radiation hypersensitivity mediated by Rad51 in mice lacking Brca2. Nature. 1997 Apr 24;386(6627):804–810. doi: 10.1038/386804a0. [DOI] [PubMed] [Google Scholar]
  24. Shen Z., Cloud K. G., Chen D. J., Park M. S. Specific interactions between the human RAD51 and RAD52 proteins. J Biol Chem. 1996 Jan 5;271(1):148–152. doi: 10.1074/jbc.271.1.148. [DOI] [PubMed] [Google Scholar]
  25. Shinohara A., Ogawa H., Matsuda Y., Ushio N., Ikeo K., Ogawa T. Cloning of human, mouse and fission yeast recombination genes homologous to RAD51 and recA. Nat Genet. 1993 Jul;4(3):239–243. doi: 10.1038/ng0793-239. [DOI] [PubMed] [Google Scholar]
  26. Somasundaram K., Zhang H., Zeng Y. X., Houvras Y., Peng Y., Zhang H., Wu G. S., Licht J. D., Weber B. L., El-Deiry W. S. Arrest of the cell cycle by the tumour-suppressor BRCA1 requires the CDK-inhibitor p21WAF1/CiP1. Nature. 1997 Sep 11;389(6647):187–190. doi: 10.1038/38291. [DOI] [PubMed] [Google Scholar]
  27. Stürzbecher H. W., Donzelmann B., Henning W., Knippschild U., Buchhop S. p53 is linked directly to homologous recombination processes via RAD51/RecA protein interaction. EMBO J. 1996 Apr 15;15(8):1992–2002. [PMC free article] [PubMed] [Google Scholar]
  28. Sung P., Bailly V., Weber C., Thompson L. H., Prakash L., Prakash S. Human xeroderma pigmentosum group D gene encodes a DNA helicase. Nature. 1993 Oct 28;365(6449):852–855. doi: 10.1038/365852a0. [DOI] [PubMed] [Google Scholar]
  29. Suzuki A., de la Pompa J. L., Hakem R., Elia A., Yoshida R., Mo R., Nishina H., Chuang T., Wakeham A., Itie A. Brca2 is required for embryonic cellular proliferation in the mouse. Genes Dev. 1997 May 15;11(10):1242–1252. doi: 10.1101/gad.11.10.1242. [DOI] [PubMed] [Google Scholar]
  30. Teng D. H., Bogden R., Mitchell J., Baumgard M., Bell R., Berry S., Davis T., Ha P. C., Kehrer R., Jammulapati S. Low incidence of BRCA2 mutations in breast carcinoma and other cancers. Nat Genet. 1996 Jun;13(2):241–244. doi: 10.1038/ng0696-241. [DOI] [PubMed] [Google Scholar]
  31. van den Berg J., Johannsson O., Håkansson S., Olsson H., Borg A. Allelic loss at chromosome 13q12-q13 is associated with poor prognosis in familial and sporadic breast cancer. Br J Cancer. 1996 Nov;74(10):1615–1619. doi: 10.1038/bjc.1996.597. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES