Variability in loss of constitutional heterozygosity across loci and among individuals: Association with candidate genes in ductal breast carcinoma

Genes involved in the metabolic activation or detoxification of environmental carcinogens may contribute to breast cancer susceptibility by influencing rates of somatic mutation. To examine this hypothesis, we studied the association between loss of constitutional heterozygosity (LOH) in ductal breast tumors and allelic variability in genes that regulate the metabolism of environmental carcinogens. LOH was measured by typing the tumor and normal tissue of 28 breast cancer cases at 33 chromosomal loci by using highly polymorphic tetranucleotide repeat markers. Genotypes in non‐tumor tissue were also measured at the cytochrome P450 1A1 (CYP1A1), cytochrome P450 2D6 (CYP2D6), glutathione‐s‐transferase μ (GSTM), epoxide hydrolase (EH), and NAD(P)H:quinone oxidoreductase (NQO1) loci. The observed proportion of LOH was 11% overall and ranged from 0% to 37% across loci. LOH greater than 20% was observed on chromosomes 1p, 2p, 10q, 11q, 17p, and 18q. The observed proportion of LOH ranged from 0% to 67% among individuals. An elevated proportion of LOH was observed for genotypes at CYP2D6 (17% for the 1/1 and 1/2 genotypes vs 8% for the 2/2 genotype), NQO1 (13% for the 1/2 and 2/2 genotypes vs 8% for the 1/1 genotype), and GSTM (15% for the null genotype vs 7% for the wild‐type genotype). No elevated proportion of LOH was observed for genotypes at CYP1A1 (12% for the 1/2 genotype vs 10% for the 1/1 genotype) or EH (11% for the 1/1 genotype vs 10% for the 1/2 genotype). There was no correlation of LOH with any other tumor characteristic such as estrogen‐ or progesterone‐receptor status or number of positive lymph nodes. These results suggest that the proportion of LOH varies substantially across loci and among individuals. Interindividual variability in LOH may thus be explained in part by genes that regulate the metabolism of environmental carcinogens. © 1996 Wiley‐Liss, Inc.

[1]  K. Buetow,et al.  Identification of an NAD(P)H:quinone oxidoreductase polymorphism and its association with lung cancer and smoking. , 1995, Pharmacogenetics.

[2]  K. Buetow,et al.  Genetics of CYP1A1: coamplification of specific alleles by polymerase chain reaction and association with breast cancer. , 1994, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[3]  P. Devilee,et al.  PCR-based microsatellite polymorphisms in the detection of loss of heterozygosity in fresh and archival tumour tissue. , 1993, British Journal of Cancer.

[4]  G. Merlo,et al.  Genetic and molecular heterogeneity of breast cancer cells. , 1993, Clinica chimica acta; international journal of clinical chemistry.

[5]  I. Bièche,et al.  Two distinct regions involved in 1p deletion in human primary breast cancer. , 1993, Cancer research.

[6]  B. Ljung,et al.  Heterogeneity for allelic loss in human breast cancer. , 1992, Journal of the National Cancer Institute.

[7]  K. Danenberg,et al.  NAD(P)H:quinone oxidoreductase gene expression in human colon carcinoma cells: characterization of a mutation which modulates DT-diaphorase activity and mitomycin sensitivity. , 1992, Cancer research.

[8]  P L Pearson,et al.  Allelotype of human breast carcinoma: a second major site for loss of heterozygosity is on chromosome 6q. , 1991, Oncogene.

[9]  Patricia J. Wozniak.  Applied Nonparametric Statistics (2nd ed.) , 1991 .

[10]  D. Nebert,et al.  Human CYP1A1 gene: cosegregation of the enzyme inducibility phenotype and an RFLP. , 1991, American journal of human genetics.

[11]  G. Omenn,et al.  Future research directions in cancer ecogenetics. , 1991, Mutation research.

[12]  L. Strong,et al.  Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. , 1990, Science.

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

[14]  J. S. Miles,et al.  Identification of the primary gene defect at the cytochrome P450 CYP2D locus , 1990, Nature.

[15]  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.

[16]  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.

[17]  K. Comstock,et al.  GST1 gene deletion determined by polymerase chain reaction. , 1990, Nucleic acids research.

[18]  H. J. Evans,et al.  p53 gene mRNA expression and chromosome 17p allele loss in breast cancer. , 1990, British Journal of Cancer.

[19]  F. Collins,et al.  Mutations in the p53 gene occur in diverse human tumour types , 1989, Nature.

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

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

[22]  D W Nebert,et al.  Human dioxin-inducible cytosolic NAD(P)H:menadione oxidoreductase. cDNA sequence and localization of gene to chromosome 16. , 1988, The Journal of biological chemistry.

[23]  Norman R. Draper,et al.  Applied regression analysis (2. ed.) , 1981, Wiley series in probability and mathematical statistics.

[24]  K. Kawajiri,et al.  Genetic Polymorphisms in the 5 '-Flanking Region Change Transcriptional Regulation of the Human Cytochrome P 45011 E 1 Gene ' , 2008 .

[25]  G. Merlo,et al.  Loss of heterozygosity on chromosome 17p13 in breast carcinomas identifies tumors with high proliferation index. , 1992, The American journal of pathology.

[26]  G. Webb,et al.  Genetic heterogeneity of the human glutathione transferases: a complex of gene families. , 1990, Pharmacology & therapeutics.

[27]  D W Nebert,et al.  P450 genes: structure, evolution, and regulation. , 1987, Annual review of biochemistry.