p53 haplotype determination in breast cancer.
p53 haplotype determination in breast cancer.
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发表时间：
1997-02
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通讯作者：
A. Weston;C. Pan;H. B. Ksieski;S. Wallenstein;G. Berkowitz;P. Tartter;I. Bleiweiss;S. Brower;R. Senie;M. Wolff
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作者：
A. Weston;C. Pan;H. B. Ksieski;S. Wallenstein;G. Berkowitz;P. Tartter;I. Bleiweiss;S. Brower;R. Senie;M. Wolff
由三种p53双等位基因多态性组成的某些种系单倍型遗传已被认为是乳腺癌和结直肠癌的危险因素[a]。Själander等，癌变（Lond.）， 17: 1313-1316, 1996；癌变（Lond.）， 16: 1461-1464, 1995]。在他们的研究中，对这三种多态性的成对单倍型进行了估计。从两两组合进一步推算出扩展单倍型。为了克服估计成对和扩展单倍型频率的必要性，已经开发了一种PCR方法来确定二倍体基因组中绝对扩展的p53单倍型。该方法需要等位基因特异性PCR，经限制性内切分析和连续扩增子分析证实。它已被应用于乳腺癌的巢式病例对照研究（284名受试者；99例病例和185例对照；182名白种人，56名西班牙裔和46名非洲裔美国人）。有证据表明，在高加索乳腺癌病例中，内含子3、密码子72和内含子6多态性的微小变异中度升高（内含子3基因型P = 0.03，等位基因频率P = 0.01；密码子72基因型P = 0.07，等位基因频率P = 0.054；内含子6基因型P = 0.02，等位基因频率P = 0.02）。因此，单倍型分布分析表明，次要p53单倍型与白种人乳腺癌风险相关（P = 0.07）。与对照组相比，乳腺癌病例的相对等位基因频率也因年龄和绝经状态而异；1-2-1单倍型在绝经后（P = 0.02）和50岁以上（P = 0.02）的病例中被过度代表，而其他次要单倍型（1- 2和罕见变异）在绝经前（P = 0.003）和50岁及以下（P = 0.02）的病例中被过度代表。每个基因座和所有对照组的基因型分布符合Hardy-Weinberg平衡。单倍型分布的差异与种族有关（白种人vs非裔美国人，白种人vs西班牙裔，P < 0.001）。这种新的单倍型方法在基因-环境相互作用的研究中具有重要意义。
Inheritance of certain germ line haplotypes consisting of three biallelic polymorphisms of p53 has been proposed as a risk factor for breast cancer and colorectal cancer [A. Själander et al., Carcinogenesis (Lond.), 17: 1313-1316, 1996, and Carcinogenesis (Lond.), 16: 1461-1464, 1995]. In their studies, pairwise haplotypes of these three polymorphisms were estimated. Extended haplotypes were further projected from the pairwise combinations. To overcome the necessity to estimate pairwise and extended haplotype frequencies, a PCR method has been developed to determine the absolute extended p53 haplotypes in diploid genomes. The method requires allele-specific PCR, confirmed by restriction analysis, and successive amplicon analysis. It has been applied to a nested case-control study of breast cancer (284 subjects; 99 cases and 185 controls; 182 Caucasians, 56 Hispanics, and 46 African-Americans). Evidence is presented that minor variants of the intron 3, codon 72, and intron 6 polymorphisms were moderately elevated in Caucasian breast cancer cases (intron 3, P = 0.03 for genotype and P = 0.01 for allelic frequency; codon 72, P = 0.07 for genotype and P = 0.054 for allelic frequency; and intron 6, P = 0.02 for genotype and P = 0.02 for allele frequency). Accordingly, analysis of haplotype distributions suggested an association of minor p53 haplotypes with breast cancer risk in Caucasians (P = 0.07). The relative allelic frequencies in breast cancer cases compared with controls also differed by age and menopausal status; the 1-2-1 haplotype was overrepresented in postmenopausal cases (P = 0.02) and cases older than 50 years (P = 0.02), whereas the other minor haplotypes (1-1-2 and rare variants) were overrepresented in premenopausal cases (P = 0.003) and cases 50 years of age and younger (P = 0.02). Genotype distributions at each locus and for all control groups were consistent with Hardy-Weinberg equilibria. Differences in haplotype distribution were associated with ethnicity (Caucasians versus African-Americans and Caucasians versus Hispanics, P < 0.001). The new haplotyping method may be useful in the study of gene-environment interactions.