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True extended haplotypes of p53: indicators of breast cancer risk.

Weston A; Wolff MS; Morabia A
Cancer Genet Cytogenet 1998 Apr; 102(2):153-154
Several case-control studies have examined the possibility that minor DNA-sequence polymorphic variants of p53 are human cancer risk factors. Generally, such common polymorphic DNA-sequence variants, which can attain a frequency of around 10%, are considered to be benign. However, in our recent preliminary report we found a specific p53 allele to be associated with modest breast cancer risk among Caucasian women. This report, expanded to include more women and using a new analytic approach, contains data that suggest a strong gene-dose effect of the p53 variant on breast cancer risk. P53 haplotypes defined by 3 polymorphisms (codon 72, intron 3, and intron 6) have been implicated in breast cancer]. Our recent studies used a novel, practical method to determine true extended haplotypes of these three polymorphisms in diploid genomes. Interestingly, we identified a haplotype composed of the three minor variants as the third most common of 8 possible, with two haplotypes absent (analysis of >750 chromosomes). This haplotype, designated 1-2-1 after the original nomenclatlure, was found to be overrepresented among Caucasian breast cancer patients compared to age- and race-matched control patients, particularly in postmenopausal women (OR = 2.5, 95 % C I = 1.3 -4.8; p = 0.009; n = 52 case patients and 88 control patients). We have now examined the effect of gene-dosage, in a larger group but including the same Caucasian women, using an analysis for linear trend in proportions. Among postmenopausal women, an increased risk with gene-dosage was observed (OR-heterozygotes = 2.7, OR-homozygotes = 4.2; age-adjusted X2 for trend = 6.05, P = 0.01). The data suggest that the penetrance of the 1-2-1 allele is low. However, if its frequency in our hospital based control population is representative of the general population, inheritance of this allele is likely to carry a substantial attributable risk. The haplotype frequencies in our control series (0.10) are similar to estimates made by Sjalander et al. in a population-based study of Swedish subjects (0.13), suggesting that this is the case. Gene-dose effects have previously been noted for HRAS-l rare alleles and polymorphisms in carcinogen metabolizing enzymes. As far as we are aware this is the first report of a gene-dose effect for a polymorphism in a tumor suppressor gene. Similar effects were not detected in African-Americans or Hispanics, although the frequency of the 1-2-1 haplotype in the control patients was found to be higher 0.28 and 0.19, respectively than in Caucasian control patients (0.11). However, the numbers of study subjects were small (22 African-American patients and 37 Control patients; 28 Hispanic patients and 62 control patients). These data suggest that other endogenous or exogenous factors, perhaps related to race, contribute to breast cancer etiology in combination with this p53 haplotype.
Breast-cancer; Cancer-rates; Cancer; Risk-factors; Statistical-analysis; Analytical-methods; Analytical-models; Analytical-processes; Carcinogens; Racial-factors; Demographic-characteristics; Genetics; Genetic-factors; Gene-mutation
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Cancer Genetics and Cytogenetics
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