Chakraborty R, Little M P, Sankaranarayanan K
Human Genetics Center, School of Public Health, The University of Texas, Houston 77225, USA.
Radiat Res. 1997 Mar;147(3):309-20.
Recent studies have identified a number of genes in the human genome at which germinal mutations predispose the individuals to one or another type of cancer. These studies also show that not all individuals carrying the mutant genes develop cancers (i.e., the mutant genes are not fully penetrant). At least some of these predisposed genotypes also have a higher sensitivity to cancers induced by ionizing radiation than those who are not so predisposed, which may be dependent on dose. This paper presents an analysis of the impact of such heterogeneity on estimates of cancer risks for an irradiated population. This is done by extending the Mendelian one-locus, two-allele model of cancer predisposition and radiosensitivity developed earlier to allow for incomplete penetrance and dose dependence of radiosensitivity differentials among genotypes. The model is applied to recently published data for breast cancer and hereditary non-polyposis colon cancer using a range of possible values for the strength of predisposition and radiosensitivity differentials. It is shown that, after radiation exposures, the ratio of cancer risks in a heterogeneous population relative to that in a homogeneous population increases with increasing dose, but that the dose dependence of the relative risk diminishes at higher doses. Likewise, the attributable risk (i.e. the proportion of the increase in risk that is due to both increased susceptibility and increased radiosensitivity) and the proportion of attributable risk due to increased radiosensitivity also increase with dose, and the dose dependence of each measurement also diminishes at higher doses. However, when the proportion of cancers due to the susceptible genotypes is small (<10%) (as is likely to be the case for breast cancer in non-Ashkenazi women), the increases in the relative risk and attributable risk are marked only when there are very large increases in cancer susceptibility (>1000-fold) and radiosensitivity (>100-fold) in the susceptible group. When the proportion of cancers due to the susceptible genotypes is appreciable (> or = 10%) (as may be the case for breast cancer in Ashkenazi Jewish women), there may be large increases in the relative risk and attributable risk for comparatively modest increases in cancer susceptibility (>10-fold) and radiosensitivity (>100-fold) in the susceptible subpopulation. For any given combination of strength of predisposition and radiosensitivity differential, incomplete penetrance dilutes the effect.
最近的研究在人类基因组中鉴定出了许多基因，生殖细胞突变会使个体易患一种或另一种癌症。这些研究还表明，并非所有携带突变基因的个体都会患癌症（即突变基因并非完全显性）。至少其中一些易感基因型对电离辐射诱发的癌症也比非易感个体具有更高的敏感性，这可能取决于剂量。本文分析了这种异质性对受辐照人群癌症风险估计的影响。通过扩展早期开发的孟德尔单基因座、双等位基因癌症易感性和放射敏感性模型，以考虑基因型间放射敏感性差异的不完全显性和剂量依赖性来实现这一目的。该模型使用一系列可能的易感性强度和放射敏感性差异值，应用于最近发表的乳腺癌和遗传性非息肉病性结肠癌的数据。结果表明，辐射暴露后，异质人群与同质人群的癌症风险比随剂量增加而增加，但相对风险的剂量依赖性在高剂量时会减弱。同样，归因风险（即由于易感性增加和放射敏感性增加导致的风险增加比例）以及由于放射敏感性增加导致的归因风险比例也随剂量增加，且每种测量的剂量依赖性在高剂量时也会减弱。然而，当易感基因型导致的癌症比例较小时（<10%）（非阿什肯纳兹族女性患乳腺癌可能就是这种情况），只有当易感组的癌症易感性（>1000倍）和放射敏感性（>100倍）有非常大的增加时，相对风险和归因风险才会有显著增加。当易感基因型导致的癌症比例可观（≥10%）时（阿什肯纳兹犹太族女性患乳腺癌可能就是这种情况），对于易感亚群中癌症易感性（>10倍）和放射敏感性（>100倍）相对适度的增加，相对风险和归因风险可能会有大幅增加。对于任何给定的易感性强度和放射敏感性差异组合，不完全显性会削弱这种影响。
