Segregation analysis of prostate cancer in France: Evidence for autosomal dominant inheritance and residual brother-brother dependence
Segregation analysis of prostate cancer in France: Evidence for autosomal dominant inheritance and residual brother-brother dependence
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DOI：
10.1046/j.1469-1809.2003.00022.x
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发表时间：
2003-03-01
影响因子：
1.9
通讯作者：
Demenais, F
中科院分区：
文献类型：
--
作者：
Valeri, A;Briollais, L;Demenais, F
关于前列腺癌（CaP）的四项分离分析，其中三项在美国进行，一项在北欧进行，已经显示了一个显性主基因的证据，但参数估计不同。最近对澳大利亚血统的分离分析发现，双位点模型比单位点模型更适合。该模型包括显性遗传增加的风险在年轻时更大，隐性遗传或x连锁增加的风险在老年时更大。最近的连锁分析导致至少8个CaP易感基因的检测，表明复杂的遗传和遗传异质性。为了评估法国前列腺癌家族聚集性的性质，通过691名CaP患者对691个家庭进行了分离分析，这些患者来自三家法国医院，未选择诊断年龄、临床阶段或家族史。这种没有特别选择先证者的家庭纳入模式是独特的，因为所有先前分析的先证者都是根据各种标准选择的。分离分析使用纳入REGRESS程序的logistic风险回归模型进行，该模型可以容纳主要基因效应，任何来源的残余家族依赖性（遗传和/或环境）和协变量，同时包括生存分析概念。分离分析显示，常染色体显性基因（等位基因频率为0.03%）分离的证据与额外的兄弟依赖性。在具有高危基因型的受试者中，估计到85岁时前列腺癌的累积风险在父亲一代为86%，在先证一代为99%。本研究支持一种罕见的高外显率常染色体显性基因的孟德尔遗传模型，并证明了额外的遗传和/或共同的兄弟姐妹环境因素参与了CaP的家族聚集性。
Four segregation analyses concerning prostate cancer (CaP), three conducted in the United States and one in Northern Europe, have shown evidence for a dominant major gene but with different parameter estimates. A recent segregation analysis of Australian pedigrees has found a better fit of a two-locus model than single-locus models. This model included a dominantly inherited increased risk that was greater at younger ages and a recessively inherited or X-linked increased risk that was greater at older ages. Recent linkage analyses have led to the detection of at least 8 CaP predisposing genes, suggesting a complex inheritance and genetic heterogeneityTo assess the nature of familial aggregation of prostate cancer in France, segregation analysis was conducted in 691 families ascertained through 691 Cap patients, recruited from three French hospitals and unselected with respect to age at diagnosis, clinical stage or family history. This mode of family inclusion, without any particular selection of the probands, is unique, as probands from all previous analyses were selected according to various criteria. Segregation analysis was carried out using the logistic hazard regressive model, as incorporated in the REGRESS program, which can accommodate a major gene effect, residual familial dependences of any origin (genetic and/or environmental), and covariates, while including survival analysis concepts.Segregation analysis showed evidence for the segregation of an autosomal dominant gene (allele frequency of 0.03%) with an additional brother-brother dependence. The estimated cumulative risks of prostate cancer by age 85 years, among subjects with the at-risk genotype, were 86% in the fathers' generation and 99% in the probands' generation. This study supports the model of Mendelian transmission of a rare autosomal dominant gene with high penetrance, and demonstrates that additional genetic and/or common sibling environmental factors are involved to account for the familial clustering of CaP.