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

Timothy R. Rebbeck, Andrew K. Godwin, Kenneth Buetow

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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, 10p, 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.

Original languageEnglish (US)
Pages (from-to)117-125
Number of pages9
JournalMolecular Carcinogenesis
Volume17
Issue number3
DOIs
StatePublished - 1996
Externally publishedYes

Fingerprint

Carcinoma, Ductal, Breast
Loss of Heterozygosity
Genotype
Genes
Environmental Carcinogens
Epoxide Hydrolases
Cytochrome P-450 CYP2D6
Breast Neoplasms
Cytochrome P-450 Enzyme System
Mutation Rate
Progesterone Receptors
Glutathione Transferase
NAD
Microsatellite Repeats

Keywords

  • Breast neoplasms
  • Carcinogen metabolism
  • Genetic susceptibility
  • Somatic mutation

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology

Cite this

Variability in loss of constitutional heterozygosity across loci and among individuals : Association with candidate genes in ductal breast carcinoma. / Rebbeck, Timothy R.; Godwin, Andrew K.; Buetow, Kenneth.

In: Molecular Carcinogenesis, Vol. 17, No. 3, 1996, p. 117-125.

Research output: Contribution to journalArticle

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abstract = "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, 10p, 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.",
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