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Fractional allelic imbalance in human breast cancer increases with tetraploidization and chromosome loss
156
Abstracts
FRACTIONAL ALLELIC IMBALANCE IN HUMAN BREAST CANCER INCREASES WITH TETRAPLOIDIZATION AND CHROMOSOME LOSS. Cees J. Cornelisse (1) Nel Kuipers-Dijkshoorn (1), Margreethe van Vliet (2), Jo Hermans (3) and Peter Devilee (1,2). Departments of Pathology (1), Human Genetics (2) and Medical Statistics (3), Faculty of Medicine, University of Leiden, The Netherlands. To identify putative tumor suppressor gene loci in breast cancer, we have recently completed a comprehensive allelotype study of 86 primary breast carcinomas, in which each non-acrocentric chromosome arm was studied with at least one polymorphic DNA-marker for the presence of allelic imbalance (AI, allelic loss or allelic gain) in the tumor (1). Here we present the statistical analysis of this data set, investigating the relationship between AI, DNA aneuploidy and several clinico-pathological parameters of tumor progression (2). AI on 13 different chromosome arms, including 3p, 11p, and 17p, correlated significantly with the total number of AI events at other sites, suggesting that they are progression-related events. AI at l q and 16q did not show such a correlation and may thus represent earlier events. Mean fractional allelic imbalance (FAI) was significantly higher in flow cytometrically aneuploid tumors than in diploid tumors (0.27 vs. 0.17, p = 0.007), and was highest in hypotetraploid tumors (0.37). This suggests that tetraploidization followed by chromosome segregation may underlie the development of AI at multiple sites. No correlation was found between mean FAI and clinico-pathological variables such as lymphnode involvement, stage, age, estrogen-receptor content and development of distant metastases, although there was a noticeable trend towards impaired survival for those patients with a higher-than-median FAI value. 1. Devilee, P., Van Vliet, M., Kuipers-Dijkshoorn, N., Pearson, P.L. and Cornelisse, C.J. Allelotype of human breast carcinoma: a second major site for loss of heterozygosity is on chromosome 6q. Oncogene, 6, 1705-1711 (1991). 2. Cornelisse, C.J., Kuipers-Dijkshoorn, N., Van Vliet, M., Hermans, J. and Devilee, P. Fractional allelic imbalance in human breast cancer increases with tetraploidization and chromosome loss. Int. J. Cancer, 51, 1-5 (1992). CHARACTERIZATION OF CHROMOSOME ALTERATIONS IN FIBROADENOMAS OF THE BREAST L.R. Cavalli*, ~.,.t~=...~.~**, I.J. Cavalli*, R. Silveira***. * Depto. de Gen~tica, UFPR, Curitiba, PR. ** Depto. de Biologia Geral, CCB, UEL, Londrina, PR. *** Servic,.o de Oncologia, Hospital Nossa Senhora das Gra;as Curitiba, PR, Brasil.
Although expanding lesions of the breast are very frequent, few cytogenetic data are available about them, especially in the case of benign tumors. This category comprises fibroadenomas, which can occur at any age during the reproductive period. Available cytogenetic data have revealed normal karyotypes in most cases, but clonal alterations affecting chromosomes 1, 11, 12 and 24 have been described. In the present investigation, three bilateral fibroadenomas were studied chromosomally; in one of them, bilaterallity occurred owing to the presence of a supernumerary breast with a previously operated fibroadenoma. The most frequent chromosome alteration detected in all three cases was monosomy of chromosome X. In addition, all three cases shared alterations of chromosome 6 (total or partial trisomy) and monosomy of chromosome 21. Monosomy of chromosome 12 and trisomy of chromosome 11 were detected in two cases, both of them at low frequency. Carcinomas of the breast are characterized by changes involving chromosomes 1, 6, 7, 11 and 16. This observation and the chromosomal findings detected in the present cases seem to indicate that chromosomes 6 and 11 may contain genes related to cell proliferation but not to malignant transformation. (CNPq, CAPES, CPG-UEL)
Abstracts
FRACTIONAL ALLELIC IMBALANCE IN HUMAN BREAST CANCER INCREASES WITH TETRAPLOIDIZATION AND CHROMOSOME LOSS. Cees J. Cornelisse (1) Nel Kuipers-Dijkshoorn (1), Margreethe van Vliet (2), Jo Hermans (3) and Peter Devilee (1,2). Departments of Pathology (1), Human Genetics (2) and Medical Statistics (3), Faculty of Medicine, University of Leiden, The Netherlands. To identify putative tumor suppressor gene loci in breast cancer, we have recently completed a comprehensive allelotype study of 86 primary breast carcinomas, in which each non-acrocentric chromosome arm was studied with at least one polymorphic DNA-marker for the presence of allelic imbalance (AI, allelic loss or allelic gain) in the tumor (1). Here we present the statistical analysis of this data set, investigating the relationship between AI, DNA aneuploidy and several clinico-pathological parameters of tumor progression (2). AI on 13 different chromosome arms, including 3p, 11p, and 17p, correlated significantly with the total number of AI events at other sites, suggesting that they are progression-related events. AI at l q and 16q did not show such a correlation and may thus represent earlier events. Mean fractional allelic imbalance (FAI) was significantly higher in flow cytometrically aneuploid tumors than in diploid tumors (0.27 vs. 0.17, p = 0.007), and was highest in hypotetraploid tumors (0.37). This suggests that tetraploidization followed by chromosome segregation may underlie the development of AI at multiple sites. No correlation was found between mean FAI and clinico-pathological variables such as lymphnode involvement, stage, age, estrogen-receptor content and development of distant metastases, although there was a noticeable trend towards impaired survival for those patients with a higher-than-median FAI value. 1. Devilee, P., Van Vliet, M., Kuipers-Dijkshoorn, N., Pearson, P.L. and Cornelisse, C.J. Allelotype of human breast carcinoma: a second major site for loss of heterozygosity is on chromosome 6q. Oncogene, 6, 1705-1711 (1991). 2. Cornelisse, C.J., Kuipers-Dijkshoorn, N., Van Vliet, M., Hermans, J. and Devilee, P. Fractional allelic imbalance in human breast cancer increases with tetraploidization and chromosome loss. Int. J. Cancer, 51, 1-5 (1992). CHARACTERIZATION OF CHROMOSOME ALTERATIONS IN FIBROADENOMAS OF THE BREAST L.R. Cavalli*, ~.,.t~=...~.~**, I.J. Cavalli*, R. Silveira***. * Depto. de Gen~tica, UFPR, Curitiba, PR. ** Depto. de Biologia Geral, CCB, UEL, Londrina, PR. *** Servic,.o de Oncologia, Hospital Nossa Senhora das Gra;as Curitiba, PR, Brasil.
Although expanding lesions of the breast are very frequent, few cytogenetic data are available about them, especially in the case of benign tumors. This category comprises fibroadenomas, which can occur at any age during the reproductive period. Available cytogenetic data have revealed normal karyotypes in most cases, but clonal alterations affecting chromosomes 1, 11, 12 and 24 have been described. In the present investigation, three bilateral fibroadenomas were studied chromosomally; in one of them, bilaterallity occurred owing to the presence of a supernumerary breast with a previously operated fibroadenoma. The most frequent chromosome alteration detected in all three cases was monosomy of chromosome X. In addition, all three cases shared alterations of chromosome 6 (total or partial trisomy) and monosomy of chromosome 21. Monosomy of chromosome 12 and trisomy of chromosome 11 were detected in two cases, both of them at low frequency. Carcinomas of the breast are characterized by changes involving chromosomes 1, 6, 7, 11 and 16. This observation and the chromosomal findings detected in the present cases seem to indicate that chromosomes 6 and 11 may contain genes related to cell proliferation but not to malignant transformation. (CNPq, CAPES, CPG-UEL)