Hartikainen Jaana M, Tuhkanen Hanna, Kataja Vesa, Eskelinen Matti, Uusitupa Matti, Kosma Veli-Matti, Mannermaa Arto
Department of Pathology, University of Kuopio, Finland.
Clin Cancer Res. 2006 Mar 1;12(5):1454-62. doi: 10.1158/1078-0432.CCR-05-1417.
Although many risk factors for breast cancer are known, most of the genetic background and molecular mechanisms still remain to be elucidated. We have previously published an autosome-wide microsatellite scan for breast cancer association and here we report a follow-up study for one of the detected regions. Ten single nucleotide polymorphisms (SNP) were genotyped in an Eastern Finnish population sample of 497 breast cancer cases and 458 controls to refine the 550-kb region on 22q12-q13 and identify the breast cancer-associated gene(s) in this region. We also studied 22q12-q13 for allelic imbalance for the detection of a possible tumor suppressor gene and to see whether the breast cancer association and allelic imbalance in this region could be connected. A SNP (rs733655) in matriptase-2 gene (TMPRSS6) was detected to associate with breast cancer risk. The genotype frequencies of rs733655 differed significantly between cases and controls in the entire sample and in the geographically and genetically more homogeneous subsample with P = 0.044 and P = 0.0003, respectively. The heterozygous genotype TC was observed to be the risk genotype in both samples (odds ratios, 1.39; 95% confidence intervals, 1.06-1.83 and odds ratios, 2.11; 95% confidence intervals, 1.46-3.05). An associated two-marker haplotype involving SNP rs733655 (empirical P = 0.041) provides further evidence for breast cancer risk factor locating on 22q12-q13, possibly being TMPRSS6. Our results suggest that matriptase-2 gene is associated with breast cancer risk in the Eastern Finnish population.
尽管已知许多乳腺癌的风险因素，但大多数遗传背景和分子机制仍有待阐明。我们之前发表了一项全常染色体微卫星扫描以寻找与乳腺癌的关联，在此我们报告对其中一个检测区域的后续研究。在芬兰东部的一个包含497例乳腺癌病例和458例对照的人群样本中，对10个单核苷酸多态性（SNP）进行基因分型，以细化22q12 - q13上的550 kb区域，并确定该区域中与乳腺癌相关的基因。我们还研究了22q12 - q13的等位基因失衡情况，以检测可能的肿瘤抑制基因，并查看该区域的乳腺癌关联与等位基因失衡是否有关联。检测到matriptase - 2基因（TMPRSS6）中的一个SNP（rs733655）与乳腺癌风险相关。在整个样本以及地理和遗传上更为同质的子样本中，rs733655的基因型频率在病例组和对照组之间存在显著差异，P值分别为0.044和0.0003。在两个样本中均观察到杂合基因型TC为风险基因型（优势比分别为1.39；95%置信区间为1.06 - 1.83和优势比为2.11；95%置信区间为1.46 - 3.05）。一个涉及SNP rs733655的相关双标记单倍型（经验P值 = 0.041）为位于22q12 - q13上、可能是TMPRSS6的乳腺癌风险因素提供了进一步证据。我们的结果表明，在芬兰东部人群中，matriptase - 2基因与乳腺癌风险相关。
