Heritability of cellular radiosensitivity: A marker of low-penetrance predisposition genes in breast cancer
Heritability of cellular radiosensitivity: A marker of low-penetrance predisposition genes in breast cancer
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DOI：
10.1086/302544
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发表时间：
1999-09-01
影响因子：
9.8
通讯作者：
Scott, D
中科院分区：
文献类型：
--
作者：
Roberts, SA;Spreadborough, AR;Scott, D
许多遗传性癌症易发病症表现出对暴露于电离辐射的细胞中诱导染色体损伤的敏感性升高，这表明 DNA 损伤处理过程中存在缺陷。我们之前发现，40% 的乳腺癌患者和 5%-10% 的对照者表现出染色体放射敏感性增强的证据，而且这种敏感性与年龄无关。我们认为这可能是低外显率的癌症易感基因的标志。为了进一步检验这一假设，我们研究了乳腺癌患者家族中放射敏感性的遗传性。在 16 名敏感患者的 37 名一级亲属中，有 23 名（62%）本身是敏感的，而 4 名反应正常的患者的 15 名一级亲属中有 1 名（7%）本身是敏感的。家庭成员之间放射敏感性的分布呈三峰分布，表明决定放射敏感性的主要基因数量有限。对 95 名家庭成员的分离分析显示了放射敏感性遗传性的明确证据，单个主要基因占家庭成员之间差异的 82%。两个等位基因以加性（共显性）方式组合，产生完整的杂合子表达。包含第二个较稀有基因的模型获得了更好的拟合，该基因对放射敏感性具有类似的附加效应，但数据显然与一系列模型一致。现在可以通过使用这种数量性状的连锁研究来寻找与乳腺癌易感性相关的新基因。
Many inherited: cancer-prone conditions show an elevated sensitivity to the induction of chromosome damage in cells exposed to ionizing radiation, indicative-of defects in the processing of DNA damage. We earlier found that 40% of patients with breast cancer and 5%-10% of controls showed evidence of enhanced chromosomal radiosensitivity-and that this sensitivity was not age related. We suggested that this could be a marker of cancer-predisposing genes of low penetrance. To further test this hypothesis, we have studied the heritability of radiosensitivity in families of patients with breast cancer. Of 37 first-degree relatives of 16 sensitive patients, 23 (62%) were themselves sensitive, compared with 1 (7%) of 15 first-degree relatives of four patients with normal responses. The distribution of radiosensitivities among the family members showed a trimodal distribution, suggesting the presence of a limited number of major genes determining radiosensitivity. Segregation analysis of 95 family members showed clear evidence of heritability of radiosensitivity, with a single major gene accounting for 82% of the variance between family members. The two alleles combine in an additive (codominant) manner, giving complete heterozygote expression. A better fit was obtained to a model that includes a second, rarer gene with a similar, additive effect on radiosensitivity, but the data are clearly consistent with a range of models. Novel genes involved in predisposition to breast cancer can now be sought through linkage studies using this quantitative trait.