Genetic alterations on chromosome 17 in human breast cancer: relationships to clinical features and DNA ploidy

SummaryWe analyzed DNA from 105 primary breast cancers to assess amplification of the ERBB2 gene and loss of heterozygosity (LOH) on chromosome 17 using 4 polymorphic markers, and investigated the relationships of these genetic alterations to clinicopathological characteristics including DNA ploidy. Amplification of the ERBB2 gene was observed in 28% of the tumors. ERBB2 was amplified in tumors of all clinical stages and amplification was significantly linked to lymph node metastasis. LOH atD17S5 was observed in 28 of 57 informative tumors, while 17 of 62 informative tumors showed allelic loss atTP53. Among the 37 tumors informative for both loci, 32% showed LOH at these loci and 49% retained both alleles, indicating that there was a significant relationship between LOH atD17S5 and atTP53. We also examined LOH at theD17S74 andNME1 loci on chromosome 17q. LOH atD17S74 andNME1 was observed in 20% and 22% of the informative tumors, respectively, but there was no significant association between LOH at these loci. Of the 4 loci tested, LOH atTP53, D17S74, andNME1 was associated with clinical stage. Lymph node metastasis was correlated with LOH atNME1. Moreover, allelic loss was more frequent in aneuploid tumors than in diploid tumors. These results suggest that certain combinations of genetic alterations on chromosome 17 may cooperate in the development and/or progression of breast cancer. Furthermore, it seems likely that analysis of these alterations in breast cancer patients may provide useful prognostic information.

[1]  R. Lidereau,et al.  Heterogeneity of genetic alterations in primary human breast tumors. , 1988, Cancer treatment and research.

[2]  W. McGuire,et al.  Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. , 1987, Science.

[3]  L. Liotta,et al.  Reduced Nm23/Awd protein in tumour metastasis and aberrant Drosophila development , 1989, Nature.

[4]  P. Devilee,et al.  Frequent somatic imbalance of marker alleles for chromosome 1 in human primary breast carcinoma. , 1991, Cancer research.

[5]  I W Taylor,et al.  Method for analysis of cellular DNA content of paraffin-embedded pathological material using flow cytometry. , 1983, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[6]  M. Leppert,et al.  Allelic Loss in Colorectal Carcinoma , 1989 .

[7]  I. Bièche,et al.  Loss of heterozygosity on chromosome 7q and aggressive primary breast cancer , 1992, The Lancet.

[8]  J. Barrett,et al.  Detection of frequent allelic loss on proximal chromosome 17q in sporadic breast carcinoma using microsatellite length polymorphisms. , 1992, Cancer research.

[9]  M. King,et al.  Linkage of early-onset familial breast cancer to chromosome 17q21. , 1990, Science.

[10]  P. Devilee,et al.  At least four different chromosomal regions are involved in loss of heterozygosity in human breast carcinoma. , 1989, Genomics.

[11]  M. Izuo,et al.  The general rules for clinical and pathological recording of breast cancer , 1989, The Japanese journal of surgery.

[12]  R. Lidereau,et al.  Loss of heterozygosity on chromosomes 17 and 18 in breast carcinoma: two additional regions identified. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[13]  C. Cornelisse,et al.  DNA ploidy and survival in breast cancer patients. , 1987, Cytometry.

[14]  C. M. Steel,et al.  Evidence implicating at least two genes on chromosome 17p in breast carcinogenesis , 1990, The Lancet.

[15]  Y. Nakamura,et al.  Clinical and pathological associations with allelic loss in colorectal carcinoma [corrected]. , 1989, JAMA.

[16]  G. Peters,et al.  Amplification of the int-2 gene in primary human breast tumors. , 1988, Oncogene research.

[17]  B. Ljung,et al.  Loss of heterozygosity on the short arm of chromosome 17 is associated with high proliferative capacity and DNA aneuploidy in primary human breast cancer. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Y. Nakamura,et al.  Accumulation of genetic alterations and progression of primary breast cancer. , 1991, Cancer research.

[19]  W. McGuire,et al.  Follow-up study of HER-2/neu amplification in primary breast cancer. , 1991, Cancer research.

[20]  A. Green,et al.  Recessive mechanisms of malignancy. , 1988, British Journal of Cancer.

[21]  T. Conway,et al.  Familial breast-ovarian cancer locus on chromosome 17q12-q23 , 1991, The Lancet.

[22]  B. Vogelstein,et al.  p53 mutations in human cancers. , 1991, Science.

[23]  A. Knudson.  Hereditary cancer, oncogenes, and antioncogenes. , 1985, Cancer research.

[24]  M. Rocchi,et al.  The nm23 gene maps to human chromosome band 17q22 and shows a restriction fragment length polymorphism with bg/II , 1992, Genes, chromosomes & cancer.

[25]  J. Weber,et al.  Closing in on a breast cancer gene on chromosome 17q. , 1992, American journal of human genetics.

[26]  O. Kallioniemi,et al.  Tumour DNA ploidy as an independent prognostic factor in breast cancer. , 1987, British Journal of Cancer.

[27]  A. Tanigami,et al.  Allelotype of breast cancer: cumulative allele losses promote tumor progression in primary breast cancer. , 1990, Cancer research.

[28]  L. Liotta,et al.  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. , 1989, Cancer research.

[29]  J. Nesland,et al.  Amplification and protein over-expression of the neu/HER-2/c-erbB-2 protooncogene in human breast carcinomas: relationship to loss of gene sequences on chromosome 17, family history and prognosis. , 1990, British Journal of Cancer.

[30]  Y. Nakamura,et al.  A mapped set of DNA markers for human chromosome 17. , 1988, Genomics.

[31]  P. Devilee,et al.  Loss of heterozygosity on 17p in human breast carcinomas: defining the smallest common region of deletion. , 1990, Cytogenetics and cell genetics.

[32]  A. Forrest,et al.  ALLELE LOSS ON SHORT ARM OF CHROMOSOME 17 IN BREAST CANCERS , 1988, The Lancet.