Abstract
We examined a panel of sporadic breast carcinomas for loss of heterozygosity (LOH) in a 10-cM interval on chromosome 10 known to encompass the PTEN gene. We detected allele loss in 27 of 70 breast tumour DNAs. Fifteen of these showed loss limited to a subregion of the area studied. The most commonly deleted region was flanked by D10S215 and D10S541 and encompasses the PTEN locus. We used a combination of denaturing gradient gel electrophoresis and single-strand conformation polymorphism analyses to investigate the presence of PTEN mutations in tumours with LOH in this region. We did not detect mutations of PTEN in any of these tumours. Our data show that, in sporadic breast carcinoma, loss of heterozygosity of the PTEN locus is frequent, but mutation of PTEN is not. These results are consistent with loss of another unidentified tumour suppressor in this region in sporadic breast carcinoma.
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16 November 2011
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Albarosa, R., Colombo, B. M., Roz, L., Magnani, I., Pollo, B., Cirenei, N., Giani, C., Conti, A. M. F., DiDonato, S. & Finocchiaro, G. (1996). Deletion mapping of gliomas suggests the presence of two small regions for candidate tumor-suppressor genes in a 17-cM interval on chromosome 10q. Am J Hum Genet, 58, 1260–1267.
Bevilacqua, G., Sobel, M. E., Liotta, L. A. & Steeg, P. S. (1989). Association of low nm23 RNA levels in human primary infiltrating ductal breast carcinomas with lymph node involvement and other histopathological indicators of high metastatic potential. Cancer Res, 49, 5185–5190.
Bieché, I. & Lidereau, R. (1995). Genetic alterations in breast cancer. Genes Chrom Cancer, 14, 227–251.
Bostrom, J., Cobbers, JMJL, Wolter, M., Tabatabai, G., Weber, R. G., Lichter, P., Collins, V. P. & Reifenberger, G. (1998). Mutation of the PTEN (MMACI) tumor suppressor gene in a subset of glioblastomas but not in meningiomas with loss of chromosome arm 10q. Cancer Res, 58, 29–33.
Brownstein, M. H., Wolf, M. & Bikowski, J. B. (1978). Cowden’s disease: a cutaneous marker of breast cancer. Cancer, 41, 2393–2398.
Cairns, P., Okami, K., Halachmi, S., Halachmi, N., Esteller, M., Herman, J. G., Jen, J., Isaacs, W. B., Bova, G. S. & Sidransky, D. (1997). Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res, 57, 4997–5000.
Chen, J., Lindblom, P. & Lindblom, A. (1998). A study of the PTEN/MMAC1 gene in 136 breast cancer families. Hum Genet, 102, 124–125.
Chumakov, I. M., Rigault, P., Le Gall, I., Bellanne-Chantelot, C., Billault, A., Guillou, S., Soularue, P., Guasconi, G., Poullier, E., Gros, I., Belova, M., Sambucy, J., Susini, L., Gervy, P., Glibert, F., Beaufils, S., Bui, H., Massart, C., De Tand, M., Dukasz, F., Lecoulant, S., Ougen, P., Perrot, V., Saumier, M., Soravito, C., Bahouayila, R., Cogen-Akenine, A., Barillot, E., Bertrand, S., Codani, J., Caterina, D., Georges, I., Lacroix, B., Lucotte, G., Sahbatou, M., Schmit, C., Sangouard, M., Tubacher, E., Dib, C., Faure, S., Fizames, C., Gyapay, G., Millasseau, P., Nguyen, S., Muselet, D., Vignal, A., Morissette, J., Menninger, J., Lieman, J., Desai, T., Banks, A., Bray-Ward, P., Ward, D., Hudson, T., Gerety, S., Foote, S., Stein, L., Page, D. C., Lander, E. S., Weissenbach, J., Le Paslier, D. & Cohen, D. (1995). A YAC contig map of the human genome. Nature, 377, 175–297.
Devilee, P. & Cornelisse, C. J. (1994). Somatic genetic changes in human breast cancer. Biochim Biophys Acta, 1198, 113–130.
Dorion-Bonnet, F., Mautalen, S., Hostein, I. & Longy, M. (1995). Allelic imbalance study of 16q in human primary breast carcinomas using microsatellite markers. Genes Chromosomes Cancer, 14, 171–181.
Feilotter, H. E., Nagai, M. A., Boag, A. H., Eng, C. & Mulligan, L. M. (1998). Analysis of PTEN and the 10q23 region in primary prostate carcinomas. Oncogene, 16, 1743–1748.
FitzGerald, M. G., Marsh, D. J., Wahrer, D., Bell, D., Caron, S., Shannon, K. E., Ishioka, C., Isselbacher, K. J., Garber, J. E., Eng, C. & Haber, D. A. (1998). Germline mutations in PTEN are an infrequent cause of genetic predisposition to breast cancer. Oncogene, 17, 727–731.
Fujii, H., Szumel, R., Marsh, C., Zhou, W. & Gabrielson, E. (1996). Genetic progression, histological grade, and allelic loss in ductal carcinoma in situ of the breast. Cancer Res, 56, 5260–5265.
Gray, I. C., Phillips, S. M. A., Lee, S. J., Neoptolemos, J. P., Weissenbach, J. & Spurr, N. K. (1996). Loss of the chromosomal region 10q23–25 in prostate cancer. Cancer Res, 55, 4800–4803.
Gray, I. C., Fallowfield, J., Ford, S., Nobile, C., Volpi, E. V. & Spurr, N. K. (1997). An integrated physical and genetic map spanning chromosome band 10q24. Genomics, 43, 85–88.
Guldberg, P., thor Straten, P., Birck, A., Ahrenkiel, V., Kirkin, A. F. & Zeuthen, J. (1997). Disruption of the MMACI/PTEN gene by deletion or mutation is a frequent event in malignant melanoma. Cancer Res, 57, 3660–3663.
Gyapay, G., Morissette, J., Vignal, A., Dib, C., Fizames, C., Millasseau, P., Marc, S., Benardi, G., Lathrop, M. & Weissenbach, J. (1994). The 1993–94 Genethon human genetic linkage map. Nature Genet, 7, 246–339.
Herbst, R. A., Weiss, J., Ehnis, A., Cavenee, W. K. & Arden, K. C. (1994). Loss of heterozygosity for 10q22–10qter in malignant melanoma progression. Cancer Res, 54, 3111–3114.
Ittmann, M. (1996). Allelic loss on chromosome 10 in prostate adenocarcinoma. Cancer Res, 56, 2143–2147.
Kagan, J., Liu, J., Stein, J. D., Wagner, S. S., Babkowski, R., Grossman, B. H. & Katz, R. L. (1998). Cluster of allele losses within a 2.5 cM region of chromosome 10 in high-grade invasive bladder cancer. Oncogene, 16, 909–913.
Karlbom, A. E., James, C. D., Boethius, J., Cavenee, W. K., Collins, V. P., Nordenskjöld, M. & Larsson, C. (1993). Loss of heterozygosity in malignant gliomas involves at least three distinct regions on chromosome 10. Hum Genet, 92, 169–174.
Kelsey, J. (1979). A review of the epidemiology of human breast cancer. Epidemiol Rev, 1, 74–109.
Kerangueven, F., Eisinger, F., Noguchi, T., Allione, F., Wargniez, V., Eng, C., Padberg, G., Theillet, C., Jacquenier, J., Longy, M., Sobol, H. & Birnbaum, D. (1996). Loss of heterozygosity in human breast carcinomas in the ataxia telangiectasia, Cowden disease and BRCA1 gene regions. Oncogene, 13, 339–347.
Kong, D., Suzuki, A., Zou, T. T., Sakurada, A., Kemp, L. W., Wakatsuki, S., Yokoyama, T., Yamakawa, H., Furukawa, T., Sato, M., Ohuchi, N., Sato, S., Yin, J., Wang, S., Abraham, J. M., Souza, R. F., Smolinski, K. N., Meltzer, S. J. & Horii, A. (1997). PTEN1 is frequently mutated in primary endometrial carcinomas. Nature Genet, 17, 143–144.
Laugé, A., Lefèbvre, C., Laurent-Puig, P., Gad, S., Eng, C., Longy, M. & stoppa-Lyonnet, D. (1998). No evidence for germline PTEN mutations in families with breast and brain tumours. Int J Cancer, (submitted)
Li, D-M & Sun, H. (1997). TEP1, encoded by a candidate tumor suppressor locus is a novel protein tyrosine phosphatase regulated by transforming growth factor β. Cancer Res, 57, 2124–2129.
Li, J., Yen, C., Liaw, D., Podsypanina, K., Bose, S., Wang, S. I., Puc, J., Miliaresis, C., Rodgers, L., McCombie, R., Bigner, S. H., Giovanella, B. C., Ittmann, M., Tycko, B., Hibshoosh, H., Wigler, M. H. & Parsons, R. (1997). PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science, 275, 1943–1947.
Liaw, D., Marsh, D. J., Li, J., Dahia, P. L. M., Wang, S. I., Zheng, Z., Bose, S., Call, K. M., Tsou, H. C., Peacocke, M., Eng, C. & Parsons, R. (1997). Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nature Genet, 16, 64–67.
Longy, M., Coulon, V., Duboué, B., David, A., Larrègue, M., Eng, C., Amati, P., Kraimps, J-L, Bottani, A., Lacombe, D. & Bonneau, D. (1998). Mutations of PTEN in patients with Bannayan-Riley-Ruvalcaba phenotype. J Med Genet, (in press)
Lynch, E. D., Ostermeyer, E. A., Lee, M. K., Arena, J. F., Ji, H., Dann, J., Swisshelm, K., Suchard, D., MacLeod, P. M., Kvinnsland, S., Gjertsen, B. T., Heimdal, K., Lubs, H., Moller, P. & King, M-C (1997). Inherited mutations in PTEN that are associated with breast cancer, Cowden disease, and juvenile polyposis. Am J Hum Genet, 61, 1254–1260.
Marsh, D. J., Zheng, Z., Zedenius, J., Kremer, H., Padberg, G. W., Larsson, C., Longy, M. & Eng, C. (1997). Differential loss of heterozygosity in the region of the Cowden locus within 10q22–23 in follicular thyroid adenomas and carcinomas. Cancer Res, 57, 500–503.
Marsh, D. J., Coulon, V., Lunetta, K. L., Rocca-Serra, P., Dahia, P. L. M., Zheng, Z., Liaw, D., Caron, S., Duboue, B., Lin, A. Y., Richardson, A-L, Bonnetblanc, J-M, Bressieux, J-M, Cabarrot-Moreau, A., Chompret, A., Demange, L., Eeles, R. A., Yahanda, A. M., Fearon, E. R., Fricker, J-P, Gorlin, R. J., Hodgson, S. V., Huson, S., Lacombe, D., LePrat, F., Odent, S., Toulouse, C., Olopade, O. I., Sobol, H., Tishler, S., Woods, C. G., Robinson, B. G., Weber, H. C., Parsons, R., Peacocke, M., Longy, M. & Eng, C. 1998a). Mutation spectrum and genotype–phenotype analyses in Cowden disease and Bannayan–Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet, 7, 507–515.
Marsh, D. J., Dahia, P. L. M., Coulon, V., Zheng, Z., Dorion-Bonnet, F., Call, K. M., Little, R., Lin, A. Y., Eeles, R. A., Goldstein, A. M., Hodgson, S. V., Richardson, A-L, Robinson, B. G., Weber, H. C., Longy, M. & Eng, C. 1998b). Allelic imbalance, including deletion of PTEN/MMAC1, at the Cowden disease locus on 10q22–23, in hamartomas from patients with Cowden syndrome and germline PTEN mutation. Genes Chromosomes Cancer, 21, 61–69.
Midulla, C., Deiorio, P., Valli, C., Felici, A., Serpiesi, D. E., Marzetti, L., Nofrani, I. & Vecchione, A. (1996). nm23 and p53 expression: correlation with DNA ploidy and other pragmatic parameters in breast cancer. Oncol Rep, 3, 957–961.
Morita, R., Saito, S., Ishikawa, J., Ogawa, O., Yoshida, O., Yamakawa, K. & Nakamura, Y. (1991). Common regions of deletion on chromosomes 5q, 6q and 10q in renal cell carcinoma. Cancer Res, 51, 5817–5820.
Moschonas, N. K., Spurr, N. K. & Mao, J. (1996). Report of the first international workshop on human chromosome 10 mapping 1995. Cytogenet Cell Genet, 72, 99–112.
Myers, M. P., Stolarov, J. P., Eng, C., Li, J., Wang, S. I., Wigler, M. H., Parson, R. & Tonks, N. K. (1997). PTEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci USA, 94, 9052–9057.
Nagai, M. A., Yamamoto, L., Salaorni, S., Pacheco, M. M., Brentani, M. M., Barbosa, E. M., Brentani, R. R., Mazoyer, S., Smith, S. A., Ponder, B. A. J. & Mulligan, L. M. (1994). Detailed deletion mapping of chromosome segment 17q12–21 in sporadic breast tumours. Genes Chromosomes Cancer, 11, 58–62.
Nagai, M. A., Medeiros, A. C., Brentani, M. M., Brentani, R. R., Marques, L. A., Mazoyer, S. & Mulligan, L. M. (1995). Five distinct deleted regions on chromosome 17 defining different subsets of human primary breast tumors. Oncology, 52, 448–453.
Nelen, M. R., Padberg, G. W., Peeters, E. A. J., Lin, A. Y., van den Helm, B., Frants, R. R., Coulon, V., Goldstein, A. M., van Reen, M. M. M., Easton, D. F., Eeles, R. A., Hodgson, S., Mulvihill, J. J., Murday, V. A., Tucker, M. A., Mariman, E. C. M., Starink, T. M., Ponder, B. A. J., Ropers, H. H., Kremer, H., Longy, M. & Eng, C. (1996). Localization of the gene for Cowden disease to chromosome 10q22–23. Nature Genet, 13, 114–116.
Nelen, M. R., van Staveren, W. C. G., Peeters, E. A. J., Hassel, M. B., Gorlin, R. J., Hamm, H., Lindboe, C. F., Fryns, J-P, Sijmons, R. H., Woods, D. G., Mariman, E. C. M., Padberg, G. W. & Kremer, H. (1997). Germline mutations in the PTEN/MMAC1 gene in patients with Cowden disease. Hum Mol Genet, 6, 1383–1387.
Parmiter, A. H., Balaban, G., Clark, W. H. J. & Nowell, P. C. (1988). Possible involvement of the chromosome region 10q24–26 in early stages of melanocytic neoplasia. Cancer Genet Cytogenet, 30, 313–317.
Peiffer, S. L., Herzog, T. J., Tribune, D. J., Mutch, D. G., Gersell, D. J. & Goodfellow, P. J. (1995). Allelic loss of sequences from the long arm of chromosome 10 and replication errors in endometrial cancers. Cancer Res, 55, 1922–1926.
Pershouse, M. A., Stubblefield, E., Hadi, A., Killary, A. M., Yung, W. K. A. & Steck, P. A. (1993). Analysis of the functional role of chromosome 10 loss in human glioblastomas. Cancer Res, 53, 5043–5050.
Rasheed, B. K. A., McLendon, R. E., Friedman, H. S., Friedman, A. H., Fuchs, H. E., Bigner, D. D. & Bigner, S. H. (1995). Chromosome 10 deletion mapping in human gliomas: a common deletion region in 10q25. Oncogene, 10, 2243–2246.
Rasheed, B. K. A., Stenzel, T. T., McLendon, R. E., Parsons, R., Friedman, A. H., Friedman, H. S., Bigner, D. D. & Bigner, S. H. (1997). PTEN gene mutations are seen in high-grade but not in low-grade gliomas. Cancer Res, 57, 4187–4190.
Rhei, E., Kang, L., Bogomolniy, F., Federici, M. G., Borgen, P. I. & Boyd, J. (1997). Mutation analysis of the putative tumor suppressor gene PTEN/MMACI in primary breast carcinomas. Cancer Res, 57, 3657–3659.
Risinger, J. I., Hayes, A. K., Berchuck, A. & Barrett, J. C. (1997). PTEN/MMAC1 mutations in endometrial cancers. Cancer Res, 57, 4736–4738.
Sato, T., Tanigami, A., Yamakawa, K., Akiyama, F., Kasumi, F., Sakamoto, G. & Nakamura, Y. (1990). Allelotype of breast cancer: cumulative allele losses promote tumor progression in primary breast cancer. Cancer Res, 50, 7184–7189.
Simon, D., Hener, S., Satyaswaroop, P. G., Farber, M. & Noumoff, J. S. (1990). Is chromosome 10 a primary chromosomal abnormality in endometrial adenocarcinomas?. Cancer Genet Cytogenet, 47, 155–162.
Singh, B., Ittmann, M. M. & Krolewski, J. J. (1998). Sporadic breast cancers exhibit loss of heterozygosity on chromosome segment 10q23 close to the Cowden disease locus. Genes Chromosomes Cancer, 21, 166–171.
Smith, S. A. & Ponder, B. A. J. (1993). Predisposing genes in breast and ovarian cancer: an overview. Tumori, 79, 291–296.
Starink, T. M., van der Veen, J. P. W., Arwert, F., de Waal, L. P., de Lange, G. G., Gille, J. J. P. & Eriksson, A. W. (1986). The Cowden syndrome: a clinical and genetic study in 21 patients. Clin Genet, 29, 222–233.
Steck, P. A., Pershouse, M. A., Jasser, S. A., Yung, W. K. A., Lin, H., Ligon, A. H., Langford, L. A., Baumgard, M. L., Hattier, T., Davis, T., Frye, C., Hu, R., Swedlund, B., Teng, D. H. F. & Tavtigian, S. V. (1997). Identification of a candidate gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced tumours. Nature Genet, 15, 356–362.
Stoppa-Lyonnet, D., Laurent-Puig, P., Essioux, L., Pagès, S., Ithier, G., Ligot, L., Fourquet, A., Salmon, R. J., Clough, K. B., Pouillart, P., Bonaïti-Pellié, C. & Thomas, G. (1997). BRCA1 sequence variations in 160 individuals referred to a breast/ovarian family cancer clinic. Am J Hum Genet, 60, 1021–1030.
Stratton, M. R. (1996). Recent advances in understanding of genetic susceptibility to breast cancer. Hum Mol Genet, 5, 1515–1519.
Suzuki, H., Freije, D., Nusskern, D. R., Okami, K., Cairns, P., Sidransky, D., Isaacs, W. B. & Bova, G. S. (1998). Interfocal heterogeneity of PTEN/MMAC1 gene alterations in multiple metastatic prostate cancer tissues. Cancer Res, 58, 204–209.
Tashiro, H., Blazes, M. S., Wu, R. Cho, K. R., Bose, S., Wang, S. I., Li, J., Parsons, R. & Ellenson, L. H. (1997). Mutations in PTEN are frequent in endometrial carcinoma but rare in other common gynecological malignancies. Cancer Res, 57, 3935–3940.
Trybus, T. M., Burgess, A. C., Wojno, K. J., Glover, T. W. & Macoska, J. A. (1996). Distinct areas of allelic loss on chromosomal regions 10p and 10q in human prostate cancer. Cancer Res, 56, 2263–2267.
Tsou, H. C., Teng, DH-F, Ping, X. L., Brancolini, V., Davis, T., Hu, R., Xie, X. X., Gruener, A. C., Schrager, C. A., Christiano, A. M., Eng, C., Steck, P., Ott, J., Tavtigian, S. V. & Peacocke, M. (1997). The role of MMAC1 mutations in early-onset breast cancer: causative in association with Cowden syndrome and excluded in BRCA1-negative cases. Am J Hum Genet, 61, 1036–1043.
Wang, S. I., Puc, J., Li, J., Bruce, J. N., Cairns, P., Sidransky, D. & Parsons, R. (1997). Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res, 57, 4183–4186.
Wright, D. K. & Manos, M. M. (1990). Sample preparation from paraffin-embedded tissues. In PCR Protocols: a Guide to Methods and Applications, pp. 153–158, Academic Press: San Diego
Zedenius, J., Wallin, G., Svensson, A., Bovée, J., Höög, A., Bäckahl, M. & Larsson, C. (1996). Deletions of the long arm of chromosome 10 in progression of follicular thyroid tumors. Hum Genet, 97, 299–303.
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Feilotter, H., Coulon, V., McVeigh, J. et al. Analysis of the 10q23 chromosomal region and the PTEN gene in human sporadic breast carcinoma. Br J Cancer 79, 718–723 (1999). https://doi.org/10.1038/sj.bjc.6690115
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DOI: https://doi.org/10.1038/sj.bjc.6690115
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