Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium.
Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium.
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发表时间：
1993-04
影响因子：
9.8
通讯作者：
D. Easton;D. Bishop;D. Ford;G. Crockford
中科院分区：
文献类型：
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作者：
D. Easton;D. Bishop;D. Ford;G. Crockford
乳腺癌已知具有遗传成分，在一些常染色体显性遗传的家庭中是一致的；在这些家庭中，这种疾病通常与卵巢癌有关。先前的遗传连锁研究已经证实，在一些这样的家族中，疾病的发生与染色体17q上的标记有关。本文报告了一项涉及214个乳腺癌家族的合作联动研究的结果，其中包括57个乳腺癌-卵巢癌家族；这几乎代表了所有已知的具有17q连锁数据的家族。17q上有6个标记，长度约为30 cM。该研究的目的是更精确地定义疾病基因的定位，遗传异质性的程度和相关家族的特征，并估计17q基因的外显率。在不存在遗传异质性的假设下，D17S588（在女性重组分数[θ f] = 0.13时最大LOD评分[Zmax] = 21.68）和D17S579（在θ f = 0.16时Zmax = 13.02）获得了最强的连锁证据。考虑遗传异质性的多点连锁分析提供的证据表明，易感基因位于标记D17S588和D17S250之间，其遗传长度估计在男性为8.3 cM，在女性为18.0 cM。在其他时间间隔中，这一观点得到了66:1的支持。该基因相对于D17S579的位置不能明确确定。在分析中使用的遗传模型下，相关乳腺癌家族比例的最佳估计为1.0 （LOD-1下限为0.79）。相比之下，有明显的证据表明，在没有卵巢癌的家庭中存在遗传异质性，估计有45%的家庭与卵巢癌有关。这些结果表明，染色体17q上的一个基因决定了大多数发生早发性乳腺癌和卵巢癌的家庭，但也存在其他易患乳腺癌的基因。通过检查连锁数据与不同外显子函数的拟合，估计与17q基因相关的累积风险在50岁时为59%，在70岁时为82%。乳腺-卵巢家族的相应估计值分别为67%和76%，无卵巢癌家族的相应估计值分别为49%和90%；这些外显子函数彼此之间没有显著差异。
Breast cancer is known to have an inherited component, consistent in some families with autosomal dominant inheritance; in such families the disease often occurs in association with ovarian cancer. Previous genetic linkage studies have established that in some such families disease occurrence is linked to markers on chromosome 17q. This paper reports the results of a collaborative linkage study involving 214 breast cancer families, including 57 breast-ovarian cancer families; this represents almost all the known families with 17q linkage data. Six markers on 17q, spanning approximately 30 cM, were typed in the families. The aims of the study were to define more precisely the localization of the disease gene, the extent of genetic heterogeneity and the characteristics of linked families and to estimate the penetrance of the 17q gene. Under the assumption of no genetic heterogeneity, the strongest linkage evidence was obtained with D17S588 (maximum LOD score [Zmax] = 21.68 at female recombination fraction [theta f] = .13) and D17S579 (Zmax = 13.02 at theta f = .16). Multipoint linkage analysis allowing for genetic heterogeneity provided evidence that the predisposing gene lies between the markers D17S588 and D17S250, an interval whose genetic length is estimated to be 8.3 cM in males and 18.0 cM in females. This position was supported over other intervals by odds of 66:1. The location of the gene with respect to D17S579 could not be determined unequivocally. Under the genetic model used in the analysis, the best estimate of the proportion of linked breast-ovarian cancer families was 1.0 (lower LOD-1 limit 0.79). In contrast, there was significant evidence of genetic heterogeneity among the families without ovarian cancer, with an estimated 45% being linked. These results suggest that a gene(s) on chromosome 17q accounts for the majority of families in which both early-onset breast cancer and ovarian cancer occur but that other genes predisposing to breast cancer exist. By examining the fit of the linkage data to different penetrance functions, the cumulative risk associated with the 17q gene was estimated to be 59% by age 50 years and 82% by age 70 years. The corresponding estimates for the breast-ovary families were 67% and 76%, and those for the families without ovarian cancer were 49% and 90%; these penetrance functions did not differ significantly from one another.