Feigelson Heather Spencer, Cox David G, Cann Howard M, Wacholder Sholom, Kaaks Rudolf, Henderson Brian E, Albanes Demetrius, Altshuler David, Berglund Goran, Berrino Franco, Bingham Sheila, Buring Julie E, Burtt Noel P, Calle Eugenia E, Chanock Stephen J, Clavel-Chapelon Francoise, Colditz Graham, Diver W Ryan, Freedman Matthew L, Haiman Christopher A, Hankinson Susan E, Hayes Richard B, Hirschhorn Joel N, Hunter David, Kolonel Laurence N, Kraft Peter, LeMarchand Loic, Linseisen Jakob, Modi William, Navarro Carmen, Peeters Petra H, Pike Malcolm C, Riboli Elio, Setiawan V Wendy, Stram Daniel O, Thomas Gilles, Thun Michael J, Tjonneland Anne, Trichopoulos Dimitrios
Department of Epidemiology and Surveillance Research, American Cancer Society, National Home Office, Atlanta, Georgia 30329, USA.
Cancer Res. 2006 Feb 15;66(4):2468-75. doi: 10.1158/0008-5472.CAN-05-3574.
The 17beta-hydroxysteroid dehydrogenase 1 gene (HSD17B1) encodes 17HSD1, which catalyzes the final step of estradiol biosynthesis. Despite the important role of HSD17B1 in hormone metabolism, few epidemiologic studies of HSD17B1 and breast cancer have been conducted. This study includes 5,370 breast cancer cases and 7,480 matched controls from five large cohorts in the Breast and Prostate Cancer Cohort Consortium. We characterized variation in HSD17B1 by resequencing and dense genotyping a multiethnic sample and identified haplotype-tagging single nucleotide polymorphisms (htSNP) that capture common variation within a 33.3-kb region around HSD17B1. Four htSNPs, including the previously studied SNP rs605059 (S312G), were genotyped to tag five common haplotypes in all cases and controls. Conditional logistic regression was used to estimate odds ratios (OR) for disease. We found no evidence of association between common HSD17B1 haplotypes or htSNPs and overall risk of breast cancer. The OR for each haplotype relative to the most common haplotype ranged from 0.98 to 1.07 (omnibus test for association: X2 = 3.77, P = 0.58, 5 degrees of freedom). When cases were subdivided by estrogen receptor (ER) status, two common haplotypes were associated with ER-negative tumors (test for trend, Ps = 0.0009 and 0.0076; n = 353 cases). HSD17B1 variants that are common in Caucasians are not associated with overall risk of breast cancer; however, there was an association among the subset of ER-negative tumors. Although the probability that these ER-negative findings are false-positive results is high, these findings were consistent across each cohort examined and warrant further study.
17β-羟类固醇脱氢酶1基因（HSD17B1）编码17HSD1，该酶催化雌二醇生物合成的最后一步。尽管HSD17B1在激素代谢中起重要作用，但针对HSD17B1与乳腺癌的流行病学研究却很少。本研究纳入了乳腺癌和前列腺癌队列联盟中五个大型队列的5370例乳腺癌病例和7480例匹配对照。我们通过对一个多民族样本进行重测序和密集基因分型来表征HSD17B1的变异，并确定了单倍型标签单核苷酸多态性（htSNP），这些htSNP捕获了HSD17B1周围33.3 kb区域内的常见变异。对包括先前研究的SNP rs605059（S312G）在内的四个htSNP进行基因分型，以标记所有病例和对照中的五种常见单倍型。采用条件逻辑回归估计疾病的比值比（OR）。我们没有发现常见的HSD17B1单倍型或htSNP与乳腺癌总体风险之间存在关联的证据。相对于最常见单倍型，每种单倍型的OR范围为0.98至1.07（关联的综合检验：X2 = 3.77，P = 0.58，5个自由度）。当根据雌激素受体（ER）状态对病例进行细分时，两种常见单倍型与ER阴性肿瘤相关（趋势检验，Ps = 0.0009和0.0076；n = 353例）。在白种人中常见的HSD17B1变异与乳腺癌总体风险无关；然而，在ER阴性肿瘤亚组中存在关联。尽管这些ER阴性结果为假阳性结果的可能性很高，但这些发现在每个研究队列中都是一致的，值得进一步研究。
