Thompson J A, Chen P L, King R A, Rich S S, Oetting W S, Armstrong C, Folsom A R, Sellers T A
Division of Epidemiology, University of Minnesota, Rochester, USA.
Cancer Epidemiol Biomarkers Prev. 2000 May;9(5):507-11.
Much research on early-onset breast cancer families has been performed and has shown that breast cancer in many of these families is linked to either BRCA1 or BRCA2. Fewer studies have examined the role of genetic predisposition in postmenopausal breast cancer. A nested case-control family study of breast cancer was conducted within the Iowa Women's Health Study, a population-based prospective study of 41,836 postmenopausal women. Probands were 251 incident cases diagnosed between 1988 and 1989. Three-generation pedigrees were developed through mailed questionnaires. From this collection of pedigrees, thirteen were identified for more detailed genetic analysis. Sibling-pair linkage analyses were performed using polymorphic markers in candidate regions in these 13 families with multiple cases of breast and other cancers. Four of the DNA markers are located on chromosome 17, and two of these (D17S579 and THRA1) flank the BRCA1 locus. Significant evidence for linkage to D17S579 was obtained in the total sample, in a model without inclusion of covariates or age at onset (P = 0.005), and in a model adjusted for five measured covariates and for variable age at onset (P = 0.008). Complete sequencing of the BRCA1 gene in these families, including all intron/exon boundaries, failed to reveal any mutations in 24 women with breast cancer from the 13 families. These data suggest that in some families identified by postmenopausal breast cancer cases, breast cancer risk may be mediated by a gene (or genes) in the BRCA1 region, but not BRCA1 itself.
针对早发性乳腺癌家族已经开展了大量研究，结果表明许多此类家族中的乳腺癌与BRCA1或BRCA2相关。较少有研究探讨遗传易感性在绝经后乳腺癌中的作用。在爱荷华州女性健康研究中开展了一项乳腺癌巢式病例对照家族研究，该研究是一项基于人群的前瞻性研究，涉及41836名绝经后女性。先证者为1988年至1989年间确诊的251例新发病例。通过邮寄问卷绘制了三代家系图谱。从这些家系图谱中，识别出13个用于更详细的基因分析。对这13个有多例乳腺癌及其他癌症病例的家族，使用候选区域中的多态性标记进行同胞对连锁分析。其中4个DNA标记位于17号染色体上，其中两个（D17S579和THRA1）位于BRCA1基因座两侧。在总样本中，在不纳入协变量或发病年龄的模型中（P = 0.005），以及在针对五个测量协变量和可变发病年龄进行调整的模型中（P = 0.008），均获得了与D17S579连锁的显著证据。对这些家族中BRCA1基因进行全序列测定，包括所有内含子/外显子边界，在来自13个家族的24例乳腺癌女性中未发现任何突变。这些数据表明，在一些由绝经后乳腺癌病例识别出的家族中，乳腺癌风险可能由BRCA1区域中的一个（或多个）基因介导，但不是由BRCA1基因本身介导。
