Haiman Christopher A, Stram Daniel O, Cheng Iona, Giorgi Elena E, Pooler Loreall, Penney Kathryn, Le Marchand Loïc, Henderson Brian E, Freedman Matthew L
University of Southern California/Norris Comprehensive Cancer Center, Room 4441, 1441 Eastlake Avenue, Los Angeles, CA 90089-9175, USA.
Cancer Epidemiol Biomarkers Prev. 2006 May;15(5):1021-5. doi: 10.1158/1055-9965.EPI-05-0896.
PTEN frequently shows loss of heterozygosity in breast and prostate cancers, and mutations in this gene are responsible for Cowden disease, a rare Mendelian syndrome that includes breast cancer as part of its phenotype. Thus, PTEN serves as a candidate susceptibility gene for both breast and prostate cancer risk. Whether common inherited variation (either coding or noncoding) at the PTEN locus contribute to nonfamilial, sporadic breast and prostate cancer risk is not known. In this study, we employed a linkage disequilibrium-based approach to test for association between common genetic variation at the PTEN locus and breast and prostate cancer risk in African-American, Native Hawaiian, Japanese, Latina, and White men and women in the Multiethnic Cohort Study. We genotyped 17 common single nucleotide polymorphisms (SNP; >/=5% frequency in at least one ethnic group) spanning the PTEN gene to define the common alleles in these populations. These SNPs were in strong linkage disequilibrium, indicating that our survey captured most of the common sequence variation across this locus. Eight tagging SNPs were selected to predict the common PTEN haplotypes (>/=0.05 frequency) in these populations (two additional tagging SNPs were required for African Americans). These SNPs were evaluated in a breast cancer case-control study (cases, n = 1,615; controls, n = 1,962) and prostate cancer case-control study (cases, n = 2,320; controls, n = 2,290) nested within the Multiethnic Cohort Study. Multiple testing was explicitly accounted for by applying a permutation-based framework. We found no strong association with any common haplotype in relation to breast or prostate cancer risk. In summary, our results show that common variants in PTEN do not substantially influence risk of these two common cancers.
PTEN在乳腺癌和前列腺癌中经常出现杂合性缺失，该基因的突变会导致考登综合征，这是一种罕见的孟德尔综合征，其表型包括乳腺癌。因此，PTEN是乳腺癌和前列腺癌风险的候选易感基因。目前尚不清楚PTEN基因座上的常见遗传变异（编码或非编码）是否会导致非家族性、散发性乳腺癌和前列腺癌风险。在本研究中，我们采用基于连锁不平衡的方法，在多民族队列研究中，检测非洲裔美国人、夏威夷原住民、日本人、拉丁裔以及白种男性和女性中，PTEN基因座上的常见遗传变异与乳腺癌和前列腺癌风险之间的关联。我们对跨越PTEN基因的17个常见单核苷酸多态性（SNP，在至少一个种族群体中的频率≥5%）进行基因分型，以确定这些人群中的常见等位基因。这些SNP处于强连锁不平衡状态，表明我们的调查涵盖了该基因座上的大部分常见序列变异。我们选择了8个标签SNP来预测这些人群中常见的PTEN单倍型（频率≥0.05）（非洲裔美国人还需要另外两个标签SNP）。在多民族队列研究中的一项乳腺癌病例对照研究（病例，n = 1615；对照，n = 1962）和一项前列腺癌病例对照研究（病例，n = 2320；对照，n = 2290）中对这些SNP进行了评估。通过应用基于置换的框架明确考虑了多重检验。我们发现，与乳腺癌或前列腺癌风险相关的任何常见单倍型均无强关联。总之，我们的结果表明，PTEN中的常见变异不会显著影响这两种常见癌症的风险。
