Chakraborty R, Sankaranarayanan K
Genetics Centers, University of Texas Houston Health Science Center 77225, USA.
Radiat Res. 1995 Sep;143(3):293-301.
Individuals genetically predisposed to cancer may be more sensitive to cancers induced by ionizing radiation than those who are not so predisposed. Should this be true, under conditions of radiation exposure, a population consisting of cancer-predisposed and non-predisposed individuals will be expected to respond with a higher total frequency of induced cancers than one in which all the individuals are assumed to have the same sensitivity to radiation-induced cancers. To study this problem quantitatively, we have developed a Mendelian autosomal one-locus, two-allele model; this model assumes that one of the alleles is mutant and the genotypes carrying the mutant allele(s) are cancer-predisposed and are also more sensitive to radiation-induced cancer. Formal analytical predictions as well as numerical illustrations of this model show that: (1) when such heterogeneity with respect to cancer predisposition and radiosensitivity is present in the population, irradiation results in a greater increase in the frequency of induced cancers than when it is absent; (2) this increase is detectable only when the proportion of cancers due to genetic predisposition is large and when the degree of predisposition is considerable; and (3) even when the effect is small, most of the radiation-induced cancers will occur in predisposed individuals. These conclusions are valid for models of cancer when predisposition and radiosensitivity may be either dominant or recessive. The published data on breast cancers in Japanese A-bomb survivors show that at 1 Sv, the radiation-related excess relative risk in women irradiated before age 20 is 13 compared to about 2 for those irradiated at later ages. We examined the application of our model to the above data using two assumptions, namely, that the proportion of cancers due to genetic susceptibility at the BRCA1 locus (1/200) and the frequency of the mutant allele (0.0033) estimated for Western populations are valid for Japanese women. With our model, these results can be explained only if there are very large differences in cancer susceptibility (> 1000-fold) and radiosensitivity (> 100-fold) of the heterozygotes.
与未携带癌症遗传易感性的个体相比，具有癌症遗传易感性的个体可能对电离辐射诱发的癌症更为敏感。如果确实如此，在辐射暴露条件下，由具有癌症遗传易感性和不具有遗传易感性的个体组成的人群，预计其诱发癌症的总频率会高于假设所有个体对辐射诱发癌症具有相同敏感性的人群。为了定量研究这个问题，我们开发了一个孟德尔常染色体单基因座、双等位基因模型；该模型假设其中一个等位基因为突变型，携带突变等位基因的基因型具有癌症遗传易感性，并且对辐射诱发的癌症也更敏感。该模型的形式分析预测以及数值示例表明：（1）当人群中存在这种关于癌症遗传易感性和辐射敏感性的异质性时，与不存在这种异质性时相比，辐射会导致诱发癌症的频率有更大幅度的增加；（2）只有当遗传易感性导致的癌症比例较大且易感性程度相当可观时，这种增加才能够被检测到；（3）即使这种影响很小，大多数辐射诱发的癌症也会发生在具有遗传易感性的个体中。当遗传易感性和辐射敏感性可能为显性或隐性时，这些结论对于癌症模型都是有效的。关于日本原子弹爆炸幸存者乳腺癌的已发表数据表明，在1 Sv时，20岁之前接受辐射的女性中与辐射相关的超额相对风险为13，而在较晚年龄接受辐射的女性中这一数值约为2。我们使用两个假设来检验我们的模型对上述数据的适用性，即对于日本女性而言，西方人群中估计的BRCA1基因座遗传易感性导致的癌症比例（1/200）以及突变等位基因的频率（0.0033）是有效的。根据我们的模型，只有当杂合子的癌症易感性（> 1000倍）和辐射敏感性（> 100倍）存在非常大的差异时，这些结果才能得到解释。
