Pankow J S, Vachon C M, Kuni C C, King R A, Arnett D K, Grabrick D M, Rich S S, Anderson V E, Sellers T A
Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis 55454-1015, USA.
J Natl Cancer Inst. 1997 Apr 16;89(8):549-56. doi: 10.1093/jnci/89.8.549.
The appearance of the female breast viewed by mammography varies considerably from one individual to another because of underlying differences in the relative proportions of fat, connective tissue, and glandular epithelium that combine to create a characteristic pattern of breast density. An association between mammographic patterns and family history of breast cancer has previously been reported. However, this association has not been found in all studies, and few data are available on possible genetic components contributing to mammographic breast density.
Our purpose was to estimate familial correlations and perform complex genetic segregation analyses to test the hypothesis that the transmission of a major gene influences mammographic breast density.
As part of a cohort study (initiated in 1944) of families with a history of breast cancer, the probands' female relatives who were older than 40 years were asked to obtain a routine mammogram. The mammograms of 1370 women from 258 independent families were analyzed. The fraction of the breast volume occupied by radiographically dense tissue was estimated visually from video displays of left or right mediolateral oblique views by one radiologist experienced in mammography who had no knowledge of individual relationships to the probands. Data on breast cancer risk factors were obtained through telephone interviews and mailed questionnaires. Unadjusted and adjusted familial correlations in breast density were calculated, and complex genetic segregation analyses were performed.
Sister-sister correlations in breast density (unadjusted and adjusted for age and either body mass index, menopausal status, hormone replacement therapy, waist-to-hip ratio, number of live births, alcohol consumption, or cigarette smoking status) were all statistically significant (r = .16-.27; all P<.05 [two-sided]). Estimated mother-daughter correlations were smaller in magnitude (r = .01-.17) and not statistically significant. Segregation analyses indicate that a major autosomal gene influences breast density. The mendelian transmission of a dominant gene provided the best fit to the data; however, hypotheses involving the inheritance of either a recessive gene or a codominant gene could not be ruled out. The mendelian dominant hypothesis, accounting for 29% of the variability in breast density, suggests that approximately 12% of the population would be expected to carry at least one variant allele of this putative gene. Women who inherit the variant allele would have a mean breast density about twice that of the rest of the population.
Our preliminary findings suggest that, in this cohort of women at risk of breast cancer, mammographic breast density may be genetically influenced.
由于构成乳房密度特征模式的脂肪、结缔组织和腺上皮相对比例存在潜在差异，乳房X线摄影显示的女性乳房外观在个体之间差异很大。此前已有报道乳房X线摄影模式与乳腺癌家族史之间存在关联。然而，并非所有研究都发现了这种关联，而且关于影响乳房X线摄影乳房密度的可能遗传成分的数据很少。
我们的目的是估计家族相关性并进行复杂的遗传分离分析，以检验主要基因的传递影响乳房X线摄影乳房密度这一假设。
作为一项对有乳腺癌家族史的家庭进行的队列研究（始于1944年）的一部分，要求先证者年龄超过40岁的女性亲属进行常规乳房X线摄影。分析了来自258个独立家庭的1370名女性的乳房X线照片。由一名精通乳房X线摄影且不了解个体与先证者关系的放射科医生，通过左或右内外侧斜位的视频显示器直观估计乳房X线片上致密组织所占乳房体积的比例。通过电话访谈和邮寄问卷获取乳腺癌风险因素的数据。计算了未调整和调整后的乳房密度家族相关性，并进行了复杂的遗传分离分析。
乳房密度的姐妹相关性（未调整以及调整年龄和体重指数、绝经状态、激素替代疗法、腰臀比、活产数、饮酒量或吸烟状况后）均具有统计学意义（r = 0.16 - 0.27；所有P < 0.05[双侧]）。估计的母女相关性数值较小（r = 0.01 - 0.17）且无统计学意义。分离分析表明，一个主要的常染色体基因影响乳房密度。显性基因的孟德尔遗传传递最符合数据；然而，涉及隐性基因或共显性基因遗传的假设不能排除。孟德尔显性假设解释了乳房密度变异的29%，表明预计约12%的人群携带该假定基因的至少一个变异等位基因。继承变异等位基因的女性的平均乳房密度约为其余人群的两倍。
我们的初步研究结果表明，在这个有乳腺癌风险的女性队列中，乳房X线摄影乳房密度可能受遗传影响。
